Note: Descriptions are shown in the official language in which they were submitted.
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ANALYTE DETECTION SYSTEM WITH DISTRIBUTED SENSING
Back ound
Field
[0001] Certain embodiments disclosed herein relate to methods and apparatus
for detennining the concentration of an analyte in a sample, such as an
analyte in a sample
of bodily fluid, as well as methods and apparatus which can be used to support
the malcing
of such determinations.
Description of the Related Art
[0002] It is a common practice to measure the levels of certain analytes, such
as -
glucose, in a bodily fluid, such as blood. Often this is done in a hospital or
clinical setting
when there is a risk that the levels of certain analytes may move outside a
desired range,
whicll in turn can jeopardize the health of a patient. Certain currently known
systems for
analyte monitoring in a hospital or clinical setting suffer from various
drawbacks.
Summary
[0003] In certain embodiinents, a sampling assembly is configured for use with
a main analyzer. The main analyzer is configured to sense an analyte in a body
fluid
obtained from a patient through a first fluid passageway extending from the
main analyzer.
The sampling assembly comprises an instrument portion separate from the main
analyzer
and comprising at least one sensor. The instrument portion is removably
engaged with the
first fluid passageway. The at least one sensor is in sensing engagement with
the first fluid
passageway such that the at least one sensor can sense a property of a fluid
within the first
fluid passageway. In certain other embodiments, the at least one sensor is
configured to
detect the arrival of the body fluid in the first fluid passageway.
[0004] In certain embodiments, a sampling assembly is configured for use with
a main analyzer. The main analyzer is configured to sense an analyte in a body
fluid
obtained from a patient through a first fluid passageway. The passageway has a
patient end
spaced from the main analyzer and an interface region where the first fluid
passageway
meets the main analyzer. The sampling assembly comprises an instrument portion
comprising at least one sensor. The instrument portion is removably engaged
with the first
fluid passageway between the patient end and the interface region. The at
least one sensor
is in sensing engagement with the first fluid passageway such that the at
least one sensor
can sense a property of a fluid contained in the first fluid passageway. In
certain other
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embodiments, the at least one sensor is configured to detect the arrival of
the body fluid in
the first fluid passageway.
[0005] In certain embodiments, a body fluid analysis system coinprises a main
analyzer configured to measure an analyte in a sample of body fluid obtained
from a
patient. The body fluid analysis system further comprises a sampling assembly
in
communication with the main analyzer. The sampling assembly comprises a first
fluid
passageway extending from the main analyzer and having a patient end spaced
from the
main analyzer. The sampling assembly further coinprises an instruinent portion
removably
engaged with the first fluid passageway and located on the first fluid
passageway spaced
from the main analyzer. The instrument portion has at least one sensor in
sensing
engagement with the first fluid passageway. In certain other einbodiments, at
least one of
the at least one sensor is configured to detect the arrival of the body fluid
in the first fluid
passageway.
[0006] hi certain embodiments, a method of handles body fluid within a first
fluid passageway which extends froin and is in fluid cominunication with a
main analyzer.
The method coinprises removably engaging the first fluid passageway with a
sensing
module separate from the main analyzer. The method further comprises, with at
least one
sensor of the sensing module, sensing a property of a fluid within the first
fluid passageway.
In certain other embodiments, the sensing coinprises sensing the arrival of
the fluid in the
first fluid passageway.
[0007] Certain objects and advantages of the invention(s) are described
herein. Of
course, it is to be understood that not necessarily all such objects or
advantages may be
achieved in accordance with any particular embodiment. Thus, for example,
those skilled in
the art will recognize that the invention(s) may be embodied or carried out in
a manner that
achieves or optimizes one advantage or group of advantages as taught herein
without
necessarily achieving other objects or advantages as may be taught or
suggested herein.
[0008] Certain embodiments are summarized above. However, despite the
foregoing discussion of certain embodiments, only the appended claims (and not
the present
summary) are intended to define the invention(s). The summarized embodiments,
and
other embodiments, will become readily apparent to those skilled in the art
from the
following detailed description of the preferred embodiments having reference
to the
attached figures, the invention(s) not being limited to any particular
embodiment(s)
disclosed.
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[0009] In certain embodiments, an apparatus for analyzing the composition of
bodily fluid coinprises a first fluid passageway having a patient end which is
configured to
provide fluid communication with a bodily fluid within a patient. The
apparatus further
comprises at least one pump coupled to the first fluid passageway. The at
least one pump
has an infusion mode in which the pump is operable to deliver infusion fluid
to the patient
through the patient end, and a sample draw mode in which the pump is operable
to draw a
sample of the bodily fluid from the patient through the patient end. The
apparatus further
comprises an analyte detection system accessible via the first fluid
passageway such that the
analyte detection system can receive at least one coinponent of the drawn
sample of bodily
fluid and determine a concentration of at least one analyte. The analyte
detection systein is
spaced from the patient end of the first fluid passageway. The apparatus
further comprises
a fluid sensor located at or near the patient end of the first fluid
passageway and spaced
from the analyte detection system. The fluid sensor is configured to sense a
property of a
fluid within the first fluid passageway. In certain other embodiments, the
fluid sensor is
configured to detect the arrival of the drawn sample of bodily fluid in the
first fluid
passageway.
[0010] In certain embodiments, a fluid-handling method comprises providing a
first
fluid passageway having a patient end and a spectroscopic analyte detection
system
accessible via the first fluid passageway. The method further comprises
infusing an
infusion fluid through the patient end. The method further comprises drawing a
body fluid
through the patient end. The method farther comprises sensing a property of a
fluid within
the first fluid passageway at a sensing location at or near the patient end
and spaced from
the analyte detection system. The method further comprise determining the
concentration
of at least one analyte in the fluid within the first fluid passageway using
the analyte
detection system. In certain embodiments, the sensing comprises detecting the
arrival of
the fluid within the first fluid passageway.
[0011] In certain embodiments, a method for analyzing the composition of a
body fluid comprises obtaining a body fluid sample from a patient end of a
first fluid
passageway. The method further comprises passing the sample through the first
fluid
passageway towards an analyte detection system. The method further comprises
detecting a
property of the sample at a location along the first fluid passageway. The
method further
comprises separating the sample into a first portion and a second portion,
passing the first
portion to the analyte detection system, and returning the second portion
through the patient
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end of the first fluid passageway. In certain other embodiments, the first
portion travels a
first distance to the analyte detection system, the second portion travels a
second distance to
the patient end, and the second distance is smaller than the first distance.
[0012] In certain embodiments, a system for obtaining a body fluid sample
comprises a first fluid passageway having a patient end which is configured to
provide fluid
cominunication with a body fluid of a patient. The systein further comprises a
sensor
located at a predetermined location along the first fluid passageway. The
sensor is
configured to detect a property of fluid within the first fluid passageway.
The system
furtlier comprises an analyte detection systein in fluid communication with
the first fluid
passageway. At least a first portion of the fluid within the first fluid
passageway at the
predetermined location travels a first distance to the analyte detection
system and at least a
second portion of the fluid within the first fluid passageway at the
predetermined location
travels a second distance to the patient. In certain other embodiments, the
second distance
is smaller than the first distance.
[0013] Certain objects and advantages of the invention(s) are described
herein. Of
course, it is to be understood that not necessarily all such objects or
advantages may be
achieved in accordance with any particular embodiment. Thus, for example,
those skilled in
the art will recognize that the invention(s) may be embodied or carried out in
a manner that
achieves or optimizes one advantage or group of advantages as taught herein
without
necessarily achieving other objects or advantages as may be taught or
suggested herein.
Certain embodiments are summarized above. However, despite the foregoing
discussion of certain embodiments, only the appended claims (and not the
present
summary) are intended to define the invention(s). The summarized embodiments,
and
other embodiments, will become readily apparent to those skilled in the art
from the
following detailed description of the preferred embodiments having reference
to the
attached figures, the invention(s) not being limited to any particular
embodiment(s)
disclosed.
Brief Description of the Drawings
[0014] FIGURE 1 is a schematic of a fluid handling system in accordance with
one embodiment;
[0015] FIGURE lA is a schematic of a fluid handling system, wherein a fluid
handling and analysis apparatus of the fluid handling system is shown in a
cutaway view;
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100161 FIGURE IB is a cross-sectional view of a bundle of the fluid handling
system of FIGURE 1 A taken along the line 1 B-1 B;
[0017] FIGURE 2 is a schematic of an embodiment of a saYnpling apparatus;
[0018] FIGURE 3 is a schematic showing details of an embodiment of a
sampling apparatus;
[0019] FIGURE 4 is a schematic of an embodiment of a sampling unit;
[0020] FIGURE 5 is a schematic of an embodiment of a sampling apparatus;
[0021] FIGURE 6A is a schematic of an embodiment of gas injector manifold;
[0022] FIGURE 6B is a schematic of an einbodiment of gas injector manifold;
[0023] FIGURES 7A-7J are schematics illustrating methods of using the
infusion and blood analysis system, where FIGURE 7A shows one embodiment of a
method of infusing a patient, and FIGURES 7B-7J illustrate steps in a method
of sampling
from a patient, where FIGURE 7B shows fluid being cleared from a portion of
the first and
second passageways; FIGURE 7C shows a sample being drawn into the first
passageway;
FIGURE 7D shows a sample being drawn into second passageway; FIGURE 7E shows
air
being injected into the sample; FIGURE 7F shows bubbles being cleared from the
second
passageway; FIGURES 7H and 71 show the sample being pushed part way into the
second
passageway followed by fluid and more bubbles; and FIGURE 7J shows the sample
being
pushed to analyzer;
[0024] FIGURE 8 is a perspective front view of an embodiment of a sampling
apparatus;
[0025] FIGURE 9 is a schematic front view of one embodiment of a sampling
apparatus cassette;
[0026] FIGURE 10 is a schematic front view of one einbodiment of a sampling
apparatus instrument;
[0027] FIGURE 11 is an illustration of one embodiment of an arterial patient
connection;
[0028] FIGURE 12 is an illustration of one embodiment of a venous patient
connection;
[0029] FIGURES 13A, 13B, and 13C are various views of one embodiment of a
pinch valve, where FIGURE 13A is a front view, FIGURE 13B is a sectional view,
and
FIGURE 13C is a sectional view showing one valve in a closed position;
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[0030] FIGURES 14A and 14B are various views of one embodiment of a pinch
valve, where FIGURE 14A is a front view and FIGURE 14B is a sectional view
showing
one valve in a closed position;
[0031] FIGURE 15 is a side view of one embodiinent of a separator;
[0032] FIGURE 16 is an exploded perspective view of the separator of FIGURE
15;
[0033] FIGURE 17 is one embodiment of a fluid analysis apparatus;
[0034] FIGURE 18 is a top view of a cuvette for use in the apparatus of
FIGURE 17;
[0035] FIGURE 19 is a side view of the cuvette of FIGURE 18;
[0036] FIGURE 20 is an exploded perspective view of the cuvette of FIGURE
18;
[0037] FIGURE 21 is a schematic of an embodiment of a sample preparation
unit;
[0038] FIGURE 22A is a perspective view of another embodiment of a fluid
handling and analysis apparatus having a main instrument and removable
cassette;
[0039] FIGURE 22B is a partial cutaway, side elevational view of the fluid
handling and analysis apparatus with the cassette spaced from the main
instrument;
[0040] FIGURE 22C is a cross-sectional view of the fluid handling and analysis
apparatus of FIGURE 22A wherein the cassette is installed onto the main
instrument;
[0041] FIGURE 23A is a cross-sectional view of the cassette of the fluid
handling and analysis apparatus of FIGURE 22A taken along the line 23A-23A;
[0042] FIGURE 23B is a cross-sectional view of the cassette of FIGURE 23A
taken along the line 23B-23B of FIGURE 23A;
[0043] FIGURE 23C is a cross-sectional view of the fluid handling and analysis
apparatus having a fluid handling network, wherein a rotor of the cassette is
in a generally
vertical orientation;
[0044] FIGURE 23D is a cross-sectional view of the fluid handling and analysis
apparatus, wherein the rotor of the cassette is in a generally horizontal
orientation;
[0045] FIGURE 23E is a front elevational view of the main instrument of the
fluid handling and analysis apparatus of FIGURE 23C;
[0046] FIGURE 24A is a cross-sectional view of the fluid handling and analysis
apparatus having a fluid handling network in accordance with another
embodiment;
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[0047] FIGURE 24B is a front elevational view of the main instrument of the
fluid handling and analysis apparatus of FIGURE 24A;
[0048] FIGURE 25A is a front elevational view of a rotor having a sample
element for holding sample fluid;
[0049] FIGURE 25B is a rear elevational view of the rotor of FIGURE 25A;
[0050] FIGURE 25C is a front elevational view of the rotor of FIGURE 25A
with the sample element filled with a sample fluid;
[0051] FIGURE 25D is a front elevational view of the rotor of FIGURE 25C
after the sample fluid has been separated;
[0052] FIGURE 25E is a cross-sectional view of the rotor taken along the line
25E-25E of FIGURE 25A;
[0053] FIGURE 25F is an enlarged sectional view of the rotor of FIGURE 25E;
[0054] FIGURE 26A is an exploded perspective view of a sainple element for
use with a rotor of a fluid handling and analysis apparatus;
[0055] FIGURE 26B is a perspective view of an assembled sample element;
[0056] FIGURE 27A is a front elevational view of a fluid interface for use
with
a cassette;
[0057] FIGURE 27B is a top elevational view of the fluid interface of FIGURE
27A;
[0058] FIGURE 27C is an enlarged side view of a fluid interface engaging a
rotor;
[0059] FIGURE 28 is a cross-sectional view of the main instrument of the fluid
handling and analysis apparatus of FIGURE 22A taken along the line 28-28;
[0060] FIGURE 29 is a graph illustrating the absorption spectra of various
components that may be present in a blood sample;
[0061] FIGURE 30 is a graph illustrating the change in the absorption spectra
of
blood having the indicated additional components of FIGURE 29 relative to a
Sample
Population blood and glucose concentration, where the contribution due to
water has been
numerically subtracted from the spectra;
[0062] FIGURE 31 is an embodiment of an analysis method for determining the
concentration of an analyte in the presence of possible interferents;
[0063] FIGURE 32 is one embodiment of a method for identifying interferents
in a sample for use with the embodiment of FIGURE 31;
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[0064] FIGURE 33A is a graph illustrating one embodiment of the method of
FIGURE 32, and FIGURE 33B is a graph further illustrating the method of FIGURE
32;
[0065] FIGURE 34 is a one embodiment of a method for generating a model for
identifying possible interferents in a sample for use with an embodiment of
FIGURE 31;
[0066] FIGURE 35 is a schematic of one embodiment of a method for
generating randomly-scaled interferent spectra;
[0067] FIGURE 36 is one embodiment of a distribution of interferent
concentrations for use with the embodiment of FIGURE 35;
[0068] FIGURE 37 is a scheinatic of one embodiment of a method for
generating combination interferent spectra;
[0069] FIGURE 38 is a schematic of one einbodiment of a method for
generating an interferent-enhanced spectral database;
[0070] FIGURE 39 is a graph illustrating the effect of interferents on the
error
of glucose estimation;
[0071] FIGURES 40A, 40B, 40C, and 40D each have a graph showing a
comparison of the absorption spectrum of glucose with different interferents
taken using
two different techniques: a Fourier Transform Infrared (FTIR) spectrometer
having an
interpolated resolution of 1 cm"1 (solid lines with triangles); and by 25
finite-bandwidth IR
filters having a Gaussian profile and full-width half-maximum (FWHM) bandwidth
of 28
cm"1 corresponding to a bandwidth that varies from 140 nm at 7.08 m, up to
279 nm at 10
m (dashed lines with circles). The Figures show a comparison of glucose with
mannitol
(FIGURE 40A), dextran (FIGURE 40B), n-acetyl L cysteine (FIGURE 40C), and
procainamide (FIGURE 40D), at a concentration level of 1 mg/dL and path length
of 1 m;
[0072] FIGURE 41 shows a graph of the blood plasma spectra for 6 blood
sample taken from three donors in arbitrary units for a wavelength range from
7 m to 10
m, where the symbols on the curves indicate the central wavelengths of the 25
filters;
[0073] FIGURES 42A, 42B, 42C, and 42D contain spectra of the Sample
Population of 6 samples having random amounts of mannitol (FIGURE 42A),
dextran
(FIGURE 42B), n-acetyl L cysteine (FIGURE 42C), and procainamide (FIGURE 42D),
at a
concentration levels of 1 mg/dL and path lengths of 1 m;
[0074] FIGURES 43A-43D are graphs comparing calibration vectors obtained
by training in the presence of an interferent, to the calibration vector
obtained by training on
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clean plasma spectra for mannitol (FIGURE 43A), dextran (FIGURE 43B), n-acetyl
L
cysteine (FIGURE 43C), and procainamide (FIGURE 43D) for water-free spectra;
[0075] FIGURE 44 is a schematic illustration of another embodiment of the
analyte detection systein;
[0076] FIGURE 45 is a plan view of one embodiment of a filter wheel suitable
for use in the analyte detection systein depicted in FIGURE 44;
[0077] FIGURE 46 is a partial sectional view of another einbodiment of an
analyte detection system;
[0078] FIGURE 47 is a detailed sectional view of a sample detector of the
analyte detection system illustrated in FIGURE 46; and
[0079] FIGURE 48 is a detailed sectional view of a reference detector of the
analyte detection system illustrated in FIGURE 46.
[0080] Reference symbols are used in the Figures to indicate certain
components, aspects or features shown therein, with reference synibols coinmon
to more
than one Figure indicating like components, aspects or features shown therein.
Detailed Description of the Preferred Embodimeiits
[0081] Although certain preferred embodiments and examples are disclosed
below, it will be understood by those skilled in the art that the inventive
subject matter
extends beyond the specifically disclosed embodiments to other alternative
embodiments
and/or uses of the invention, and to obvious modifications and equivalents
thereof. Thus it
is intended that the scope of the inventions herein disclosed should not be
limited by the
particular disclosed embodiments described below. Thus, for example, in any
method or
process disclosed herein, the acts or operations making up the method/process
may be
performed in any suitable sequence, and are not necessarily limited to any
particular
disclosed sequence. For purposes of contrasting various embodiments with the
prior art,
certain aspects and advantages of these embodiments are described where
appropriate
herein. Of course, it is to be understood that not necessarily all such
aspects or advantages
may be achieved in accordance with any particular embodiment. Thus, for
example, it
should be recognized that the various embodiments may be carried out in a
manner that
achieves or optimizes one advantage or group of advantages as taught herein
without
necessarily achieving other aspects or advantages as may be taught or
suggested herein.
While the systems and methods discussed herein can be used for invasive
techniques, the
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systems and methods can also be used for non-invasive techniques or other
suitable
techniques, and can be used in hospitals, healthcare facilities, ICUs, or
residences.
OVERVIEW OF EMBODIMENTS OF FLUID HANDLING SYSTEMS
[0082] Disclosed herein are fluid handling systems and various methods of
analyzing sainple fluids. FIGURE 1 illustrates an embodiment of a fluid
handling system 10
which can determine the concentration of one or more substances in a saniple
fluid, such as
a whole blood sample from a patient P. The fluid handling system 10 can also
deliver an
infusion fluid 14 to the patient P.
[0078] The fluid handling systein 10 is located bedside and generally
comprises
a container 15 holding the infusion fluid 14 and a sampling system 100 which
is in
communication with both the container 15 and the patient P. In some
embodiments, the
fluid handling system 10 can be in fluid communication with an extracorporeal
fluid
conduit contaiiling a volume of a bodily fluid. A tube 13 extends from the
container 15 to
the sampling system 100. A tube 12 extends from the sampling system 100 to the
patient P.
In some embodiments, in lieu of the depicted tube 12, any suitable
extracorporeal fluid
conduit, such as a catheter, IV tube or an IV network, can be connected to the
sampling
systeni 100 with a connector such as the depicted connector 110. The
extracorporeal fluid
conduit need not be attached to the patient P; for example, the extracorporeal
fluid conduit
can be in fluid communication with a container of bodily fluid of interest
(e.g. blood), or
the extracorporeal fluid conduit can serve as a stand-alone volume of the
bodily fluid of
interest. In some embodiments, one or more components of the fluid handling
system 10
can be located at another facility, room, or other suitable remote location.
One or more
components of the fluid handling system 10 can communicate with one or more
other
components of the fluid handling system 10 (or with other devices) by any
suitable
communication means, such as communication interfaces including, but not
limited to,
optical interfaces, electrical interfaces, and wireless interfaces. These
interfaces can be part
of a local network, internet, wireless network, or other suitable networks.
[0083] The Infusion fluid 14 can comprise water, saline, dextrose, lactated
Ringer's solution, drugs, insulin, mixtures thereof, or other suitable
substances. The
illustrated sainpling system 100 allows the infusion fluid to pass to the
patient P and/or uses
the infusion fluid in the analysis. In some embodiments, the fluid handling
system 10 may
not employ infusion fluid. The fluid handling system 10 may thus draw samples
without
delivering any fluid to the patient P.
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[0084] The sampling system 100 can be removably or permanently coupled to
the tube 13 and tube 12 via connectors 110, 120. The patient connector 110 can
selectively
control the flow of fluid tlirough a bundle 130, which includes a patient
connection
passageway 112 and a sampling passageway 113, as shown in FIGURE 1B. The
sampling
system 100 can also draw one or more samples from the patient P by any
suitable means.
The sainpling system 100 can perform one or more analyses on the sample, and
then returns
the sainple to the patient or a waste container. In some embodiments, the
sainpling system
100 is a modular unit that can be removed and replaced as desired. The
sampling system
100 can include, but is not limited to, fluid handling and analysis
apparatuses, connectors,
passageways, catheters, tubing, fluid control elements, valves, pumps, fluid
sensors,,
pressure sensors, temperature sensors, hematocrit sensors, hemoglobin sensors,
colorimetric
sensors, and gas (or "bubble") sensors, fluid conditioning elements, gas
injectors, gas
filters, blood plasma separators, and/or cominunication devices (e.g.,
wireless devices) to
permit the transfer of information within the sampling system or between
sampling system
100 and a network. The illustrated sampling system 100 has a patient connector
110 and a
fluid handling and analysis apparatus 140, which analyzes a sample drawn from
the patient
P. The fluid handling and analysis apparatus 140 and patient connector 110
cooperate to
control the flow of infusion fluid into, and/or samples withdrawn from, the
patient P.
Samples'can also be withdrawn and transferred in other suitable manners.
[0085] FIGURE 1A is a close up view of the fluid handling and analysis
apparatus 140 which is partially cutaway to reveal some of its internal
components. The
fluid handling and analysis apparatus 140 preferably includes a pump 203 that
controls the
flow of fluid from the container 15 to the patient P and/or the flow of fluid
drawn from the
patient P. The pump 203 can selectively control fluid flow rates, direction(s)
of fluid
flow(s), and other fluid flow paraineters as desired. As used herein, the term
"pump" is a
broad term and means, without limitation, a pressurization/pressure device,
vacuum device,
or any other suitable means for causing fluid flow. The pump 203 can include,
but is not
limited to, a reversible peristaltic pump, two unidirectional pumps that work
in concert with
valves to provide flow in two directions, a unidirectional pump, a
displacement pump, a
syringe, a diaphragm pump, roller pump, or other suitable pressurization
device.
[0086] The illustrated fluid handling and analysis apparatus 140 has a display
141 and input devices 143. The illustrated fluid handling and analysis
apparatus 140 can
also have a sampling unit 200 configured to analyze the drawn fluid sample.
The sampling
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unit 200 can thus receive a sample, prepare the sample, and/or subject the
sample (prepared
or unprepared) to one or more tests. The sampling unit 200 can then analyze
results from
the tests. The sampling unit 200 can include, but is not limited to,
separators, filters,
centrifuges, sample elements, and/or detection systems, as described in detail
below. The
sampling unit 200 (see FIGURE 3) can include an analyte detection systein for
detecting the
concentration of one or more analytes in the body fluid sample. In some
embodiments, the
sampling unit 200 can prepare a sample for analysis. If the fluid handling and
analysis
apparatus 140 performs an analysis on plasina contained in whole blood taken
fiom the
patient P, filters, separators, centrifuges, or other types of sample
preparation devices can
be used to separate plasma from other components of the blood. After the
separation
process, the sampling unit 200 can analyze the plasma to determine, for
example, the
patient P's glucose level. The sanlpling unit 200 can employ spectroscopic
methods,
colorimetric methods, electrochemical methods, or other suitable methods for
analyzing
samples.
[0087] With continued reference to FIGURES 1 and 1A, the fluid 14 in the
container 15 can flow through the tube 13 and into a fluid source passageway
111. The
fluid can further flow through the passageway 111 to the pump 203, which can
pressurize
the fluid. The fluid 14 can then flow from the pump 203 through the patient
connection
passageway 112 and catheter 11 into the patient P. To analyze the patient's P
body fluid
(e.g., whole blood, blood plasma, interstitial fluid, bile, sweat, excretions,
etc.), the fluid
handling and analysis apparatus 140 can draw a sample from the patient P
through the
catheter 11 to a patient connector 110. The patient connector 110 directs the
fluid sample
into the sampling passageway 113 which leads to the sampling unit 200. The
sampling unit
200 can perform one or more analyses on the sample. The fluid handling and
analysis
apparatus 140 can then output the results obtained by the sampling unit 200 on
the display
141.
[0088] In some embodiments, the fluid handling system 10 can draw and
analyze body fluid sample(s) from the patient P to provide real-time or near-
real-time
measurement of glucose levels. Body fluid samples can be drawn from the
patient P
continuously, at regular intervals (e.g., every 5, 10, 15, 20, 30 or 60
minutes), at irregular
intervals, or at any time or sequence for desired measurements. These
measurements can
be displayed bedside with the display 141 for convenient monitoring of the
patient P.
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[0089] The illustrated fluid handling system 10 is mounted to a stand 16 and
can
be used in hospitals, ICUs, residences, healthcare facilities, and the like.
In some
embodiments, the fluid handling system 10 can be transportable or portable for
an
ainbulatory patient. The ambulatory fluid handling system 10 can be coupled
(e.g.,
strapped, adhered, etc.) to a patient, and may be smaller than the bedside
fluid handling
system 10 illustrated in FIGURE 1. In some embodiments, the fluid handling
system 10 is
an implantable system sized for subcutaneous implantation and can be used for
continuous
monitoring. In some embodiments, the fluid handling system 10 is miniaturized
so that the
entire fluid handling system can be implanted. In other embodiments, only a
portion of the
fluid handling systein 10 is sized for iinplantation.
[0090] In some embodiments, the fluid handling systein 10 is a disposable
fluid
handling system and/or has one or more disposable components. As used herein,
the term
"disposable" when applied to a systein or component (or combination of
components), such
as a cassette or sample element, is a broad tenn and means, without
limitation, that the
component in question is used a finite number of times and then discarded.
Some
disposable components are used only once and then discarded. Other disposable
components are used more than once and then discarded. For example, the fluid
handling
and analysis apparatus 140 can have a main instrument and a disposable
cassette that can be
installed onto the main instrument, as discussed below. The disposable
cassette can be
used for predetermined length of time, to prepare a predetermined amount of
sample fluid
for analysis, etc. In some embodiments, the cassette can be used to prepare a
plurality of
samples for subsequent analyses by the main instrument. The reusable main
instrument can
be used with any number of cassettes as desired. Additionally or
alternatively, the cassette
can be a portable, handheld cassette for convenient transport. In these
einbodiments, the
cassette can be manually mounted to or removed from the inain instrument. In
some
embodiments, the cassette may be a non disposable cassette which can be
permanently
coupled to the main instrument, as discussed below.
[0091] Disclosed herein are a number of embodiments of fluid handling
systems, sainpling systems, fluid handling and analysis apparatuses, analyte
detection
systems, and methods of using the same. Section I below discloses various
embodiments of
the fluid handling system that may be used to transport fluid from a patient
for analysis.
Section II below discloses several embodiments of fluid handling methods that
may be used
with the apparatus discussed in Section I. Section III below discloses several
embodiments
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of a sampling system that may be used with the apparatus of Section I or the
methods of
Section II. Section IV below discloses various embodiments of a sample
analysis system
that may be used to detect the concentration of one or more analytes in a
material sample.
Section V below discloses methods for determining analyte concentrations from
sample
spectra.
SECTION I - FLUID HANDLING SYSTEM
[0092] FIGURE 1 is a schematic of the fluid handling system 10 which includes
the container 15 supported by the stand 16 and having an interior that is
fillable with the
fluid 14, the catheter 11, and the sampling system 100. Fluid handling system
10 includes
one or more passageways 20 that form conduits between the container, the
sampling
system, and the catheter. Generally, sampling system 100 is adapted to accept
a fluid
supply, such as fluid 14, and to be connected to a patient, including, but not
limited to
catheter 11 which is used to catheterize a patient P. Fluid 14 includes, but
is not limited to,
fluids for infusing a patient such as saline, lactated Ringer's solution, or
water. Sampling
system 100, when so connected, is then capable of providing fluid to the
patient. In
addition, sampling system 100 is also capable of drawing samples, such as
blood, from the
patient through catheter 11 and passageways 20, and analyzing at least a
portion of the
drawn sample. Sampling system 100 measures characteristics of the drawn sample
including, but not limited to, one or more of the blood plasma glucose, blood
urea nitrogen
(BUN), hematocrit, hemoglobin, or lactate levels. Optionally, sampling system
100
includes other devices or sensors to measure other patient or apparatus
related information
including, but not limited to, patient blood pressure, pressure changes within
the sampling
system, or sample draw rate.
[0093] More specifically, FIGURE 1 shows sanipling system 100 as including
the patient connector 110, the fluid handling and analysis apparatus 140, and
the connector
120. Sampling system 100 may include combinations of passageways, fluid
control and
measureinent devices, and analysis devices to direct, sample, and analyze
fluid.
Passageways 20 of sampling system 100 include the fluid source passageway 111
from
connector 120 to fluid handling and analysis apparatus 140, the patient
connection
passageway 112 fronl the fluid handling and analysis apparatus to patient
connector 110,
and the sampling passageway 113 from the patient connector to the fluid
handling and
analysis apparatus. The reference of passageways 20 as including one or more
passageway,
for example passageways 111, 112, and 113 are provided to facilitate
discussion of the
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system. It is understood that passageways may include one or more separate
components
and may include other intervening comporients-including, but not limited to,
pumps, valves,
manifolds, and analytic equipment.
[0094] As used herein, the term "passageway" is a broad terin and is used in
its
ordinary sense and includes, without limitation except as explicitly stated,
as any opening
through a material tlzrough which a fluid, such as a liquid or a gas, may pass
so as to act as
a conduit. Passageways include, but are not limited to, flexible, inflexible
or partially
flexible tubes, laaninated structures having openings, bores through
materials, or any other
structure that can act as a conduit and any combination or connections
thereof. The internal
surfaces of passageways that provide fluid to a patient or that are used to
transport blood are
preferably biocompatible materials, including but not limited to silicone,
polyetheretherketone (PEEK), or polyethylene (PE). One type of preferred
passageway is a
flexible tube having a fluid contacting surface formed from a biocompatible
material. A
passageway, as used herein, also includes separable portions that, when
connected, form a
passageway.
[0095] The inner passageway surfaces may include coatings of various sorts to
enhance certain properties of the conduit, such as coatings that affect the
ability of blood to
clot or to reduce friction resulting from fluid flow. Coatings include, but
are not limited to,
molecular or ionic treatinents.
[0096] As used herein, the term "connected" is a broad term and is used in its
ordinary sense and includes, without limitation except as explicitly stated,
with respect to
two or more things (e.g., elements, devices, patients, etc.): a condition of
physical contact
or attachment, whether direct, indirect (via, e.g., intervening member(s)),
continuous,
selective, or intermittent; and/or a condition of being in fluid, electrical,
or optical-signal
communication, whether direct, indirect, continuous, selective (e.g., where
there exist one
or more intervening valves, fluid handling components, switches, loads, or the
like), or
intermittent. A condition of fluid communication is considered to exist
whether or not
there exists a continuous or contiguous liquid or fluid column extending
between or among
the two or more things in question. Various types of connectors can connect
components of
the fluid handling system described herein. As used herein, the term
"connector" is a broad
term and is used in its ordinary sense and includes, without limitation except
as explicitly
stated, as a device that connects passageways or electrical wires to provide
communication
(whether direct, indirect, continuous, selective, or interinittent) on either
side of the
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connector. Comiectors contemplated herein include a device for connecting any
opening
through which a fluid may pass. These connectors may have intervening valves,
switches,
fluid handling devices, asid the like for affecting fluid flow. In some
embodimen.ts, a
connector may also house devices for the measurement, control, and preparation
of fluid, as
described in several of the embodiments.
[0097] Fluid handling and analysis apparatus 140 may control the flow of
fluids
through passageways 20 and the analysis of samples drawn from a patient P, as
described
subsequently. Fluid handling and analysis apparatus 140 includes the display
141 and input
devices, such as buttons 143. Display 141 provides information on the
operation or results
of an analysis performed by fluid handling and analysis apparatus 140. In one
embodiment,
display 141 indicates the function of buttons 143, which are used to input
infonnation into
fluid handling and analysis apparatus 140. Information that may be input into
or obtained
by fluid handling and analysis apparatus 140 includes, but is not limited to,
a required
infusion or dosage rate, sampling rate, or patient specific information which
may include,
but is not limited to, a patient identification nuinber or medical
information. In an other
alternative embodiment, fluid handling and analysis apparatus 140 obtains
information on
patient P over a communications network, for example an hospital communication
network
having patient specific information which may include, but is not limited to,
medical
conditions, medications being administered, laboratory blood reports, gender,
and weight.
As one example of the use of fluid handling system 10, which is not meant to
limit the
scope of the present invention, FIGURE 1 shows catheter 11 connected to
patient P.
[0098] As discussed subsequently, fluid handling system 10 may catheterize a
patient's vein or artery. Sampling system 100 is releasably connectable to
container 15 and
catheter 11. Thus, for example, FIGURE 1 shows container 15 as including the
tube 13 to
provide for the passage of fluid to, or from, the container, and catheter 11
as including the
tube 12 external to the patient. Connector 120 is adapted to join tube 13 and
passageway
111. Patient connector 110 is adapted to join tube 12 and to provide for a
connection
between passageways 112 and 113.
[0099] Patient connector 110 may also include one or more devices that
control,
direct, process, or otherwise affect the flow through passageways 112 and 113.
In some
embodiments, one or more lines 114 are provided to exchange signals between
patient
connector 110 and fluid handling and analysis apparatus 140. The lines 114 can
be
electrical lines, optical communicators, wireless communication channels, or
other means
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for communication. As shown in FIGURE 1, sampling system 100 may also include
passageways 112 and 113, and lines 114. The passageways and electrical lines
between
apparatus 140 and patient connector 110 are referred to, with out limitation,
as the bundle
130.
[0100] In various embodiments, fluid handling and analysis apparatus 140
and/or patient connector 110, includes other elements (not shown in FIGURE 1)
that
include, but are not limited to: fluid control elements, including but not
limited to valves
and pumps; fluid sensors, including but not limited to pressure sensors,
temperature
sensors, hematocrit sensors, hemoglobin sensors, colorimetric sensors, and gas
(or
"bubble") sensors; fluid conditioning elements, including but not limited to
gas injectors,
gas filters, and blood plasma separators; and wireless communication devices
to permit the
transfer of information within the sampling system or between sampling system
100 and a
wireless network.
[0101] In one embodiment, patient connector 110 includes devices to determine
when blood has displaced fluid 14 at the connector end, and thus provides an
indication of
when a sample is available for being drawn through passageway 113 for
sampling. The
presence of such a device at patient connector 110 allows for the operation of
fluid handling
system 10 for analyzing samples without regard to the actual length of tube
12.
Accordingly, bundle 130 may include elements to provide fluids, including air,
or
information communication between patient connector 110 and fluid handling and
analysis
apparatus 140 including, but not limited to, one or more other passageways
and/or wires.
[0102] In one embodiment of sampling system 100, the passageways and lines
of bundle 130 are sufficiently long to permit locating patient connector 110
near patient P,
for example with tube 12 having a length of less than 0.1 to 0.5 meters, or
preferably
approximately 0.15 meters and with fluid handling and analysis apparatus 140
located at a
convenient distance, for example on a nearby stand 16. Thus, for example,
bundle 130 is
from 0.3 to 3 meters, or more preferably from 1.5 to 2.0 meters in length. It
is preferred,
though not required, that patient connector 110 and connector 120 include
removable
connectors adapted for fitting to tubes 12 and 13, respectively. Thus, in one
embodiment,
container 15/tube 13 and catheter 11/tube 12 are both standard medical
components, and
sampling system 100 allows for the easy connection and disconnection of one or
both of the
container and catheter from fluid handling system 10.
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[0103] In another embodiment of sampling systenl 100, tubes 12 and 13 and a
substantial portion of passageways 111 and 112 have approximately the same
internal
cross-sectional area. It is preferred, though not required, that the internal
cross-sectional
area of passageway 113 is less than that of passageways 111 and 112 (see
FIGURE 1B). As
described subsequently, the difference in areas pennits fluid handling systein
10 to transfer
a small sample volume of blood from patient connector 110 into fluid handling
and analysis
apparatus 140.
[0104] Thus, for example, in one embodiment passageways 111 and 112 are
formed froin a tube having an iiiner diameter from 0.3 millimeter to 1.50
millimeter, or
more preferably having a dianleter from 0.60 millimeter to 1.2 millimeter.
Passageway 113
is formed from a tube having an inner diameter from 0.3 millimeter to 1.5
millimeter, or
more preferably having an inner diameter of from 0.6 millimeter to 1.2
millimeter.
[0105] While FIGURE 1 shows sampling system 100 connecting a patient to a
fluid source, the scope of the present disclosure is not meant to be limited
to this
embodiment. Alternative embodiments include, but are not limited to, a greater
or fewer
number of connectors or passageways, or the connectors may be located at
different
locations within fluid handling system 10, and alternate fluid paths. Thus,
for example,
passageways 111 and 112 may be formed from one tube, or may be formed from two
or
more coupled tubes including, for example, branches to other tubes within
sampling system
100, and/or there may be additional branches for infusing or obtaining samples
from a
patient. In addition, patient connector 110 and connector 120 and sampling
system 100
alteniatively include additional pumps and/or valves to control the flow of
fluid as
described below.
[0106] FIGURES 1A and 2 illustrate a sampling system 100 configured to
analyze blood from patient P which may be generally similar to the embodiment
of the
sampling system illustrated in FIGURE 1, except as further detailed below.
Where possible,
similar elements are identified with identical reference numerals in the
depiction of the
embodiments of FIGURES 1 to 2. FIGURES 1A and 2 show patient connector 110 as
including a sampling assembly 220 and a connector 230, portions of passageways
111 and
113, and lines 114, and fluid handling and analysis apparatus 140 as including
the pump
203, the sampling unit 200, and a controller 210. The pump 203, sampling unit
200, and
controller 210 are contained within a housing 209 of the fluid handling and
analysis
apparatus 140. The passageway 111 extends from the connector 120 through the
housing
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209 to the pump 203. The bundle 130 extends from the pump 203, sampling unit
200, and
controller 210 to the patient connector 110.
[01071 In FIGURES 1A and 2, the passageway 111 provides fluid
communication between connector 120 and pump 203 and passageway 113 provides
fluid
coxnmunication between pump 203 and connector 110. Controller 210 is in
communication
with pulnp 203, sampling unit 200, and sampling assembly 220 through lines
114.
Controller 210 has access to meinory 212, and optionally has access to a media
reader 214,
including but not limited to a DVD or CD-ROM reader, and communications link
216,
which can comprise a wired or wireless communications network, including but
not limited
to a dedicated line, an intranet, or an Internet connection.
[0108] As described subsequently in several embodiments, sampling unit 200
may include one or more passageways, pumps and/or valves, and sarnpling
assembly 220
may include passageways, sensors, valves, and/or sample detection devices.
Controller 210
collects information from sensors and devices witliin sampling assembly 220,
from sensors
and analytical equipment within sampling unit 200, and provides coordinated
signals to
control pump 203 and pumps and valves, if present, in sampling asseinbly 220.
(0109] Fluid handling and analysis apparatus 140 includes the ability to pump
in
a forward direction (towards the patient) and in a reverse direction (away
from the patient).
Thus, for example, pump 203 may direct fluid 14 into patient P or draw a
sample, such as a
blood sample from patient P, from catheter 11 to sampling assembly 220, where
it is further
directed through passageway 113 to sampling unit 200 for analysis. Preferably,
pump 203
provides a forward flow rate at least sufficient to keep the patient vascular
line open. In one
embodiment, the forward flow rate is from 1 to 5 ml/hr. In some embodiments,
the flow
rate of fluid is about 0.05 ml/hr, 0.1 ml/hr, 0.2 ml/hr, 0.4 ml/hr, 0.6 ml/hr,
0.8 ml/hr, 1.0
ml/hr, and ranges encompassing such flow rates. In some embodiments, for
example, the
flow rate of fluid is less than about 1.0 ml/hr. In certain embodiments, the
flow rate of fluid
may be about 0.1 ml/hr or less. When operated in a reverse direction, fluid
handling and
analysis apparatus 140 includes the ability to draw a sample from the patient
to sampling
assembly 220 and through passageway 113. In one embodiment, pump 203 provides
a
reverse flow to draw blood to sampling assembly 220, preferably by a
sufficient distance
past the sampling assembly to ensure that the sampling assembly contains an
undiluted
blood sample. In one embodiment, passageway 113 has an inside diameter of from
25 to
200 microns, or more preferably from 50 to 100 microns. Sampling unit 200
extracts a
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small sample, for example from 10 to 100 microliters of blood, or inore
preferably
approximately 40 microliters voluine of blood, from sampling assembly 220.
[0110] In one einbodiment, pump 203 is a directionally controllable puanp that
acts on a flexible portion of passageway 111. Examples of a single,
directionally
controllable pump include, but are not limited to a reversible peristaltic
pump or two
unidirectional pumps that work in concert with valves to provide flow in two
directions. In
an alternative embodiment, pump 203 includes a combination of pumps, including
but not
limited to displacement pumps, such as a syringe, and/or valve to provide bi-
directional
flow control through passageway 111.
[0111] Controller 210 includes one or more processors for controlling the
operation of fluid handling system 10 and for analyzing sample measureineiits
fioin fluid
handling and analysis apparatus 140. Controller 210 also accepts input from
buttons 143
and provides information on display 141. Optionally, controller 210 is in bi-
directional
commuiii,cation with a wired or wireless communication system, for example a
hospital
network for patient information. The one or more processors comprising
controller 210 may
include one or more processors that are located either within fluid handling
and analysis
apparatus 140 or that are networked to the unit.
[0112] The control of fluid handling system 10 by controller 210 may include,
but is not limited to, controlling fluid flow to infuse a patient and to
sample, prepare, and
analyze samples. The analysis of measurements obtained by fluid handling and
analysis
apparatus 140 of may include, but is not limited to, analyzing samples based
on inputted
patient specific information, from information obtained from a database
regarding patient
specific information, or from information provided over a network to
controller 210 used in
the analysis of measurements by apparatus 140.
[0113] Fluid handling system 10 provides for the infusion and sampling of a
patient blood as follows. With fluid handling system 10 connected to bag 15
having fluid
14 and to a patient P, controller 210 infuses a patient by operating pump 203
to direct the
fluid into the patient. Thus, for example, in one embodiment, the controller
directs that
samples be obtained from a patient by operating pump 203 to draw a sample. In
one
embodiment, pump 203 draws a predetermined sample volume, sufficient to
provide a
sample to sampling assembly 220. In another embodiment, pump 203 draws a
sample until
a device within sampling assembly 220 indicates that the sample has reached
the patient
connector 110. As an example which is not meant to limit the scope of the
present
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invention, one such indication is provided by a sensor that detects changes in
the color of
the sample. Another example is the use of a device t4at indicates changes in
the material
within passageway 111 including, but not limited to, a decrease in the amount
of fluid 14, a
change with time in the amount of fluid, a measure of the amount of
hemoglobin, or an
indication of a change from fluid to blood in the passageway.
[0114] When the sample reaches sampling assembly 220, controller 210
provides an operating signal to valves and/or pumps in sainpling system 100
(not shown) to
draw the saniple from sampling assembly 220 into sampling unit 200. After a
satnple is
drawn towards sampling unit 200, controller 210 then provides signals to pump
203 to
resume infusing the patient. In one embodiment, controller 210 provides
signals to pump
203 to resume infusing the patient while the sample is being drawn from
sainpling
assembly 220. In an alternative embodiment, controller 210 provides signals to
pump 203
to stop infusing the patient while the sample is being drawn from sampling
assembly 220.
In another alternative embodiment, controller 210 provides signals to pump 203
to slow the
drawing of blood from the patient while the sample is being drawn from
sainpling assembly
220.
[0115] In another alternative embodiment, controller 210 monitors indications
of obstructions in passageways or catheterized blood vessels during reverse
pumping and
moderates the pumping rate and/or direction of pump 203 accordingly. Thus, for
example,
obstructed flow from an obstructed or kinked passageway or of a collapsing or
collapsed
catheterized blood vessel that is being pumped will result in a lower pressure
than an
unobstructed flow. In one embodiment, obstructions are monitored using a
pressure sensor
in sampling assembly 220 or along passageways 20. If the pressure begins to
decrease
during pumping, or reaches a value that is lower than a predetermined value
then controller
210 directs pump 203 to decrease the reverse pumping rate, stop pumping, or
pump in the
forward direction in an effort to reestablish unobstructed pumping.
[0116] FIGURE 3 is a schematic showing details of a sampling system 300
which may be generally similar to the embodiments of sampling system 100 as
illustrated in
FIGURES 1 and 2, except as further detailed below. Sampling system 300
includes
sampling assembly 220 having, along passageway 112: connector 230 for
connecting to
tube 12, a pressure sensor 317, a colorimetric sensor 311, a first bubble
sensor 314a, a first
valve 312, a second valve 313, and a second bubble sensor 314b. Passageway 113
forms a
"T" with passageway 111 at a junction 318 that is positioned between the first
valve 312
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and second valve 313, and includes a gas injector manifold 315 and a third
valve 316. The
lines 114 comprise control and/or signal lines extending from colorimetric
sensor 311, first,
second, and third valves (312, 313, 316), first and second bubble sensors
(314a, 314b), gas
injector manifold 315, and pressure sensor 317. Sampling system 300 also
includes
sampling unit 200 which has a bubble sensor 321, a sample analysis device 330,
a first
valve 323a, a waste receptacle 325, a second valve 323b, and a pump 328.
Passageway 113
forms a "T" to fonn a waste line 324 and a pump line 327.
[0117] It is preferred, though not necessary, that the sensors of sampling
systein
100 are adapted to accept a passageway through which a sample may flow and
that sense
through the walls of the passageway. As described subsequently, this
arrangement allows
for the sensors to be reusable and for the passageways to be disposable. It is
also preferred,
though not necessary, that the passageway is smooth and without abrupt
dimensional
changes which may damage blood or prevent smooth flow of blood. In addition,
is also
preferred that the passageways that deliver blood from the patient to the
analyzer not
contain gaps or size changes that permit fluid to stagnate and not be
transported through the
passageway.
[0118] In one embodiment, the respective passageways on which valves 312,
313, 316, and 323 are situated along passageways that are flexible tubes, and
valves 312,
313, 316, and 323 are "pinch valves," in which one or more movable surfaces
compress the
tube to restrict or stop flow therethrough. In one embodiment, the pinch
valves include one
or more moving surfaces that are actuated to move together and "pinch" a
flexible
passageway to stop flow therethrough. Examples of a pinch valve include, for
example,
Model PV256 Low Power Pinch Valve (Instech Laboratories, Inc., Plymouth
Meeting, PA).
Alternatively, one or more of valves 312, 313, 316, and 323 may be other
valves for
controlling the flow through their respective passageways.
[0119] Colorimetric sensor 311 accepts or forms a portion of passageway 111
and provides an indication of the presence or absence of blood within the
passageway. In
one embodiment, colorimetric sensor 311 permits controller 210 to
differentiate between
fluid 14 and blood. Preferably, colorimetric sensor 311 is adapted to receive
a tube or other
passageway for detecting blood. This permits, for example, a disposable tube
to be placed
into or through a reusable colorimetric sensor. In an alternative embodiment,
colorimetric
sensor 311 is located adjacent to bubble sensor 314b. Examples of a
colorimetric sensor
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include, for example, an Optical Blood Leak/Blood vs. Saline Detector
available from
J.ntrotek International (Edgewood, NJ).
[0120] As described subsequently, sainpling system 300 injects a gas -
referred
to herein and without limitation as a "bubble" - into passageway 113. Sampling
system 300
includes gas injector manifold 315 at or near junction 318 to inject one or
more bubbles,
each separated by liquid, into passageway 113. The use of bubbles is useful in
preventing
longitudinal mixing of liquids as they flow through passageways both in the
delivery of a
sample for analysis with dilution and for cleaning passageways between
samples. Thus, for
example the fluid in passageway 113 includes, in one embodiment of the
invention, two
volumes of liquids, such as sample S or fluid 14 separated by a bubble, or
multiple volumes
of liquid each separated by a bubble therebetween.
[0121] Bubble sensors 314a, 314b and 321 each accept or fonn a portion of
passageway 112 or 113 and provide an indication of the presence of air, or the
change
between the flow of a fluid and the flow of air, through the passageway.
Examples of
bubble sensors include, but are not limited to ultrasonic or optical sensors,
that can detect
the difference between small bubbles or foam from liquid in the passageway.
Once such
bubble detector is an MEC Series Air Bubble/ Liquid Detection Sensor (Introtek
International, Edgewood, NY). Preferably, bubble sensor 314a, 314b, and 321
are each
adapted to receive a tube or other passageway for detecting bubbles. This
permits, for
example, a disposable tube to be placed through a reusable bubble sensor.
[0122] Pressure sensor 317 accepts or forms a portion of passageway 111 and
provides an indication or measurement of a fluid within the passageway. When
all valves
between pressure sensor 317 and catheter 11 are open, pressure sensor 317
provides an
indication or measurement of the pressure within the patient's catheterized
blood vessel. In
one embodiment, the output of pressure sensor 317 is provided to controller
210 to regulate
the operation of pump 203. Thus, for example, a pressure measured by pressure
sensor 317
above a predetermined value is taken as indicative of a properly working
system, and a
pressure below the predetermined value is taken as indicative of excessive
pumping due to,
for example, a blocked passageway or blood vessel. Thus, for example, with
pump 203
operating to draw blood from patient P, if the pressure as measured by
pressure sensor 317
is within a range of normal blood pressures, it may be assumed that blood is
being drawn
from the patient and pumping continues. However, if the pressure as measured
by pressure
sensor 317 falls below some level, then controller 210 instructs pump 203 to
slow or to be
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operated in a forward direction to reopen the blood vessel. One such pressure
sensor is a
Deltran IV part number DPT-412 (Utah Medical Products, Midvale, UT).
[0123] Sample analysis device 330 receives a sample and performs an analysis.
In several embodiments, device 330 is configured to prepare of the sample for
analysis.
Thus, for example, device 330 may include a sample preparation unit 332 and an
analyte
detection systein 334, where the sample preparation unit is located between
the patient and
the analyte detection system. In general, sample preparation occurs between
sampling and
analysis. Thus, for example, sample preparation unit 332 may take place
reinoved from
analyte detection, for example within sampling assembly 220, or may take place
adjacent or
within analyte detection system 334.
[0124] As used herein, the term "analyte" is a broad term and is used in its
ordinary sense and includes, without limitation, any chemical species the
presence or
concentration of which is sought in the material sample by an analyte
detection system. For
example, the analyte(s) include, but not are limited to, glucose, ethanol,
insulin, water,
carbon dioxide, blood oxygen, cholesterol, bilirubin, ketones, fatty acids,
lipoproteins,
albumin, urea, creatinine, white blood cells, red blood cells, heinoglobin,
oxygenated
hemoglobin, carboxyhemoglobin, organic molecules, inorganic molecules,
pharmaceuticals, cytochrome, various proteins and chromophores,
microcalcifications,
electrolytes, sodium, potassium, chloride, bicarbonate, and hormones. As used
herein, the
term "material sample" (or, alternatively, "sample") is a broad term and is
used in its
ordinary sense and includes, without limitation, any collection of material
which is suitable
for analysis. For example, a material sample may comprise whole blood, blood
components
(e.g., plasma or serum), interstitial fluid, intercellular fluid, saliva,
urine, sweat and/or other
organic or inorganic materials, or derivatives of any of these materials. In
one embodiment,
whole blood or blood components may be drawn from a patient's capillaries.
[0125] In one embodiment, sample preparation unit 332 separates blood plasma
from a whole blood sample or removes contaminants from a blood sample and thus
comprises one or more devices including, but not limited to, a filter,
membrane, centrifuge,
or some combination thereof. In alternative embodiments, analyte detection
system 334 is
adapted to analyze the sample directly and sample preparation unit 332 is not
required.
[0126] Generally, sampling assembly 220 and sampling unit 200 direct the fluid
drawn from sampling assembly 220 into passageway 113 into sample analysis
device 330.
FIGURE 4 is a schematic of an embodiment of a sampling unit 400 that permits
some of
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the sample to bypass sample analysis device 330. Sampling unit 400 may be
generally
similar to sampling unit 200, except as furtherr detailed below. Sampling unit
400 includes
bubble sensor 321, valve 323, sample analysis device 330, waste line 324,
waste receptacle
325, valve 326, puinp line 327, pump 328, a valve 322, and a waste line 329.
Waste line
329 includes valve 322 and forms a "T" at puinp line 337 and waste line 329.
Valves 316,
322, 323, and 326 permit a flow through passageway 113 to be routed through
sample
analysis device 330, to be routed to waste receptacle 325, or to be routed
through waste line
324 to waste receptacle 325.
[0127] FIGURE 5 is a schematic of one embodiment of a sampling system 500
which may be generally similar to the embodiments of sampling system 100 or
300 as
illustrated in FIGURES 1 through 4, except as further detailed below. Sampling
system 500
includes an embodiment of a sampling unit 510 and differs from sampling system
300 in
part, in that liquid drawn from passageway 111 may be returned to passageway
111 at a
junction 502 between pump 203 and connector 120.
[0128] With reference to FIGURE 5, sampling unit 510 includes a return line
503 that intersects passageway 111 on the opposite side of pump 203 from
passageway 113,
a bubble sensor 505 and a pressure sensor 507, both of which are controlled by
controller
210. Bubble sensor 505 is generally similar to bubble sensors 314a, 314b and
321 and
pressure sensor 507 is generally similar to pressure sensor 317. Pressure
sensor 507 is
useful in determining the correct operation of sampling system 500 by
monitoring pressure
in passageway 111. Thus, for example, the pressure in passageway 111 is
related to the
pressure at catheter 11 when pressure sensor 507 is in fluid communication
with catheter 11
(that is, when any intervening valve(s) are open). The output of pressure
sensor 507 is used
in a manner similar to that of pressure sensor 317 described previously in
controlling
pumps of sampling system 500.
[0129] Sampling unit 510 includes valves 501, 326a, and 326b under the
control of controller 210. Valve 501 provides additional liquid flow control
between
sampling unit 200 and sampling unit 510. Pump 328 is preferably a bi-
directional pump
that can draw fluid from and into passageway 113. Fluid may either be drawn
from and
returned to passageway 501, or may be routed to waste receptacle 325. Valves
326a and
326b are situated on either side of pump 328. Fluid can be drawn through
passageway 113
and into return line 503 by the coordinated control of pump 328 and valves
326a and 326b.
Directing flow from return line 503 can be used to prime sampling system 500
with fluid.
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Thus, for example, liquid may be pulled into sampling unit 510 by operating
pump 328 to
pull liquid from passageway 113 while valve 326a is open and valve 326b is
closed. Liquid
may then be pumped back into passageway 113 by operating pump 328 to push
liquid into
passageway 113 while valve 326a is closed and valve 326b is open.
[0130] FIGURE 6A is a schematic of an embodiment of gas injector manifold
315 which may be generally similar or included within the embodiinents
illustrated in
FIGURES 1 through 5, except as further detailed below. Gas injector manifold
315 is a
device that injects one or more bubbles in a liquid within passageway 113 by
opening
valves to the atmosphere and lowering the liquid pressure within the manifold
to draw in
air. As described subsequently, gas injector manifold 315 facilitates the
injection of air or
other gas bubbles into a liquid within passageway 113. Gas injector manifold
315 has three
gas injectors 610 including a first injector 610a, a second injector 610b, and
a third injector
610c. Each injector 610 includes a corresponding passageway 611 that begins at
one of
several laterally spaced locations along passageway 113 and extends through a
corresponding valve 613 and terminates at a corresponding end 615 that is open
to the
atmosphere. In an alternative embodiment, a filter is placed in end 615 to
filter out dust or
particles in the atmosphere. As described subsequently, each injector 610 is
capable of
injecting a bubble into a liquid within passageway 113 by opening the
corresponding valve
613, closing a valve on one end of passageway 113 and operating a pump on the
opposite
side of the passageway to lower the pressure and pull atmospheric air into the
fluid. In one
embodiment of gas injector manifold 315, passageways 113 and 611 are formed
within a
single piece of material (e.g., as bores formed in or through a plastic or
metal housing (not
shown)). In an alternative embodiment, gas injector manifold 315 includes
fewer than three
injectors, for example one or two injectors, or includes more than three
injectors. In another
alternative embodiment, gas injector manifold 315 includes a controllable high
pressure
source of gas for injection into a liquid in passageway 113. It is preferred
that valves 613
are located close to passageway 113 to minimize trapping of fluid in
passageways 611.
[0131] Importantly, gas injected into passageways 20 should be prevented from
reaching catheter 11. As a safety precaution, one embodiment prevents gas from
flowing
towards catheter 11 by the use of bubble sensor 314a as shown, for example, in
FIGURE 3.
If bubble sensor 314a detects gas within passageway 111, then one of several
alternative
embodiments prevents unwanted gas flow. In one embodiment, flow in the
vicinity of
sampling assembly 220 is directed into line 113 or through line 113 into waste
receptacle
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325. With further reference to FIGURE 3, upon the detection of gas by bubble
sensor 314a,
valves 316 and 323a are opened, valve 313 and the valves 613a, 613b and 613c
of gas
injector manifold 315 are closed, and pump 328 is turned on to direct flow
away from the
portion of passageway 111 between sampling assembly 220 and patient P into
passageway
113. Bubble sensor 321 is monitored to provide an indication of when
passageway 113
clears out. Valve 313 is then opened, valve 312 is closed, and the remaining
portion of
passageway 111 is then cleared. Alternatively, all flow is iminediately halted
in the
direction of catheter 11, for exainple by closing all valves and stopping all
pumps. In an
alternative embodiment of sampling assembly 220, a gas-permeable membrane is
located
within passageway 113 or within gas injector manifold 315 to remove unwanted
gas from
fluid handling system 10, e.g., by venting such gas through the membrane to
the
atmosphere or a waste receptacle.
[0132] FIGURE 6B is a schematic of an embodiment of gas injector manifold
315' which may be generally similar to, or included within, the embodiments
illustrated in
FIGURES 1 through 6A, except as further detailed below. In gas injector
manifold 315', air
line 615 and passageway 113 intersect at junction 318. Bubbles are injected by
opening
valve 316 and 613 while drawing fluid into passageway 113. Gas injector
manifold 315' is
thus more compact that gas injector manifold 315, resulting in a more
controllable and
reliable gas generator.
SECTION II - FLUID HANDLING METHODS
[0133] One embodiment of a method of using fluid handling system 10,
including sainpling assembly 220 and sampling unit 200 of FIGURES 2, 3 and 6A,
is
illustrated in Table 1 and in the schematic fluidic diagrams of FIGURES 7A-7J.
In general,
the pumps and valves are controlled to infuse a patient, to extract a sample
from the patient
up passageway 111 to passageway 113, and to direct the sample along passageway
113 to
device 330. In addition, the pumps and valves are controlled to inject bubbles
into the fluid
to isolate the fluid from the diluting effect of previous fluid and to clean
the lines between
sampling. The valves in FIGURES 7A-7J are labeled with suffices to indicate
whether the
valve is open or closed. Thus a valve "x," for example, is shown as valve "x-
o" if the valve
is open and "x-c" if the valve is closed.
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M 00 N M M M M ~ M M
N M M M ~ b ~ K~) M M
y >
> > > ~ ~ ~ ~ ~
Infuse (FIGURE 7A) F Off O O C C C C C C
patient Infuse patient
Sample (FIGURE 7B) R Off C 0 one or more C C C
patient Clear fluid from are o en
passageways 0 0 0
(FIGURE 7C) R Off 0 0 C C C C C C
Draw sainple until
after colorimetric
sensor 311 senses
blood
(FIGURE 7D) Off On 0 C C C C 0 C 0
Inject sample into
bubble manifold
Alternative to R On 0 0 C C C 0 C 0
FIGURE 7D
(FIGURE 7E) Off On C C se uentiall 0 C 0
Inject bubbles O O O
(FIGURE 7F) F Off C O C C C O O C
Clear bubbles
from p atient line
(FIGURE 7G) F Off 0 0 C C C C C C
Clear blood from
patient line
(FIGURE 7H) F Off C 0 C C C 0 0 C
Move bubbles out
of bubbler
(FIGURE 71) Add Off On C C se uentiall 0 C 0
cleaning bubbles 0 0 0
(FIGURE 7J) Push F Off C 0 C C C 0 0 C
sample to analyzer
until bubble sensor
321 detects bubble
F Forward (fluid into patient), R= Reverse (fluid from patient), O= Open, C =
Closed
Table 1. Methods of operating system 10 as illustrated in FIGURES 7A-7J
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[0134] FIGURE 7A. illustrates one embodiment of a method of infusing a
patient. In the step of FIGURE 7A, pump 203 is operated forward (pumping
towards the
patient) puinp 328 is off, or stopped, valves 313 and 312 are open, and valves
613a, 613b,
613c, 316, 323a, and 323b are closed. With these operating conditions, fluid
14 is provided
to patient P. In a preferred einbodiment, all of the other passageways at the
time of the step
of FIGURE 7A substantially contain fluid 14.
[0135] The next nine figures (FIGURES 7B-7J) illustrate steps in a method of
sampling from a patient. The following steps are not meaiit to be inclusive of
all of the
steps of sainpling from a patient, and it is understood that alternative
einbodiinents may
include more steps, fewer steps, or a different ordering of steps. FIGURE 7B
illustrates a
first sampling step, where liquid is cleared from a portion of patient
connection passageway
and sampling passageways 112 and 113. In the step of FIGURE 7B, pump 203 is
operated
in reverse (pumping away from the patient), pump 328 is off, valve 313 is
open, one or
more of valves 613a, 613b, and 613c are open, and valves 312, 316, 323a, and
326b are
closed. With these operating conditions, air 701 is drawn into sampling
passageway 113
and back into patient connection passageway 112 until bubble sensor 314b
detects the
presence of the air.
[0136] FIGURE 7C illustrates a second sampling step, where a sample is drawn
from patient P into patient connection passageway 112. In the step of FIGURE
7C, punlp
203 is operated in reverse, pump 328 is off, valves 312 and 313 are open, and
valves 316,
613a, 613b, 613c, 323a, and 323b are closed. Under these operating conditions,
a sample S
is drawn into passageway 112, dividing air 701 into air 701a within sampling
passageway
113 and air 701b within the patient connection passageway 112. Preferably this
step
proceeds until sample S extends just past the junction of passageways 112 and
113. In one
embodiment, the step of FIGURE 7C proceeds until variations in the output of
colorimetric
sensor 311 indicate the presence of a blood (for example by leveling off to a
constant
value), and then proceeds for an additional set amount of time to ensure the
presence of a
sufficient volume of sample S.
[0137] FIGURE 7D illustrates a third sampling step, where a sample is drawn
into sampling passageway 113. In the step of FIGURE 7D, pump 203 is off, or
stopped,
pump 328 is on, valves 312, 316, and 326b are open, and valves 313, 613a,
613b, 613c and
323a are closed. Under these operating conditions, blood is drawn into
passageway 113.
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Preferably, pump 328 is operated to pull a sufficient amount of sample S into
passageway
113. In one embodiment, pump 328 draws a sample S having a volume from 30 to
50
inicroliters. In an alternative embodiment, the sample is drawn into both
passageways 112
and 113. Pump 203 is operated in reverse, pump 328 is on, valves 312, 313,
316, and 323b
are open, and valves 613a, 613b, 613c and 323a are closed to ensure fresh
blood in sample
S.
[0138] FIGURE 7E illustrates a fourth sainpling step, where air is injected
into
the sample. Bubbles which span the cross-sectional area of sampling passageway
113 are
useful in preventing contamination of the sample as it is pumped along
passageway 113. In
the step of FIGURE 7E, pump 203 is off, or stopped, pump 328 is on, valves
316, and 323b
are open , valves 312, 313 and 323a are closed, and valves 613a, 613b, 613c
are each
opened and closed sequentially to draw in three separated bubbles. With these
operating
conditions, the pressure in passageway 113 falls below atmospheric pressure
and air is
drawn into passageway 113. Alternatively, valves 613a, 613b, 613c may be
opened
simultaneously for a sliort period of time, generating three spaced bubbles.
As shown in
FIGURE 7E, injectors 610a, 610b, and 610c inject bubbles 704, 703, and 702,
respectively,
dividing sample S into a forward sample S1, a middle sample S2, and a rear
sample S3.
[0139] FIGURE 7F illustrates a fifth sampling step, where bubbles are cleared
from patient connection passageway 112. In the step of FIGURE 7F, pump 203 is
operated
in a forward direction, pump 328 is off, valves 313, 316, and 323a are open,
and valves
312, 613a, 613b, 613c, and 323b are closed. With these operating conditions,
the
previously injected air 701b is drawn out of first passageway 111 and into
second
passageway 113. This step proceeds until air 701b is in passageway 113.
[0140] FIGURE 7G illustrates a sixth sampling step, where blood in
passageway 112 is returned to the patient. In the step of FIGURE 7G, pump 203
is operated
in a forward direction, pump 328 is off, valves 312 and 313 are open, and
valves 316, 323a,
613a, 613b, 613c and 323b are closed. With these operating conditions, the
previously
injected air remains in passageway 113 and passageway 111 is filled with fluid
14.
[0141] FIGURES 7H and 71 illustrates a seventh and eighth sampling steps,
where the sample is pushed part way into passageway 113 followed by fluid 14
and more
bubbles. In the step of FIGURE 7H, pump 203 is operated in a forward
direction, pump 328
is off, valves 313, 316, and 323a are open, and valves 312, 613a, 613b, 613c,
and 323b are
closed. With these operating conditions, sample S is moved partway into
passageway 113
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with bubbles injected, either sequentially or simultaneously, into fluid 14
from injectors
610a, 610b, and 610c. In the step of FIGURE 71, the pumps and valves are
operated as in
the step of FIGURE 7E, and fluid 14 is divided into a forward solution Cl, a
middle
solution C2, and a rear solution C3 separated by bubbles 705, 706, and 707.
[0142] The last step shown in FIGURE 7 is FIGURE 7J, wliere middle sample
S2 is pushed to sample analysis device 330. In the step of FIGURE 7J, pump 203
is
operated in a forward direction, pump 328 is off, valves 313, 316, and 323a
are open, and
valves 312, 613a, 613b, 613c, and 323b are closed. In this configuration, the
sample is
pushed into passageway 113. When bubble sensor 321 detects bubble 702, pump
203
continues pumping until sample S2 is taken into device sample analysis 330.
Additional
pumping using the settings of the step of FIGURE 7J permits the sainple S2 to
be analyzed
and for additional bubbles and solutions to be pushed into waste receptacle
325, cleansing
passageway 113 prior to accepting a next sample.
SECTION III - SAMPLING SYSTEM
[0143] FIGURE 8 is a perspective front view of a third embodiment of a
sampling system 800 which may be generally similar to sampling system 100, 300
or 500
and the embodiments illustrated in FIGURES 1 through 7, except as further
detailed below.
The fluid handling and analysis apparatus 140 of sampling system 800 includes
the
combination of an instrument 810 and a sampling system cassette 820. FIGURE 8
illustrates instrument 810 and cassette 820 partially removed from each other.
Instrument
810 includes controller 210 (not shown), display 141 and input devices 143, a
cassette
interface 811, and lines 114. Cassette 820 includes passageway 111 which
extends from
connector 120 to connector 230, and further includes passageway 113, a
junction 829 of
passageways 111 and 113, an instrument interface 821, a front surface 823, an
inlet 825 for
passageway 111, and an inlet 827 for passageways 111 and 113. In addition,
sampling
assembly 220 is formed from a sampling assembly instrument portion 813 having
an
opening 815 for accepting junction 829. The interfaces 811 and 821 engage the
components
of instrument 810 and cassette 820 to facilitate pumping fluid and analyzing
samples from a
patient, and sampling assembly instrument portion 813 accepts junction 829 in
opening 815
to provide for sampling from passageway 111.
[0144] FIGURES 9 and 10 are front views of a sampling system cassette 820
and instrument 810, respectively, of a sampling system 800. Cassette 820 and
instrument
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810, when assembled, form various components of FIGURES 9 and 10 that
cooperate to
form an apparatus consisting of sampling unit 510 of FIGURE 5, sampling
assembly 220 of
FIGURE 3, and gas injection manifold 315' of FIGURE 6B.
[0145] More specifically, as shown in FIGURE 9, cassette 820 includes
passageways 20 including: passageway 111 having portions llla, 112a, 112b,
112c, 112d,
112e, and 112f; passageway 113 having portions 113a, 113b, 113c, 113d, 113e,
and 113f;
passageway 615; waste receptacle 325; disposable components of sample analysis
device
330 including, for example, a sample preparation unit 332 adapted to allow
only blood
plasma to pass therethrough and a sample chainber 903 for placement within
analyte
detection system 334 for measuring properties of the blood plasma; and a
displaceinent
pump 905 having a piston control 907.
[0146] As shown in FIGURE 10, instrument 810 includes bubble sensor units
1001a, 1001b, and 1001c, colorimetric sensor, which is a hemoglobin sensor
unit 1003, a
peristaltic pump roller 1005a and a roller support 1005b, pincher pairs 1007a,
1007b,
1007c, 1007d, 1007e, 1007f, 1007g, and 1007h, an actuator 1009, and a pressure
sensor
unit 1011. In addition, instrument 810 includes portions of sample analysis
device 330
which are adapted to measure a sample contained within sample chamber 903 when
located
near or within a probe region 1002 of an optical analyte detection system 334.
[0147] Passageway portions of cassette 820 contact various components of
instrument 810 to form sanlpling system 800. With reference to FIGURE 5 for
example,
pump 203 is formed from portion llla placed between peristaltic pump roller
1005a and
roller support 1005b to move fluid through passageway 111 when the roller is
actuated;
valves 501, 323, 326a, and 326b are formed with pincher pairs 1007a, 1007b,
1007c, and
1007d surrounding portions 113a, 113c, 113d, and 113e, respectively, to permit
or block
fluid flow therethrough. Pmnp 328 is formed from actuator 1009 positioned to
move piston
control 907. It is preferred that the interconnections between the components
of cassette
820 and instrument 810 described in this paragraph are made with one motion.
Thus for
example the placement of interfaces 811 and 821 places the passageways against
and/or
between the sensors, actuators, and other components.
[0148] In addition to placement of interface 811 against interface 821, the
assembly of apparatus 800 includes assembling sampling assembly 220. More
specifically,
an opening 815a and 815b are adapted to receive passageways 111 and 113,
respectively,
with junction 829 within sampling assembly instrument portion 813. Thus, for
example,
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with reference to FIGURE 3, valves 313 and 312 are formed when portions 112b
and 112c
are placed within pinchers of pinch valves 1007e and 1007f, respectively,
bubble sensors
314b and 314a are formed when bubble sensor units 1001b, and 1001c are in
sufficient
contact with portions 112a and 112d, respectively, to determine the presence
of bubbles
therein; hemoglobin detector is formed when hemoglobin sensor 1003 is in
sufficient
contact with portion 112e, and pressure sensor 317 is formed when portion 112f
is in
sufficient contact with pressure sensor unit 1011 to measure the pressure of a
fluid therein.
With reference to FIGURE 6B, valves 316 and 613 are fonned when portions 113f
and 615
are placed within pinchers of pinch valves 1007h and 1007g, respectively.
[0149] In operation, the assembled main instrument 810 and cassette 820 of
FIGURES 9-10 can function as follows. The system can be considered to begin in
an idle
state or infusion mode in which the roller pump 1005 operates in a forward
direction (with
the impeller 1005a turning counterclockwise as shown in FIGURE 10) to pump
infusion
fluid from the container 15 through the passageway 111 and the passageway 112,
toward
and into the patient P. In this infusion mode the pump 1005 delivers infusion
fluid to the
patient at a suitable infusion rate as discussed elsewhere herein.
[0150] When it is time to conduct a measurement, air is first drawn into the
system to clear liquid from a portion of the passageways 112, 113, in a manner
similar to
that shown in FIGURE 7B. Here, the single air injector of FIGURE 9 (extending
from the
junction 829 to end 615, opposite the passageway 813) functions in place of
the manifold
shown in FIGURES 7A-7J. Next, to draw a sample, the pump 1005 operates in a
sample
draw mode, by operating in a reverse direction and pulling a sample of bodily
fluid (e.g.
blood) from the patient into the passageway 112 through the connector 230. The
sample is
drawn up to the hemoglobin sensor 1003, and is preferably drawn until the
output of the
sensor 1003 reaches a desired plateau level indicating the presence of an
undiluted blood
sample in the passageway 112 adjacent the sensor 1003.
[0151] From this point the pumps 905, 1005, valves 1007e, 1007f, 1007g,
1007h, bubble sensors 1001b, 1001c and/or hemoglobin sensor 1003 can be
operated to
move a series of air bubbles and sample-fluid columns into the passageway 113,
in a
manner similar to that shown in FIGURES 7D-7F. The pump 905, in place of the
pump
328, is operable by moving the piston control 907 of the pump 905 in the
appropriate
direction (to the left or right as shown in FIGURES 9-10) with the actuator
1009.
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[0152] Once a portion of the bodily fluid sainple and any desired bubbles have
moved into the passageway 113, the valve 1007h can be closed, and the
remainder of the
initial drawn sainple or volume of bodily fluid in the passageway 112 cail be
returned to the
patient, by operating the pump 1005 in the forward or infusion direction until
the
passageway 112 is again filled with infusion fluid.
[0153] With appropriate operation of the valves 1007a-1007h, and the pump(s)
905 and/or 1005, at least a portion of the bodily fluid sample in the
passageway 113 (which
is 10-100 microliters in volume, or 20, 30, 40, 50 or 60 microliters, in
various
embodiments) is moved through the sample preparation unit 332 (in the depicted
embodiment a filter or membrane; alternatively a centrifuge as discussed in
greater detail
below). Thus, only one or more components of the bodily fluid (e.g., only the
plasma of a
blood sample) passes through the unit 332 or filter/membrane and enters the
sample
chamber or cel1903. Alternatively, where the unit 332 is omitted, the "whole"
fluid moves
into the sample chamber 903 for analysis.
[0154] Once the component(s) or whole fluid is in the sample chamber 903, the
analysis is conducted to determine a level or concentration of one or more
analytes, such as
glucose, lactate, carbon dioxide, blood urea nitrogen, hemoglobin, and/or any
other suitable
analytes as discussed elsewhere herein. Where the analyte detection system
1700 is
spectroscopic (e.g. the system 1700 of FIGURES 17 or 44-46), a spectroscopic
analysis of
the component(s) or whole fluid is conducted.
[0155] After the analysis, the body fluid sample within the passageway 113 is
moved into the waste receptacle 325. Preferably, the pump 905 is operated via
the actuator
1009 to push the body fluid, behind a column of saline or infusion fluid
obtained via the
passageway 909, back through the sample chamber 903 and sample preparation
unit 332,
and into the receptacle 325. Thus, the chamber 903 and unit 332 are back-
flushed and
filled with saline or infusion fluid while the bodily fluid is delivered to
the waste receptacle.
Following this flush a second analysis can be made on the saline or infusion
fluid now in
the chamber 903, to provide a "zero" or background reading. At this point, the
fluid
handling network of FIGURE 9, other than the waste receptacle 325, is empty of
bodily
fluid, and the system is ready to draw another bodily fluid sample for
analysis.
[0156] In some embodiments of the apparatus 140, a pair of pinch valve
pinchers acts to switch flow between one of two branches of a passageway.
FIGURES 13A
and 13B are front view and sectional view, respectively, of a first embodiment
pinch valve
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1300 in an open configuration that can direct flow either one or both of two
branches, or
legs, of a passageway. Pinch valve 1300 includes two separately controllable
pinch valves
acting on a "Y" shaped passageway 1310 to allow switch of fluid between
various legs. In
particular, the internal surface of passageway 1310 forms a first leg 1311
having a flexible
pinch region 1312, a second leg 1313 having a flexible pinch region 1314, and
a third leg
1315 that joins the first and second legs at an intersection 1317. A first
pair of pinch valve
pinchers 1320 is positioned about pinch region 1312 and a second pair of pinch
valve
pinchers 1330 is positioned about pinch region 1314. Each pair of pinch valve
pinchers
1320 and 1330 is positioned on opposite sides of their corresponding pinch
regions 1312,
1314 and perpendicular to passageway 1310, and are individually controllable
by controller
210 to open and close, that is allow or prohibit fluid communication across
the pinch
regions. Thus, for example, when pinch valve pinchers 1320 (or 1330) are
brought
sufficiently close, each part of pinch region 1312 (or 1314) touches another
part of the
pinch region and fluid may not flow across the pinch region.
[0157] As an example of the use of pinch valve 1300, FIGURE 13B shows the
first and second pair of pinch valve pinchers 1320, 1330 in an open
configuration. FIGURE
13C is a sectional view showing the pair of pinch valve pinchers 1320 brought
together,
thus closing off a portion of first leg 1311 from the second and third legs
1313, 1315. In
part as a result of the distance between pinchers 1320 and intersection 1317
there is a
volume 1321 associated with first leg 1311 that is not isolated ("dead
space"). It is
preferred that dead space is minimized so that fluids of different types can
be switched
between the various legs of the pinch valve. In one embodiment, the dead space
is reduced
by placing the placing the pinch valves close to the intersection of the legs.
In another
embodiment, the dead space is reduced by having passageway walls of varying
thickness.
Thus, for example, excess material between the pinch valves and the
intersection will more
effectively isolate a valved leg by displacing a portion of volume 1321.
[0158] As an example of the use of pinch valve 1300 in sampling system 300,
pinchers 1320 and 1330 are positioned to act as valve 323 and 326,
respectively.
[0159] FIGURES 14A and 14B are various views of a second embodiment
pinch valve 1400, where FIGURE 14A is a front view and FIGURE 14B is a
sectional view
showing one valve in a closed position. Pinch valve 1400 differs from pinch
valve 1300 in
that the pairs of pinch valve pinchers 1320 and 1330 are replaced by pinchers
1420 and
1430, respectively, that are aligned with passageway 1310.
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[0160] Alternative embodiment of pinch valves includes 2, 3, 4, or more
passageway segments that meet at a common junction, with pinchers located at
one or more
passageways near the junction.
[0161] FIGURES 11 and 12 illustrate various embodiment of coimector 230
which may also form or be attached to disposable portions of cassette 820 as
one
einbodiment of an arterial patient connector 1100 and one embodiment a venous
patient
connector 1200. Connectors 1100 and 1200 may be generally similar to the
embodiment
illustrated in FIGURES 1-10, except as further detailed below.
[0162] As shown in FIGURE 11, arterial patient connector 1100 includes a
stopcock 1101, a first tube portion 1103 having a length X, a blood sampling
port 1105 to
acquire blood samples for laboratory analysis, and fluid handling and analysis
apparatus
140, a second tube 1107 having a length Y, and a tube connector 1109. Arterial
patient
connector 1100 also includes a pressure sensor unit 1102 that is generally
similar to
pressure sensor unit 1011, on the opposite side of sampling assembly 220.
Length X is
preferably from to 6 inches (0.15 meters) to 50 inches (1.27 meters) or
approximately 48
inches (1.2 meters) in length. Length Y is preferably from 1 inch (25
millimeters) to 20
inches (0.5 meters), or approximately 12 inches (0.3 meters) in length. As
shown in
FIGURE 12, venous patient connector 1200 includes a clamp 1201, injection port
1105,
and tube connector 1109.
SECTION IV - SAMPLE ANALYSIS SYSTEM
[0163] In several embodiments, analysis is performed on blood plasma. For
such embodiments, the blood plasma must be separated from the whole blood
obtained
from the patient. In general, blood plasma may be obtained from whole blood at
any point
in fluid handling systein 10 between when the blood is drawn, for example at
patient
connector 110 or along passageway 113, and when it is analyzed. For systems
where
measurements are preformed on whole blood, it may not be necessary to separate
the blood
at the point of or before the measurements is perform.ed.
[0164] For illustrative pur.poses, this section describes several embodiments
of
separators and analyte detection systems which may form part of system 10. The
separators
discussed in the present specification can, in certain embodiments, comprise
fluid
component separators. As used herein, the term "fluid component separator" is
a broad
term and is used in its ordinary sense and includes, without limitation, any
device that is
operable to separate one or more components of a fluid to generate two or more
unlike
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substances. For example, a fluid component separator can be operable to
separate a sample
of whole blood into plasma and non-plasma components, and/or to separate a
solid-liquid
mix (e.g. a solids-contaminated liquid) into solid and liquid components. A
fluid
component separator need not achieve complete separation between or among the
generated
unlike substances. Examples of fluid component separators include filters,
membranes,
centrifuges, electrolytic devices, or components of any of the foregoing.
Fluid component
separators can be "active" in that they are operable to separate a fluid more
quickly than is
possible through the action of gravity on a static, "standing" fluid. Section
IV.A below
discloses a filter which can be used as a blood separator in certain
embodiments of the
apparatus disclosed herein. Section IV.B below discloses an analyte detection
systein
which can be used in certain embodiments of the apparatus disclosed herein.
Section IV.C
below discloses a sainple element which can be used in certain embodiments of
the
apparatus disclosed herein. Section IV.D below discloses a centrifuge and
sample chamber
which can be used in certain embodiments of the apparatus disclosed herein.
SECTION IV.A - BLOOD FILTER
[0165] Without limitation as to the scope of the present invention, one
embodiment of sample preparation unit 332 is shown as a blood filter 1500, as
illustrated in
FIGURES 15 and 16, where FIGURE 15 is a side view of one embodiment of a
filter, and
FIGURE 16 is an exploded perspective view of the filter.
[0166] As shown in the embodiment of FIGURE 15, filter 1500 that includes a
housing 1501 with an inlet 1503, a first outlet 1505 and a second outlet 1507.
Housing
1501 contains a membrane 1509 that divides the internal volume of housing 1501
into a
first volume 1502 that include inlet 1503 and first outlet 1505 and a second
volume 1504.
FIGURE 16 shows one einbodiment of filter 1500 as including a first plate 1511
having
inlet 1503 and outlet 1505, a first spacer 1513 having an opening forming
first volume
1502, a second spacer 1515 having an opening forming second volume 1504, and a
second
plate 1517 having outlet 1507.
[0167] Filter 1500 provides for a continuous filtering of blood plasma from
whole blood. Thus, for example, when a flow of whole blood is provided at
inlet 1503 and
a slight vacuum is applied to the second volume 1504 side of membrane 1509,
the
membrane filters blood cells and blood plasma passes through second outlet
1507.
Preferably, there is transverse blood flow across the surface of membrane 1509
to prevent
blood cells from clogging filter 1500. Accordingly, in one embodiment of the
inlet 1503
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and first outlet 1505 may be configured to provide the transverse flow across
membrane
1509.
[0168] In one embodiment, membrane 1509 is a thin and strong polyiner film.
For example, the membrane filter may be a 10 micron thick polyester or
polycarbonate
film. Preferably, the membrane filter has a smooth glass-like surface, and the
holes are
uniform, precisely sized, and clearly defined. The material of the film may be
chemically
inert and have low protein binding characteristics.
[0169] One way to manufacture membrane 1509 is with a Track Etching
process. Preferably, the "raw" film is exposed to charged particles in a
nuclear reactor,
which leaves "tracks" in the film. The tracks may then be etched through the
film, which
results in holes that are precisely sized and unifonnly cylindrical. For
example, GE
Osmonics, Inc. (4636 Somerton Rd. Trevose, PA 19053-6783) utilizes a similar
process to
manufacture a material that adequately serves as the membrane filter. The
surface the
membrane filter depicted above is a GE Osmonics Polycarbonate TE film.
[0170] As one example of the use of filter 1500, the plasma from 3 cc of blood
may be extracted using a polycarbonate track etch film ("PCTE") as the
membrane filter.
The PCTE may have a pore size of 2[tm and an effective area of 170
millimeter2.
Preferably, the tubing coimected to the supply, exhaust and plasma ports has
an internal
diameter of 1 millimeter. Tn one embodiment of a method employed with this
configuration,
100 gl of plasma can be initially extracted from the blood. After saline is
used to rinse the
supply side of the cell, another 100 l of clear plasma can be extracted. The
rate of plasma
extraction in this method and configuration can be about 15-25 g1/min.
[0171] Using a continuous flow mechanism to extract plasma may provide
several benefits. In one preferred embodiment, the continuous flow mechanism
is reusable
with multiple samples, and there is negligible sample carryover to contaminate
subsequent
samples. One embodiment may also eliminate most situations in which plugging
may
occur. Additionally, a preferred configuration provides for a low internal
volume.
[0172] Additional information on filters, methods of use thereof, and related
technologies may be found in U.S. Patent Application Publication No.
2005/0038357,
published on February 17, 2005, titled SAMPLE ELEMENT WITH BARRIER
MATERIAL; and U.S. Patent Application No. 11/122,794, filed on May 5, 2005,
titled
SAMPLE ELEMENT WITH SEPARATOR. The entire contents of the above noted
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publication and patent application are hereby incorporated by reference herein
and made a
part of this specification.
SECTION IV.B - ANALYTE DETECTION SYSTEM
[0173] One embodiment of analyte detection system 334, which is not meant to
limit the scope of the present invention, is shown in FIGURE 17 as an optical
analyte
detection system 1700. Analyte detection system 1700 is adapted to measure
spectra of
blood plasma. The blood plasma provided to analyte detection system 334 may be
provided
by sainple preparation unit 332, including but not limited to a filter 1500.
[0174] Analyte detection system 1700 comprises an energy source 1720
disposed along a major axis X of system 1700. When activated, the energy
source 1720
generates an energy beam E which advances from the energy source 1720 along
the major
axis X. In one embodiment, the energy source 1720 comprises an infrared source
and the
energy beam E comprises an infrared energy beam.
[0175] The energy beam E passes through an optical filter 1725 also situated
on
the major axis X, before reaching a probe region 1710. Probe region 1710 is
portion of
apparatus 322 in the path of an energized beam E that is adapted to accept a
material
sample S. In one embodiinent, as shown in FIGURE 17, probe region 1710 is
adapted to
accept a sample element or cuvette 1730, which supports or contains the
material sample S.
In one embodiment of the present invention, sample element 1730 is a portion
of
passageway 113, such as a tube or an optical cell. After passing through the
sample element
1730 and the sample S, the energy beam E reaches a detector 1745.
[0176] As used herein, "sample element" is a broad term and is used in its
ordinary sense and includes, without limitation, structures that have a sample
chamber and
at least one sample chamber wall, but more generally includes any of a number
of structures
that can hold, support or contain a material sample and that allow
electromagnetic radiation
to pass through a sample held, supported or contained thereby; e.g., a
cuvette, test strip, etc.
[0177] In one embodiment of the present invention, sample element 1730 forms
a disposable portion of cassette 820, and the remaining portions of system
1700 form
portions of instrument 810, and probe region 1710 is probe region 1002.
[0178] With further reference to FIGURE 17, the detector 1745 responds to
radiation incident thereon by generating an electrical signal and passing the
signal to
processor 210 for analysis. Based on the signal(s) passed to it by the
detector 1745, the
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processor computes the concentration of the analyte(s) of interest in the
sample S, and/or
the absorbance/transmittance characteristics of the sample S at one or more
wavelengths or
wavelength bands employed to analyze the sample. The processor 210 computes
the
concentration(s), absorbance(s), transmittance(s), etc. by executing a data
processing
algorithm or program instructions residing within memory 212 accessible by the
processor
210.
[0179] In the embodiment shown in FIGURE 17, the filter 1725 may comprise a
varying-passband filter, to facilitate changing, over time and/or during a
measurement taken
with apparatus 322, the wavelength or wavelength band of the energy beam E
that may pass
the filter 1725 for use in analyzing the sample S. (In various other
einbodiments, the filter
1725 may be omitted altogether.) Some examples of a varying-passband filter
usable with
apparatus 322 include, but are not limited to, a filter wheel (discussed in
further detail
below), an electronically tunable filter, such as those manufactured by Aegis
Semiconductor (Woburn, MA), a custom filter using an "Active Thin Films
platforin," a
Fabry-Perot interferometer, such as those inanufactured by Scientific
Solutions, Inc. (North
Chelmsford, MA), a custom liquid crystal Fabry-Perot (LCFP) Tunable Filter, or
a tunable
monochrometer, such as a HORIBA (Jobin Yvon, Inc. (Edison, NJ) H1034 type with
7-10
m grating, or a custom designed system.
[0180] In one embodiment detection system 1700, filter 1725 comprises a
varying-passband filter, to facilitate changing, over time and/or during a
measureinent taken
with the detection systein 1700, the wavelength or wavelength band of the
energy beam E
that may pass the filter 25 for use in analyzing the sample S. When the energy
beam E is
filtered with a varying-passband filter, the absorption/transmittance
characteristics of the
sample S can be analyzed at a number of wavelengths or wavelength bands in a
separate,
sequential manner. As an example, assume that it is desired to analyze the
sample S at N
separate wavelengths (Wavelength 1 through Wavelength N). The varying-passband
filter is
first operated or tuned to permit the energy beam E to pass at Wavelength 1,
while
substantially blocking the beam E at most or all other wavelengths to which
the detector
1745 is sensitive (including Wavelengths 2-N). The absorption/transmittance
properties of
the sample S are then measured at Wavelength 1, based on the beam E that
passes through
the sample S and reaches the detector 1745. The varying-passband filter is
then operated or
tuned to permit the energy beam E to pass at Wavelength 2, while substantially
blocking
other wavelengths as discussed above; the sample S is then analyzed at
Wavelength 2 as
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was done at Wavelength 1. This process is repeated until all of the
wavelengths of interest
have been einployed to aiialyze the sample S. The collected
absorption/transmittance data
can then be analyzed by the processor 210 to determine the concentration of
the analyte(s)
of interest in the material sample S. The measured spectra of sample S is
referred to herein
in general as Cs(2~1;), that is, a wavelengtll dependent spectra in which CS
is, for example, a
transmittance, an absorbance, an optical density, or some other measure of the
optical
properties of sample S having values at or about a number of wavelengths Xi,
where i
ranges over the number of measurements taken. The measurement Cs(Xi) is a
linear array of
measurements that is alternatively written as Csi.
[0181] The spectral region of system 1700 depends on the analysis technique
and the analyte and mixtures of interest. For example, one useful spectral
region for the
measurement of glucose in blood using absorption spectroscopy is the inid-IR
(for exainple,
about 4 microns to about 11 microns). In one embodiment system 1700, energy
source 1720
produces a beam E having an output in the range of about 4 microns to about 11
microns.
Although water is the main contributor to the total absorption across this
spectral region,
the peaks and other structures present in the blood spectrum from about 6.8
microns to 10.5
microns are due to the absorption spectra of other blood components. The 4 to
11 micron
region has been found advantageous because glucose has a strong absorption
peak structure
from about 8.5 to 10 microns, whereas most other blood constituents have a low
and flat
absorption spectrum in the 8.5 to 10 micron range. The main exceptions are
water and
hemoglobin, both of which are interferents in this region.
[0182] The amount of spectral detail provided by system 1700 depends on the
analysis technique and the analyte and mixture of interest. For example, the
measurement
of glucose in blood by mid-IR absorption spectroscopy is accomplished with
from 11 to 25
filters within a spectral region. In one embodiment system 1700, energy source
1720
produces a beam E having an output in the range of about 4 microns to about 11
microns,
and filter 1725 include a number of narrow band filters within this range,
each allowing
only energy of a certain wavelength or wavelength band to pass therethrough.
Thus, for
example, one embodiment filter 1725 includes a filter wheel having 11 filters
with a
nominal wavelength approximately equal to one of the following: 3 gm, 4.06 m,
4.6 m,
4.9 m, 5.25 m, 6.12 m, 6.47 m, 7.98 m, 8.35 m, 9.65 m, and 12.2 m.
[0183] In one embodiment, individual infrared filters of the filter wheel are
multi-cavity, narrow band dielectric stacks on germanium or sapphire
substrates,
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manufactured by either OCLI (JDS Uniphase, San Jose, CA) or Spectrogon US,
Inc.
(Parsippany, NJ). Thus, for example, each filter may nominally be 1 millimeter
thick and 10
millimeter square. The peak transmission of the filter stack is typically
between 50% and
70%, and the bandwidths are typically between 150 nm and 350 nni with center
wavelengths between 4 and 10 in. Alternatively, a second blocking IR filter is
also
provided in front of the individual filters. The teinperature sensitivity is
preferably <0.01 %
per degree C to assist in maintaining nearly constant measurements over
enviromnental
conditions.
[0184] In one embodiment, the detection system 1700 computes an analyte
concentration reading by first measuring the electromagnetic radiation
detected by the
detector 1745 at each center wavelength, or wavelength band, without the
sample eleinent
1730 present on the major axis X (this is known as an "air" reading). Second,
the system
1700 measures the electromagnetic radiation detected by the detector 1745 for
each center
wavelength, or wavelength band, with the material sample S present in the
sample element
1730, and the sample element and sample S in position on the major axis X
(i.e., a "wet"
reading). Finally, the processor 210 computes the concentration(s),
absorbance(s) and/or
transmittances relating to the sample S based on these compiled readings.
[0185] In one embodiment, the plurality of air and wet readings are used to
generate a pathlength corrected spectrum as follows. First, the measurements
are
norinalized to give the transmission of the sample at each wavelength. Using
both a signal
and reference measurement at each wavelength, and letting S; represent the
signal of
detector 1745 at wavelength i and R; represent the signal of the detector at
wavelength i, the
transmittance, T; at wavelength i may computed as Ti = S;(wet) / S;(air).
Optionally, the
spectra may be calculated as the optical density, OD;, as - Log(T;). Next, the
transmission
over the wavelength range of approximately 4.5 m to approximately 5.5 m is
analyzed to
determine the pathlength. Specifically, since water is the primary absorbing
species of
blood over this wavelength region, and since the optical density is the
product of the optical
pathlength and the known absorption coefficient of water (OD = L (7, where L
is the optical
pathlength and 6 is the absorption coefficient), any one of a number of
standard curve
fitting procedures may be used to determine the optical pathlength, L from the
measured
OD. The pathlength may then be used to determine the absorption coefficient of
the sample
at each wavelength. Alternatively, the optical pathlength may be used in
further calculations
to convert absorption coefficients to optical density.
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[0186] Blood samples may be prepared and analyzed by system 1700 in a
variety of configurations. In one embodiment, sample S is obtained by drawing
blood,
either using a syringe or as part of a blood flow system, and transferring the
blood into
sample chamber 903. In another embodiment, sample S is drawn into a sample
container
that is a sample chamber 903 adapted for insertion into system 1700.
[0187] FIGURE 44 depicts another embodiment of the analyte detection system
1700, which may be generally similar to the embodiment illustrated in FIGURE
17, except
as further detailed below. Where possible, similar elements are identified
with identical
reference numerals in the depiction of the embodiments of FIGURES 17 and 44.
[0188] The detection system 1700 shown in FIGURE 44 includes a collimator
30 located between source 1720 and filter 1725 and a beam sampling optics 90
between the
filter and sample element 1730. Filter 1725 includes a primary filter 40 and a
filter wheel
assembly 4420 which can insert one of a plurality of optical filters into
energy beam E.
System 1700 also includes a sample detector 150 may be generally similar to
sample
detector 1725, except as further detailed below.
[0189] As shown in FIGURE 44, energy beam E from source 1720 passes
through collimator 30 through which the before reaching a primary optical
filter 40 which is
disposed downstream of a wide end 36 of the collimator 30. Filter 1725 is
aligned with the
source 1720 and collimator 30 on the major axis X and is preferably configured
to operate
as a broadband filter, allowing only a selected band, e.g. between about 2.5
m and about
12.5 m, of wavelengths emitted by the source 1720 to pass therethrough, as
discussed
below. In one embodiment, the energy source 1720 comprises an infrared source
and the
energy beam E comprises an infrared energy beam. One suitable energy source
1720 is the
TOMA TECH TM IR-50 available from HawkEye Technologies of Milford,
Connecticut.
[0190] With further reference to FIGURE 44, primary filter 40 is mounted in a
mask 44 so that only those portions of the energy beam E which are incident on
the primary
filter 40 can pass the plane of the mask-primary filter assembly. The primary
filter 40 is
generally centered on and oriented orthogonal to the major axis X and is
preferably circular
(in a plane orthogonal to the major axis X) with a diameter of about 8 mm. Of
course, any
other suitable size or shape may be employed. As discussed above, the primary
filter 40
preferably operates as a broadband filter. In the illustrated embodiment, the
primary filter
40 preferably allows only energy wavelengths between about 4 m and about 11
m to pass
therethrough. However, other ranges of wavelengths can be selected. The
primary filter 40
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advantageously reduces the filtering burden of secondary optical filter(s) 60
disposed
downstream of the primary filter 40 and improves the rejection of
electromagnetic radiation
having a wavelength outside of the desired wavelength band. Additionally, the
primary
filter 40 can help minimize the heating of the secondary filter(s) 60 by the
energy beam E
passing therethrough. Despite these advantages, the primary filter 40 and/or
mask 44 may
be omitted in alternative enibodiments of the system 1700 shown in FIGURE 44.
[0191] The primary filter 40 is preferably configured to substantially
maintain
its operating characteristics (center wavelength, passband width) where some
or all of the
energy beam E deviates from normal incidence by a cone angle of up to about
twelve
degrees relative to the major axis X. In further embodiments, this cone angle
may be up to
about 15 to 35 degrees, or from about 15 degrees or 20 degrees. The primary
filter 40 may
be said to "substantially maintain" its operating characteristics where any
changes therein
are insufficient to affect the performance or operation of the detection
system 1700 in a
manner that would raise significant concerns for the user(s) of the system in
the context in
which the system 1700 is employed.
[0192] In the embodiment illustrated in FIGURE 44, filter wheel assembly 4420
includes an optical filter wheel 50 and a stepper motor 70 connected to the
filter wheel and
configured to generate a force to rotate the filter wheel 50. Additionally, a
position sensor
80 is disposed over a portion of the circumference of the filter wheel 50 and
may be
configured to detect the angular position of the filter wheel 50 and to
generate a
corresponding filter wheel position signal, thereby indicating which filter is
in position on
the major axis X. Alternatively, the stepper motor 70 may be configured to
track or count
its own rotation(s), thereby tracking the angular position of the filter
wheel, and pass a
corresponding position signal to the processor 210. Two suitable position
sensors are
models EE-SPX302-W2A and EE-SPX402-W2A available from Omron Corporation of
Kyoto, Japan.
[0193] Optical filter wheel 50 is employed as a varying-passband filter, to
selectively position the secondary filter(s) 60 on the major axis X and/or in
the energy beam
E. The filter wheel 50 can therefore selectively tune the wavelength(s) of the
energy beam E
downstream of the wheel 50. These wavelength(s) vary according to the
characteristics of
the secondary filter(s) 60 mounted in the filter wheel 50. The filter wheel 50
positions the
secondary filter(s) 60 in the energy beam E in a "one-at-a-time" fashion to
sequentially
vary, as discussed above, the wavelengths or wavelength bands employed to
analyze the
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material sample S. An alternative to filter wheel 50 is a linear filter
translated by a motor
(not shown). The linear filter may be, for example, a linear array of separate
filters or a
single filter with filter properties that change in a linear dimension.
[0194] In alternative arrangements, the single primary filter 40 depicted in
FIGURE 44 may be replaced or supplemented with additional primary filters
mounted on
the filter wheel 50 upstream of each of the secondary filters 60. As yet
another alternative,
the primary filter 40 could be iinplemented as a primary filter wheel (not
shown) to position
different primary filters on the major axis X at different times during
operation of the
detection system 1700, or as a tunable filter.
[0195] The filter wheel 50, in the embodiment depicted in FIGURE 45, can
comprise a wheel body 52 and a plurality of secondary filters 60 disposed on
the body 52,
the center of each filter being equidistant from a rotational center RC of the
wheel body.
The filter wheel 50 is configured to rotate about an axis which is (i)
parallel to the major
axis X and (ii) spaced from the major axis X by an orthogonal distance
approximately equal
to the distance between the rotational center RC and any of the center(s) of
the secondary
filter(s) 60. Under this arrangement, rotation of the wheel body 52 advances
each of the
filters sequentially through the major axis X, so as to act upon the energy
beam E.
However, depending on the analyte(s) of interest or desired measurement speed,
only a
subset of the filters on the wheel 50 may be employed in a given measureinent
run. A home
position notch 54 may be provided to indicate the home position of the wheel
50 to a
position sensor 80.
[0196] In one embodiment, the wheel body 52 can be formed from molded
plastic, with each of the secondary filters 60 having, for example a thickness
of 1 mm and a
mm x 10 mm or a 5 mm x 5 mm square configuration. Each of the filters 60, in
this
embodiment of the wheel body, is axially aligned with a circular aperture of 4
mm
diameter, and the aperture centers define a circle of about 1.70 inches
diameter, which
circle is concentric with the wheel body 52. The body 52 itself is circular,
with an outside
diameter of 2.00 inches.
[0197} Each of the secondary filter(s) 60 is preferably configured to operate
as a
narrow band filter, allowing only a selected energy wavelength or wavelength
band (i.e., a
filtered energy beam (Ef) to pass therethrough. As the filter wheel 50 rotates
about its
rotational center RC, each of the secondary filter(s) 60 is, in turn, disposed
along the major
axis X for a selected dwell time corresponding to each of the secondary
filter(s) 60.
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[0198] The "dwell time" for a given secondary filter 60 is the time interval,
in
an individual measurenient run of the system 1700, during which botli of the
following
conditions are true: (i) the filter is disposed on the major axis X; and (ii)
the source 1720 is
energized. The dwell time for a given filter may be greater than or equal to
the time during
which the filter is disposed on the major axis X during an individual
measurement run. In
one embodiment of the analyte detection systenz 1700, the dwell time
corresponding to each
of the secondary filter(s) 60 is less than about 1 second. However, the
secondary filter(s) 60
can have other dwell times, and each of the filter(s) 60 may have a different
dwell time
during a given measureinent run.
[0199] From the secondary filter 60, the filtered energy beam (Ef) passes
through a beam sampling optics 90, which includes a beam splitter 4400
disposed along the
major axis X and having a face 4400a disposed at an included angle relative
to the major
axis X. The splitter 4400 preferably separates the filtered energy beam (Ef)
into a sample
beam (Es) and a reference beam (Er).
[0200] With further reference to FIGURE 44, the sample beam (Es) passes next
through a first lens 4410 aligned with the splitter 4400 along the major axis
X. The first
lens 4410 is configured to focus the sample beam (Es) generally along the axis
X onto the
material sample S. The sample S is preferably disposed in a sainple element
1730 between
a first window 122 and a second window 124 of the sainple element 1730. The
sample
element 1730 is further preferably removably disposed in a holder 4430, and
the holder
4430 has a first opening 132 and a second opening 134 configured for alignment
with the
first window 122 and second window 124, respectively. Alternatively, the
sainple element
1730 and sample S may be disposed on the major axis X without use of the
holder 4430.
[0201] At least a fraction of the sample beam (Es) is transmitted through the
sample S and continues onto a second lens 4440 disposed along the major axis
X. The
second lens 4440 is configured to focus the sample beam (Es) onto a sample
detector 150,
thus increasing the flux density of the sample beam (Es) incident upon the
sample detector
150. The sample detector 150 is configured to generate a signal corresponding
to the
detected sample beam (Es) and to pass the signal to a processor 210, as
discussed in more
detail below.
[0202] Beam sampling optics 90 further includes a third lens 160 and a
reference detector 170. The reference beam (Er) is directed by beam sampling
optics 90
from the beam splitter 4400 to a,-third lens 160 disposed along a minor axis Y
generally
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orthogonal to the major axis X. The third lens 160 is configured to focus the
reference beam
(Er) onto reference detector 170, thus increasing the flux density of the
reference beam (Er)
incident upon the reference detector 170. In one embodiment, the lenses 4410,
4440, 160
may be fornled from a material whicli is highly transmissive of infrared
radiation, for
example gennanium or silicoii. In addition, any of the lenses 4410, 4440 and
160 may be
implemented as a system of lenses, depending on the desired optical
performance. The
reference detector 170 is also configured to generate a signal corresponding
to the detected
reference beain (Er) and to pass the signal to the processor 210, as discussed
in more detail
below. Except as noted below, the sample and reference detectors 150, 170 may
be
generally similar to the detector 1745 illustrated in FIGURE 17. Based on
signals received
from the sample and reference detectors 150, 170, the processor 210 computes
the
concentration(s), absorbance(s), transmittance(s), etc. relating to the sample
S by executing
a data processing algorithm or program instructions residing within the memory
212
accessible by the processor 210.
[0203] In further variations of the detection system 1700 depicted in FIGURE
44, beam sampling optics 90, including the beain splitter 4400, reference
detector 170 and
other structures on the minor axis Y may be omitted, especially where the
output intensity
of the source 1720 is sufficiently stable to obviate any need to reference the
source intensity
in operation of the detection system 1700. Thus, for example, sufficient
signals may be
generated by detectors 170 and 150 with one or more of lenses 4410, 4440, 160
omitted.
Furthermore, in any of the embodiments of the analyte detection system 1700
disclosed
herein, the processor 210 and/or memory 212 may reside partially or wholly in
a standard
personal computer ("PC") coupled to the detection system 1700.
[0204] FIGURE 46 depicts a partial cross-sectional view of another
embodiment of an analyte detection system 1700, which may be generally similar
to any of
the embodiments illustrated in FIGURES 17, 44, and 45, except as further
detailed below.
Where possible, similar elements are identified with identical reference
numerals in the
depiction of the embodiments of FIGURES 17, 44, and 45.
[0205] The energy source 1720 of the embodiment of FIGURE 46 preferably
comprises an emitter area 22 which is substantially centered on the major axis
X. In one
embodiment, the emitter area 22 may be square in shape. However the emitter
area 22 can
have other suitable shapes, such as rectangular, circular, elliptical, etc.
One suitable emitter
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area 22 is a square of about 1.5 mm on a side; of course, any other suitable
shape or
'~ :=. "te
dimensions may be employed.
[0206] The energy source 1720 is preferably configured to selectably operate
at
a modulation frequency between about 1 Hz and 30 Hz and have a peak operating
temperature of between about 1070 degrees Kelvin and 1170 degrees Kelvin.
Additionally,
the source 1720 preferably operates with a modulation depth greater than about
80% at all
modulation frequencies. The energy source 1720 preferably emits
electromagnetic radiation
in any of a nuinber of spectral ranges, e.g., within infrared wavelengths; in
the mid-infrared
wavelengths; above about 0.8 m; between about 5.0 in and about 20.0 m;
and/or
between about 5.25 m and about 12.0 m. However, in other embodiments, the
detection
system 1700 may einploy an energy source 1720 which is unmodulated and/or
which emits
in wavelengths found anywhere from the visible spectrum through the microwave
spectrum, for example anywhere from about 0.4 m to greater than about 100 m.
In still
other embodiments, the energy source 1720 can emit electromagnetic radiation
in
wavelengths between about 3.5 m and about 14 m, or between about 0.8 g.m and
about
2.5 m, or between about 2.5 in and 20 m, or between about 20 m and about
100 in,
or between about 6.85 m and about 10.10 m. In yet other embodiments, the
energy
source 1720 can emit electromagnetic radiation within the radio frequency (RF)
range or
the terahertz range. All of the above-recited operating characteristics are
merely exemplary,
and the source 1720 may have any operating characteristics suitable for use
with the analyte
detection system 1700.
[0207] A power supply (not shown) for the energy source 1720 is preferably
configured to selectably operate with a duty cycle of between about 30% and
about 70%.
Additionally, the power supply is preferably configured to selectably operate
at a
modulation frequency of about 10Hz, or between about 1 Hz and about 30 Hz. The
operation of the power supply can be in the form of a square wave, a sine
wave, or any
other waveform defined by a user.
[0208] With further reference to FIGURE 46, the collimator 30 comprises a
tube 30a with one or more highly-reflective inner surfaces 32 which diverge
from a
relatively narrow upstream end 34 to a relatively wide downstream end 36 as
they extend
downstream, away from the energy source 1720. The narrow end 34 defines an
upstream
aperture 34a which is situated adjacent the emitter area 22 and permits
radiation generated
by the emitter area to propagate downstream into the collimator. The wide end
36 defines a
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downstreain aperture 36a. Like the emitter area 22, each of the inner
surface(s) 32,
upstream aperture 34a and downstream aperture 36a is preferably substantially
centered on
the major axis X.
[0209] As illustrated in FIGURE 46, the iimer surface(s) 32 of the collimator
may have a generally curved shape, such as a parabolic, hyperbolic, elliptical
or spherical
shape. One suitable collimator 30 is a compound parabolic concentrator (CPC).
In one
embodiment, the collimator 30 can be up to about 20 inm in length. In another
embodiment,
the collimator 30 can be up to about 30 mm in length. However, the collimator
30 can have
any length, and the inner surface(s) 32 may have any shape, suitable for use
with the analyte
detection system 1700.
[0210] The inner surfaces 32 of the collimator 30 cause the rays making up the
energy beam E to straighten (i.e., propagate at angles increasingly parallel
to the major axis
X) as the beam E advances downstream, so that the energy beam E becoines
increasingly or
substantially cylindrical and oriented substantially parallel to the major
axis X.
Accordingly, the inner surfaces 32 are highly reflective and minimally
absorptive in the
wavelengths of interest, such as infrared wavelengths.
[02111 The tube 30a itself may be fabricated from a rigid material such as
aluminum, steel, or any other suitable material, as long as the inner surfaces
32 are coated
or otherwise treated to be highly reflective in the wavelengths of interest.
For example, a
polished gold coating may be employed. Preferably, the inner surface(s) 32 of
the
collimator 30 define a circular cross-section when viewed orthogonal to the
major axis X;
however, other cross-sectional shapes, such as a square or other polygonal
shapes, parabolic
or elliptical shapes may be employed in alternative embodiments.
[0212] As noted above, the filter wheel 50 shown in FIGURE 46 comprises a
plurality of secondary filters 60 which preferably operate as narrow band
filters, each filter
allowing only energy of a certain wavelength or wavelength band to pass
therethrough. In
one configuration suitable for detection of glucose in a sample S, the filter
wheel 50
comprises twenty or twenty-two secondary filters 60, each of which is
configured to allow a
filtered energy beam (Ef) to travel therethrough with a nominal wavelength
approximately
equal to one of the following: 3 m, 4.06 m, 4.6 m, 4.9 m, 5.25 m, 6.12
m, 6.47 m,
7.98 m, 8.35 m, 9.65 m, and 12.2 .m. (Moreover, this set of wavelengths
may be
employed with or in any of the embodiments of the analyte detection system
1700 disclosed
herein.) Each secondary filter's 60 center wavelength is preferably equal to
the desired
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nominal wavelength plus or minus about 2%. Additionally, the secondary filters
60 are
preferably configured to have a bandwidth of about 0.2 m, or alternatively
equal to the
nominal wavelength plus or minus about 2%-10%.
[0213] In another embodiment, the filter wheel 50 comprises twenty secondary
filters 60, eacll of wliich is configured to allow a filtered energy beam (Ef)
to travel
therethrough with a nominal center wavelengths of: 4.275 m, 4.5 .m, 4.7 m,
5.0 m, 5.3
m, 6.056 m, 7.15 in, 7.3 in, 7.55 gm, 7.67 m, 8.06 m, 8.4 m, 8.56 m,
8.87 m,
9.15 in, 9.27 m, 9.48 m, 9.68 m, 9.82 m, and 10.06 m. (This set of
wavelengths
may also be einployed with or in any of the embodiments of the analyte
detection system
1700 disclosed herein.) In still another embodiment, the secondary filters 60
may conform
to any one or combination of the following specifications: center wavelength
tolerance of
0.01 m; half-power bandwidth tolerance of 0.01 m; peak transmission
greater than or
equal to 75%; cut-on/cut-off slope less than 2%; center-wavelength temperature
coefficient
less than .01 % per degree Celsius; out of band attenuation greater than OD 5
from 3 m to
12 m; flatness less than 1.0 waves at 0.6328 gm; surface quality of E-E per
Mil-F-48616;
and overall thickness of about 1 mm.
[0214) In still another embodiment, the secondary filters mentioned above may
conform to any one or combination of the following half-power bandwidth
("HPBW")
specifications:
Center Wavelength HPBW Center Wavelength HPBW
( m) ( m) ( .m) ( m)
4.275 0.05 8.06 0.3
4.5 0.18 8.4 0.2
4.7 0.13 8.56 0.18
5.0 0.1 8.87 0.2
5.3 0.13 9.15 0.15
6.056 0.135 9.27 0.14
7.15 0.19 9.48 0.23
7.3 0.19 9.68 0.3
7.55 0.18 9.82 0.34
7.67 0.197 10.06 0.2
[0215] In still further embodiments, the secondary filters may have a center
wavelength tolerance of 0.5 % and a half-power bandwidth tolerance of iz
0.02 m.
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[0216] Of course, the number of secondary filters employed, and the center
wavelengths and other characteristics thereof, may vary in fiu-ther
embodiments of thd'
systein 1700, whether such further embodiments are employed to detect glucose,
or other
analytes instead of or in addition to glucose. For example, in another
embodiment, the filter
wheel 50 can have fewer than fifty secondary filters 60. In still another
embodiment, the
filter whee150 can have fewer than twenty secondary filters 60. In yet another
embodiment,
the filter wheel 50 can have fewer than ten secondary filters 60.
[0217] In one embodiment, the secondary filters 60 each measure about 10 mm
long by 10 min wide in a plane orthogonal to the major axis X, with a
thickness of about 1
mm. However, the secondary filters 60 can have any other (e.g., smaller)
dimensions
suitable for operation of the analyte detection system 1700. Additionally, the
secondary
filters 60 are preferably configured to operate at a temperature of between
about 5 C and
about 35 C and to allow transmission of more than about 75% of the energy
beam E
therethrough in the wavelength(s) which the filter is configured to pass.
[0218] According to the embodiment illustrated in FIGURE 46, the primary
filter 40 operates as a broadband filter and the secondary filters 60 disposed
on the filter
wheel 50 operate as narrow band filters. However, one of ordinary skill in the
art will
realize that other structures can be used to filter energy wavelengths
according to the
embodiments described herein. For example, the primary filter 40 may be
omitted and/or an
electronically tunable filter or Fabry-Perot interferometer (not shown) can be
used in place
of the filter wheel 50 and secondary filters 60. Such a tunable filter or
interferometer can be
configured to permit, in a sequential, "one-at-a-time" fashion, each of a set
of wavelengths
or wavelength bands of electromagnetic radiation to pass therethrough for use
in analyzing
the material sample S.
[0219] A reflector tube 98 is preferably positioned to receive the filtered
energy
beam (Ef) as it advances from the secondary filter(s) 60. The reflector tube
98 is preferably
secured with respect to the secondary filter(s) 60 to substantially prevent
introduction of
stray electromagnetic radiation, such as stray light, into the reflector tube
98 from outside of
the detection system 1700. The inner surfaces of the reflector tube 98 are
highly reflective
in the relevant wavelengths and preferably have a cylindrical shape with a
generally circular
cross-section orthogonal to the major and/or minor axis X, Y. However, the
inner surface of
the tube 98 can have a cross-section of any suitable shape, such as oval,
square, rectangular,
etc. Like the collimator 30, the reflector tube 98 may be formed from a rigid
material such
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as aluminum, steel, etc., as long as the inner surfaces are coated or
otherwise treated to be
highly reflective in the wavelengths of interest. For example, a polished gold
coating may
be employed.
[0220] According to the embodiment illustrated in FIGURE 46, the reflector
tube 98 preferably comprises a major section 98a and a minor section 98b. As
depicted, the
reflector tube 98 can be T-shaped with the major section 98a having a greater
length than
the minor section 98b. In anotller example, the major section 98a and the
minor section 98b
can have the same length. The major section 98a extends between a first end
98c and a
second end 98d along the major axis X. The minor section 98b extends between
the major
section 98a and a third end 98e along the minor axis Y.
[0221] The major section 98a conducts the filtered energy beam (Ef) from the
first end 98c to the beam splitter 4400, which is housed in the major section
98a at the
intersection of the major and minor axes X, Y. The major section 98a also
conducts the
sample beam (Es) from the beam splitter 4400, through the first lens 4410 and
to the second
end 98d. From the second end 98d the sample beam (Es) proceeds through the
sample
element 1730, holder 4430 and second lens 4440, and to the sample detector
150. Similarly,
the minor section 98b conducts the reference beam (Er) through beam sampling
optics 90
from the beam splitter 4400, through the third lens 160 and to the third end
98e. From the
third end 98e the reference beam (Er) proceeds to the reference detector 170.
[0222] The sample beam (Es) preferably comprises from about 75% to about
85% of the energy of the filtered energy beam (Ef). More preferably, the
sample beam (Es)
comprises about 80% of the energy of the filtered energy beam (Es). The
reference beam
(Er) preferably comprises from about 10% and about 50% of the energy of the
filtered
energy beam (Es). More preferably, the reference beam (Er) comprises about 20%
of the
energy of the filtered energy beam (Ef). Of course, the sample and reference
beains may
take on any suitable proportions of the energy beam E.
[0223] The reflector tube 98 also houses the first lens 4410 and the third
lens
160. As illustrated in FIGURE 46, the reflector tube 98 houses the first lens
4410 between
the beam splitter 4400 and the second end 98d. The first lens, 4410 is
preferably disposed so
that a plane 4612 of the lens 4410 is generally orthogonal to the major axis
X. Similarly, the
tube 98 houses the third lens 160 between the beam splitter 4400 and the third
end 98e. The
third lens 160 is preferably disposed so that a plane 162 of the third lens
160 is generally
orthogonal to the minor axis Y. The first lens 4410 and the third lens 160
each has a focal
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length configured to substantially focus the sample beam (Es) and reference
beam (Er),
respectively, as the beams (Es, Er) pass through the lenses 4410, 160. In
particular, the first
lens 4410 is configured, and disposed relative to the holder 4430, to focus
the sample beam
(Es) so that substantially the entire sample beam (Es) passes through the
material sample S,
residing in the sample element 1730. Likewise, the third lens 160 is
configured to focus the
reference beam (Er) so that substantially the entire reference beam (Er)
impinges onto the
reference detector 170.
[0224] The sample eleinent 1730 is retained within the holder 4430, which is
preferably oriented along a plane generally orthogonal to the major axis X.
The holder 4430
is configured to be slidably displaced between a loading position and a
measurement
position within the analyte detection system 1700. In the measurement
position, the holder
4430 contacts a stop edge 136 which is located to orient the sample element
1730 and the
sample S contained therein on the major axis X.
[0225] The structural details of the holder 4430 depicted in FIGURE 46 are
unimportant, so long as the holder positions the sample element 1730 and
sample S on and
substantially orthogonal to the major axis X, while permitting the energy beam
E to pass
through the sample element and sample. As with the embodiment depicted in
FIGURE 44,
the holder 4430 may be omitted and the sanlple element 1730 positioned alone
in the
depicted location on the major axis X. However, the holder 4430 is useful
where the sample
element 1730 (discussed in further detail below) is constructed from a highly
brittle or
fragile material, such as barium fluoride, or is manufactured to be extremely
thin.
[0226] As with the embodiment depicted in FIGURE 44, the sample and
reference detectors 150, 170 shown in FIGURE 46 respond to radiation incident
thereon by
generating signals and passing them to the processor 210. Based these signals
received from
the sample and reference detectors 150, 170, the processor 210 computes the
concentration(s), absorbance(s), transmittance(s), etc. relating to the sample
S by executing
a data processing algorithm or program instructions residing within the memory
212
accessible by the processor 210. In further variations of the detection system
1700 depicted
in FIGURE 46, the beam splitter 4400, reference detector 170 and other
structures on the
minor axis Y may be omitted, especially where the output intensity of the
source 1720 is
sufficiently stable to obviate any need to reference the source intensity in
operation of the
detection system 1700.
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[0227] FIGURE 47 depicts a sectional view of the sample detector 150 in
accordance with one enibodiinent. Sample detector 150 is mounted in a detector
housing
152 having a receiving portion 152a and a cover 152b. However, any suitable
structure may
be used as the sainple detector 150 and housing 152. The receiving portion
152a preferably
defines an aperture 152c and a lens chamber 152d, which are generally aligned
with the
major axis X when the housing 152 is mounted in the analyte detection system
1700. The
aperture 152c is configured to allow at least a fraction of the sample beain
(Es) passing
through the sample S and the sample element 1730 to advance through the
aperture 152c
and into the lens chainber 152d.
[0228] The receiving portion 152a houses the second lens 4440 in the lens
chamber 152d proximal to the aperture 152c. The sample detector 150 is also
disposed in
the lens chamber 152d downstream of the second lens 4440 such that a detection
plane 154
of the detector 150 is substantially orthogonal to the major axis X. The
second lens 4440 is
positioned such that a plane 142 of the lens 4440 is substantially orthogonal
to the major
axis X. The second lens 4440 is configured, and is preferably disposed
relative to the holder
4430 and the sanlple detector 150, to focus substantially all of the sample
beain (Es) onto
the detection plane 154, thereby increasing the flux density of the sample
beam (Es)
incident upon the detection plane 154.
[0229] With further reference to FIGURE 47, a support member 156 preferably
holds the sample detector 150 in place in the receiving portion 152a. In the
illustrated
embodiment, the support member 156 is a spring 156 disposed between the sample
detector
150 and the cover 152b. The spring 156 is configured to maintain the detection
plane 154
of the sample detector 150 substantially orthogonal to the major axis X. A
gasket 157 is
preferably disposed between the cover 152b and the receiving portion 152a and
surrounds
the support member 156.
[02301 The receiving portion 152a preferably also houses a printed circuit
board
158 disposed between the gasket 157 and the sample detector 150. The board 158
connects
to the sample detector 150 through at least one connecting meinber 150a. The
sample
detector 150 is configured to generate a detection signal corresponding to the
sample beam
(Es) incident on the detection plane 154. The sample detector 150 communicates
the
detection signal to the circuit board 158 through the connecting member 150a,
and the
board 158 transmits the detection signal to the processor 210.
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[0231] In one embodiment, the sample detector 150 comprises a generally
cylindrical housing 150a, e.g. a type TO-39 "metal can" package, which defines
a generally
circular housing aperture 150b at its "upstream" end. In one embodiment, the
housing 150a
has a diameter of about 0.323 inches and a depth of about 0.248 inches, and
the aperture
150b may have a diameter of about 0.197 inches.
[0232] A detector window 150c is disposed adjacent the aperture 150b, with its
upstream surface preferably about 0.078 inches (+/- 0.004 inches) from the
detection plane
154. (The detection plane 154 is located about 0.088 inches (+/- 0.004 inches)
from the
upstream edge of the housing 150a, where the housing has a thickness of about
0.010
inches.) The detector window 150c is preferably transmissive of infrared
energy in at least a
3-12 micron passband; accordingly, one suitable material for the window 150c
is
germanium. The endpoints of the passband may be "spread" further to less than
2.5
microns, and/or greater than 12.5 microns, to avoid unnecessary absorbance in
the
wavelengths of interest. Preferably, the transmittance of the detector window
150c does not
vary by more than 2% across its passband. The window 150c is preferably about
0.020
inches in thickness. The sample detector 150 preferably substantially retains
its operating
characteristics across a temperature range of -20 to +60 degrees Celsius.
[0233] FIGURE 48 depicts a sectional view of the reference detector 170 in
accordance with one embodiment. The reference detector 170 is mounted in a
detector
housing 172 having a receiving portion 172a and a cover 172b. However, any
suitable
structure may be used as the sample detector 150 and housing 152. The
receiving portion
172a preferably defines an aperture 172c and a chamber 172d which are
generally aligned
with the minor axis Y, when the housing 172 is mounted in the analyte
detection system
1700. The aperture 172c is configured to allow the reference beam (Er) to
advance through
the aperture 172c and into the chamber 172d.
[0234] The receiving portion 172a houses the reference detector 170 in the
chamber 172d proximal to the aperture 172c. The reference detector 170 is
disposed in the
chamber 172d such that a detection plane 174 of the reference detector 170 is
substantially
orthogonal to the minor axis Y. The third lens 160 is configured to
substantially focus the
reference beam (Er) so that substantially the entire reference beam (Er)
impinges onto the
detection plane 174, thus increasing the flux density of the reference beam
(Er) incident
upon the detection plane 174.
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[0235] With further reference to FIGURE 48, a support member 176 preferably
holds the reference detector 170 in place in the receiving portion 172a. In
the illustrated
embodiment, the support member 176 is a spring 176 disposed between the
reference
detector 170 and the cover 172b. The spring 176 is configured to maintain the
detection
plane 174 of the reference detector 170 substantially orthogonal to the minor
axis Y. A
gasket 177 is preferably disposed between the cover 172b and the receiving
portion 172a
and surrounds the support member 176.
[0236] The receiving portion 172a preferably also houses a printed circuit
board
178 disposed between the gasket 177 and the reference detector 170. The board
178
connects to the reference detector 170 through at least one connecting
ineinber 170a. The
reference detector 170 is configured to generate a detection signal
corresponding to the
reference beam (Er) incident on the detection plane 174. The reference
detector 170
communicates the detection signal to the circuit board 178 through the
connecting member
170a, and the board 178 transmits the detection signal to the processor 210.
[0237] In one embodiment, the construction of the reference detector 170 is
generally similar to that described above with regard to the sample detector
150.
[0238] In one embodiment, the sample and reference detectors 150, 170 are both
configured to detect electromagnetic radiation in a spectral wavelength range
of between
about 0.8 m and about 25 m. However, any suitable subset of the foregoing
set of
wavelengths can be selected. In another embodiment, the detectors 150, 170 are
configured
to detect electromagnetic radiation in the wavelength range of between about 4
m and
about 12 m. The detection planes 154, 174 of the detectors 150, 170 may each
define an
active area about 2 mm by 2 mm or from about 1 mm by 1 mm to about 5 mm by 5
mm; of
course, any other suitable dimensions and proportions may be employed.
Additionally, the
detectors 150, 170 may be configured to detect electromagnetic radiation
directed thereto
within a cone angle of about 45 degrees from the major axis X.
[0239] In one embodiment, the sample and reference detector subsystems 150,
170 may further comprise a system (not shown) for regulating the temperature
of the
detectors. Such a temperature-regulation system may comprise a suitable
electrical heat
source, thermistor, and a proportional-plus-integral-plus-derivative (PID)
control. These
components may be used to regulate the temperature of the detectors 150, 170
at about 35
C. The detectors 150, 170 can also optionally be operated at other desired
temperatures.
Additionally, the PID control preferably has a control rate of about 60 Hz
and, along with
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the heat source and thermistor, maintains the temperature of the detectors
150, 170 witliin
about 0.1 C of the desired temperature.
[0240] The detectors 150, 170 can operate in either a voltage mode or a
current
mode, wherein either mode of operation preferably includes the use of a pre-
ainp module.
Suitable voltage mode detectors for use with the ailalyte detection systein
1700 disclosed
herein include: models LIE 302 and 312 by InfraTec of Dresden, Germany; model
L2002
by BAE Systems of Rockville, Maryland; and model LTS-1 by Dias of Dresden,
Germany.
Suitable current mode detectors include: InfraTec models LIE 301, 315, 345 and
355; and
2x2 current-mode detectors available from Dias.
[0241] In one einbodiment, one or both of the detectors 150, 170 inay meet the
following specifications, when assmning an incident radiation intensity of
about 9.26 x 10-4
watts (rms) per cm2, at 10 Hz modulation and within a cone angle of about 15
degrees:
detector area of 0.040 cm2 (2 mm x 2 mm square); detector input of 3.70 x 10-$
watts (rms)
at 10 Hz; detector sensitivity of 360 volts per watt at 10 Hz; detector output
of 1.333 x 10-2
volts (rms) at 10 Hz; noise of 8.00 x 10-8 volts/sqrtHz at 10 Hz; and signal-
to-noise ratios of
1.67 x 10$ rms/sqrtHz and 104.4 dB/sqrtHz; and detectivity of 1.00 x 109 cm
sqrtHz/watt.
[0242] In alternative embodiments, the detectors 150, 170 may comprise
microphones and/or other sensors suitable for operation of the detection
system 1700 in a
photoacoustic mode.
[0243] The components of any of the embodiments of the analyte detection
system 1700 may be partially or completely contained in an enclosure or casing
(not shown)
to prevent stray electromagnetic radiation, such as stray light, from
contaminating the
energy beam E. Any suitable casing may be used. Similarly, the components of
the
detection system 1700 may be mounted on any suitable frame or chassis (not
shown) to
maintain their operative alignment as depicted in FIGURES 17, 44, and 46. The
frame and
the casing may be formed together as a single unit, member or collection of
members.
[0244] Iu one method of operation, the analyte detection system 1700 shown in
FIGURES 44 or 46 measures the concentration of one or inore analytes in the
material
sample S, in part, by comparing the electromagnetic radiation detected by the
sample and
reference detectors 150, 170. During operation of the detection system 1700,
each of the
secondary filter(s) 60 is sequentially aligned with the major axis X for a
dwell time
corresponding to the secondary filter 60. (Of course, where an electronically
tunable filter
or Fabry-Perot interferometer is used in place of the filter wheel 50, the
tunable filter or
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interferometer is sequentially tuned to each of a set of desired wavelengths
or wavelength
bands in lieu of the sequential aligmnent of each of the secondary filters
with the major axis
X.) The energy source 1720 is then operated at (any) modulation frequency, as
discussed
above, during the dwell time period. The dwell time may be different for each
secondary
filter 60 (or each wavelength or band to which the tunable filter or
interferometer is tuned).
In one embodiment of the detection system 1700, the dwell time for each
secondary filter
60 is less than about 1 second. Use of a dwell time specific to each secondary
filter 60
advantageously allows the detection system 1700 to operate for a longer period
of time at
wavelengths where errors can have a greater effect on the computation of the
analyte
concentration in the material sample S. Correspondingly, the detection system
1700 can
operate for a shorter period of time at wavelengths where errors have less
effect on the
computed analyte concentration. The dwell times may otherwise be nonuniform
ainong the
filters/wavelengths/bands employed in the detection system.
[02451 For each secondary filter 60 selectively aligned with the major axis X,
the sample detector 150 detects the portion of the sample beanl (Es), at the
wavelength or
wavelength band corresponding to the secondary filter 60, that is transmitted
through the
material sample S. The sample detector 150 generates a detection signal
corresponding to
the detected electromagnetic radiation and passes the signal to the processor
210.
Simultaneously, the reference detector 170 detects the reference beam (Er)
transmitted at
the wavelength or wavelength band corresponding to the secondary filter 60.
The reference
detector 170 generates a detection signal corresponding to the detected
electromagnetic
radiation and passes the signal to the processor 210. Based on the signals
passed to it by the
detectors 150, 170, the processor 210 computes the concentration of the
analyte(s) of
interest in the sample S, and/or the absorbance/transmittance characteristics
of the sample S
at one or more wavelengths or wavelength bands employed to analyze the sample.
The
processor 210 computes the concentration(s), absorbance(s), transmittance(s),
etc. by
executing a data processing algorithm or program instructions residing within
the memory
212 accessible by the processor 210.
[0246] The signal generated by the reference detector may be used to monitor
fluctuations in the intensity of the energy beam emitted by the source 1720,
which
fluctuations often arise due to drift effects, aging, wear or other
imperfections in the source
itself. This enables the processor 210 to identify changes in intensity of the
sample beam
(Es) that are attributable to changes in the emission intensity of the source
1720, and not to
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the composition of the sample S. By so doing, a potential source of error in
computations of
concentration, absorbance, etc. is minimized or eliminated.
[0247] In one embodiment, the detection system 1700 computes an analyte
concentration reading by first measuring the electromagnetic radiation
detected by the
detectors 150, 170 at each center wavelength, or wavelength band, without the
sample
element 1730 present on the major axis X (this is known as an "air" reading).
Second, the
system 1700 measures the electromagnetic radiation detected by the detectors
150, 170 for
each center wavelength, or wavelength band, with the material sample S present
in the
sample element 1730, and the sample element 1730 and sainple S in position on
the major
axis X (i.e., a "wet" reading). Finally, the processor 180 computes the
concentration(s),
absorbance(s) and/or transmittances relating to the sample S based on these
coinpiled
readings.
[0248] In one embodiment, the plurality of air and wet readings are used to
generate a pathlength corrected spectrum as follows. First, the measurements
are
normalized to give the transmission of the sample at each wavelength. Using
both a signal
and reference measurement at each wavelength, and letting Si represent the
signal of
detector 150 at wavelength i and R; represent the signal of detector 170 at
wavelength i, the
transmission, ii is computed as i1= Si(wet)/Ri(wet) / S;(air)/Ri(air).
Optionally, the spectra
may be calculated as the optical density, OD;, as - Log(T).
[0249) Next, the transmission over the wavelength range of approximately 4.5
m to approximately 5.5 m is analyzed to determine the pathlength.
Specifically, since
water is the priinary absorbing species of blood over this wavelength region,
and since the
optical density is the product of the optical pathlength and the known
absorption coefficient
of water (OD = L 6, where L is the optical pathlength and (y is the absorption
coefficient),
any one of a number of standard curve fitting procedures may be used to
determine the
optical pathlength, L from the measured OD. The pathlength may then be used to
determine
the absorption coefficient of the sample at each wavelength. Alternatively,
the optical
pathlength may be used in further calculations to convert absorption
coefficients to optical
density.
[0250] Additional information on analyte detection systems, methods of use
thereof, and related technologies may be found in the above-mentioned and
incorporated
U.S. Patent Application Publication No. 2005/0038357, published on February
17, 2005,
titled SAMPLE ELEMENT WITH BARRIER MATERIAL.
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SECTION IV.C - SAMPLE ELEMENT
[0251] FIGURE 18 is a top view of a sample element 1730, FIGURE 19 is a
side view of the sample element, and FIGURE 20 is an exploded perspective view
of the
sample element. In one embodiment of the present invention, sample element
1730 includes
sample chainber 903 that is in fluid communication with and accepts filtered
blood from
sample preparation unit 332. The sample element 1730 comprises a sample
chamber 903
defined by sample chainber walls 1802. The sample chamber 903 is configured to
hold a
material sainple which may be drawn from a patient, for analysis by the
detection system
with which the sample element 1730 is employed.
[0252] In the embodiment illustrated in FIGURES 18-19, the sample chamber
903 is defined by first and secoiid lateral chamber walls 1802a, 1802b and
upper and lower
chamber walls 1802c, 1802d; however, any suitable number and configuration of
chamber
walls may be employed. At least one of the upper and lower chanzber walls
1802c, 1802d is
formed from a material which is sufficiently transmissive of the wavelength(s)
of
electromagnetic radiation that are employed by the sample analysis apparatus
322 (or any
other system with which the sample element is to be used). A chamber wall
which is so
transmissive may thus be termed a "window;" in one embodiment, the upper and
lower
chamber walls 1802c, 1802d comprise first and second windows so as to permit
the
relevant wavelength(s) of electromagnetic radiation to pass through the sample
chamber
903. Iii another embodiment, only one of the upper and lower chamber walls
1802c, 1802d
comprises a window; in such an embodiment, the other of the upper and lower
chamber
walls may comprise a reflective surface configured to back-reflect any
electromagnetic
energy emitted into the sample chamber 903 by the analyte detection system
with which the
sample element 1730 is employed. Accordingly, this embodiment is well suited
for use with
an analyte detection system in which a source and a detector of
electromagnetic energy are
located on the same side as the sample element.
[0253] In various embodiments, the material that makes up the window(s) of the
sample element 1730 is completely transmissive, i.e., it does not absorb any
of the
electromagnetic radiation from the source 1720 and filters 1725 that is
incident upon it. In
another embodiment, the material of the window(s) has some absorption in the
electromagnetic range of interest, but its absorption is negligible. In yet
another
embodiment, the absorption of the material of the window(s) is not negligible,
but it is
stable for a relatively long period of time. In another embodiment, the
absorption of the
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window(s) is stable for only a relatively short period of time, but sample
analysis apparatus
322 is configured to observe the absorption of the material and eliminate it
from the analyte
measurement before the material properties can change measurably. Materials
suitable for
forming the window(s) of the sample element 1730 include, but are not limited
to, calcium
fluoride, barium fluoride, germanium, silicon, polypropylene, polyethylene, or
any polymer
with suitable transmissivity (i.e., transmittance per unit tlliclcness) in the
relevant
wavelength(s). Where the window(s) are formed from a polymer, the selected
polymer can
be isotactic, atactic or syndiotactic in structure, so as to enliance the flow
of the sample
between the window(s). One type of polyethylene suitable for constructing the
sample
element 1730 is type 220, extruded or blow molded, available from ICUBE Ltd.
of Staefa,
Switzerland.
[0254] In one embodiment, the sample element 1730 is configured to allow
sufficient transmission of electromagnetic energy having a wavelength of
between about 4
m and about 10.5 m through the window(s) thereof. However, the sample element
1730
can be configured to allow transmission of wavelengths in any spectral range
emitted by the
energy source 1720. In another embodiment, the sample element 1730 is
configured to
receive an optical power of more than about 1.0 MW/cm2 from the sainple beam
(Es)
incident thereon for any electromagnetic radiation wavelength transmitted
through the filter
1725. Preferably, the sample chamber 903 of the sample element 1730 is
configured to
allow a sample beam (Es) advancing toward the material sample S within a cone
angle of
45 degrees from the major axis X (see FIGURE 17) to pass therethrough.
[0255] In the embodiment illustrated in FIGURES 18-19, the sainple element
further comprises a supply passage 1804 extending from the sample chamber 903
to a
supply opening 1806 and a vent passage 1808 extending from the sample chamber
903 to a
vent opening 1810. While the vent and supply openings 1806, 1810 are shown at
one end of
the sample element 1730, in other embodiments the openings may be positioned
on other
sides of the sample element 1730, so long as it is in fluid communication with
the passages
1804 and 1808, respectively.
[0256] In operation, the supply opening 1806 of the sample element 1730 is
placed in contact with the material sample S, such as a fluid flowing from a
patient. The
fluid is then transported through the sample supply passage 1804 and into the
sample
chamber 903 via an external pump or by capillary action.
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[0257] Where the upper and lower chamber walls 1802c, 1802d comprise
windows, the distance T (measured along an axis substantially orthogonal to
the sample
chamber 903 and/or windows 1802a, 1802b, or, alternatively, measured along an
axis of an
energy beam (such as but not limited to the energy beam E discussed above)
passed through
the sample chamber 903) between them comprises an optical pathlength. In
various
embodiments, the pathlength is between about 1 m and about 300 in, between
about 1
m and about 100 in, between about 25 m and about 40 m, between about 10 m
and
about 40 m, between about 25 m and about 60 m, or between about 30 m and
about 50
m. In still other embodiments, the optical pathlength is about 50 m, or about
25 gin. In
some instances, it is desirable to hold the pathlength T to within about plus
or minus I in
from any pathlength specified by the analyte detection system with which the
sample
element 1730 is to be employed. Likewise, it may be desirable to orient the
walls 1802c,
1802d with respect to each other within plus or minus 1 m of parallel, and/or
to maintain
each of the walls 1802c, 1802d to within plus or minus 1 m of planar (flat),
depending on
the analyte detection system with which the sample element 1730 is to be used.
In
alternative embodiments, walls 1802c, 1802d are flat, textured, angled, or
some
combination thereof.
[0258] In one embodiment, the transverse size of the sample chamber 903 (i.e.,
the size defined by the lateral chamber walls 1802a, 1802b) is about equal to
the size of the
active surface of the sample detector 1745. Accordingly, in a further
embodiment the
sample chamber 903 is round with a diameter of about 4 millimeter to about 12
millimeter,
and more preferably from about 6 millimeter to about 8 millimeter.
[0259] The sample element 1730 shown in FIGURES 18-19 has, in one
embodiment, sizes and dimensions specified as follows. The supply passage 1804
preferably has a length of about 15 millimeter, a width of about 1.0
millimeter, and a height
equal to the pathlength T. Additionally, the supply opening 1806 is preferably
about 1.5
millimeter wide and smoothly transitions to the width of the sample supply
passage 1804.
The sample eleinent 1730 is about 0.5 inches (12 millimeters) wide and about
one inch (25
millimeters) long with an overall thickness of between about 1.0 millimeter
and about 4.0
millimeter. The vent passage 1808 preferably has a length of about 1.0
millimeter to 5.0
millimeter and a width of about 1.0 millimeter, with a thickness substantially
equal to the
pathlength between the walls 1802c, 1802d. The vent aperture 1810 is of
substantially the
same height and width as the vent passage 1808. Of course, other dimensions
may be
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employed in other embodiments while still achieving the advantages of the
sample element
1730.
[0260] The sample element 1730 is preferably sized to receive a material
sample
S having a volume less than or equal to about 15 L (or less than or equal to
about 10 L,
or less than or equal to about 5 L) and more preferably a material sample S
having a
volume less than or equal to about 2 L. Of course, the volume of the sample
element 1730,
the volume of the sample chamber 903, etc. can vary, depending on many
variables, such as
the size and sensitivity of the sample detector 1745, the intensity of the
radiation emitted by
the energy source 1720, the expected flow properties of the sample, and
whether flow
enhancers are incorporated into the sample eleinent 1730. The transport of
fluid to the
sample chamber 903 is achieved preferably through capillary action, but inay
also be
achieved through wicking or vacuum action, or a combination of wicking,
capillary action,
peristaltic, pumping, and/or vacuum action.
[0261] FIGURE 20 depicts one approach to constructing the sample element
1730. In this approach, the sample element 1730 comprises a first layer 1820,
a second
layer 1830, and a third layer 1840. The second layer 1830 is preferably
positioned between
the first layer 1820 and the third layer 1840. The first layer 1820 forms the
upper chamber
wall 1802c, and the third layer 1840 forms the lower chamber wall 1802d. Where
either of
the chamber walls 1802c, 1802d comprises a window, the window(s)/wall(s)
1802c/1802d
in question may be formed from a different material as is employed to form the
balance of
the layer(s) 1820/1840 in which the wall(s) are located. Alternatively, the
entirety of the
layer(s) 1820/1840 may be formed of the material selected to form the
window(s)/wall(s)
1802c, 1802d. In this case, the window(s)/wall(s) 1802c, 1802d are integrally
formed with
the layer(s) 1820, 1840 and simply comprise the regions of the respective
layer(s) 1820,
1840 which overlie the sample chamber 903.
[0262] With further reference to FIGURE 20, second layer 1830 may be forined
entirely of an adhesive that joins the first and third layers 1820, 1840. In
other
embodiments, the second layer 1830 may be formed from similar materials as the
first and
third layers, or any other suitable material. The second layer 1830 may also
be formed as a
carrier with an adhesive deposited on both sides thereof. The second layer
1830 includes
voids which at least partially form the sample chamber 903, sample supply
passage 1804,
supply opening 1806, vent passage 1808, and vent opening 1810. The thickness
of the
second layer 1830 can be the same as any of the pathlengths disclosed above as
suitable for
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the sample element 1730. The first and third layers can be formed from any of
the materials
disclosed above as suitable for forming the window(s) of the sample element
1730. In one
embodiment, layers 1820, 1840 are formed from material having sufficient
structural
integrity to maintain its shape when filled with a sample S. Layers 1820, 1830
may be, for
example, calcium fluoride having a thickness of 0.5 millimeter. In another
einbodiment, the
second layer 1830 comprises the adhesive portion of Adhesive Transfer Tape no.
9471LE
available from 3M Corporation. Iii another embodiment, the second layer 1830
comprises
an epoxy, available, for example, from TechFilm (31 Dunham Road, Billerica, MA
01821),
that is bound to layers 1820, 1840 as a result of the application of pressure
and heat to the
layers.
[0263] The sample chamber 903 preferably comprises a reagentless chainber. In
other words, the internal volume of the sample cliamber 903 and/or the wall(s)
1802
defining the chamber 903 are preferably inert with respect to the sample to be
drawn into
the chamber for analysis. As used herein, "inert" is a broad term and is used
in its ordinary
sense and includes, without limitation, substances which will not react with
the sample in a
manner which will significantly affect any measureinent made of the
concentration of
analyte(s) in the sample with sample analysis apparatus 322 or any other
suitable systenl,
for a sufficient time (e.g., about 1-30 minutes) following entry of the sample
into the
chamber 903, to perinit measurement of the concentration of such analyte(s).
Alternatively,
the sample chamber 903 may contain one or more reagents to facilitate use of
the sample
element in sample assay techniques which involve reaction of the sample with a
reagent.
[0264] In one embodiment of the present invention, sample element 1730 is
used for a limited number of ineasureinents and is disposable. Thus, for
example, with
reference to FIGURES 8-10, sample element 1730 forms a disposable portion of
cassette
820 adapted to place sample chamber 903 within probe region 1002.
[0265] Additional information on sample elements, methods of use thereof, and
related technologies may be found in the above-mentioned and incorporated U.S.
Patent
Application Publication No. 2005/0038357, published on February 17, 2005,
titled
SAMPLE ELEMENT WITH BARRIER MATERIAL; and in the above-mentioned and
incorporated U.S. Patent Application No. 11/122,794, filed on May 5, 2005,
titled
SAMPLE ELEMENT WITH SEPARATOR.
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SECTION IV.D - CENTRIFUGE
[02661 FIGURE 21 is a schematic of one embodiment of a sample preparation
unit 2100 utilizing a centrifuge and which may be generally similar to the
sample
preparation unit 332, except as further detailed below. In general, the sample
preparation
unit 332 includes a centrifuge in place of, or in addition to a filter, such
as the filter 1500.
Sample preparation unit 2100 includes a fluid handling element in the fomi of
a centrifuge
2110 having a sample element 2112 and a fluid interface 2120. Sample element
2112 is
illustrated in FIGURE 21 as a somewhat cylindrical eleinent. This embodiment
is
illustrative, and the sample element may be cylindrical, planar, or any other
shape or
configuration that is compatible with the function of holding a nlaterial
(preferably a liquid)
in the centrifuge 2110. The centrifuge 2110 can be used to rotate the saniple
element 2112
such that the material held in the sample element 2112 is separated.
[0267] In some embodiments, the fluid interface 2120 selectively controls the
transfer of a sample from the passageway 113 and into the sample element 2112
to permit
centrifuging of the sample. In another embodiment, the fluid interface 2120
also permits a
fluid to flow though the sample element 2112 to cleanse or otherwise prepare
the sainple
element for obtaining an analyte measurement. Thus, the fluid interface 2120
can be used
to flush and fill the sample element 2112.
[0268] As shown in FIGURE 21, the centrifuge 2110 comprises a rotor 2111
that includes the sample element 2112 and an axle 2113 attached to a motor,
not shown,
which is controlled by the controller 210. The sample element 2112 is
preferably generally
similar to the sample element 1730 except as described subsequently.
[0269] As is further shown in FIGURE 21, fluid interface 2120 includes a fluid
injection probe 2121 having a first needle 2122 and a fluid removal probe
2123. The fluid
removal probe 2123 has a second needle 2124. When sample element 2112 is
properly
oriented relative to fluid interface 2120, a sample, fluid, or other liquid is
dispensed into or
passes through the sample element 2112. More specifically, fluid injection
probe 2121
includes a passageway to receive a sample, such as a bodily fluid from the
patient connector
110. The bodily fluid can be passed through the fluid injection probe 2121 and
the first
needle 2122 into the sample element 2112. To remove material from the sample
element
2112, the sample 2112 can be aligned with the second needle 2124, as
illustrated. Material
can be passed through the second needle 2124 into the fluid removal probe
2123. The
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material can then pass through a passageway of the removal probe 2123 away
from the
sample element 2112.
[0270] One position that the sample element 2112 may be rotated through or to
is a sainple measurement location 2140. The location 2140 may coincide with a
region of
an analysis system, such as an optical analyte detection systein. For example,
the location
2140 may coincide with a probe region 1002, or with a measurement location of
anotlier
apparatus.
[0271] The rotor 2111 may be driven in a direction indicated by arrow R,
resulting in a centrifugal force on sample(s) within sample element 2112. The
rotation of a
sample(s) located a distance froin the center of rotation creates centrifugal
force. In some
embodiments, the sample element 2112 holds whole blood. The centrifugal force
may
cause the denser parts of the whole blood sample to move further out from the
center of
rotation than lighter parts of the blood sainple. As such, one or more
components of the
whole blood can be separated from each other. Other fluids or samples can also
be
removed by centrifugal forces. In one embodiment, the sample element 2112 is a
disposable container that is mounted on to a disposable rotor 2111.
Preferably, the container
is plastic, reusable and flushable. In other embodiments, the sample element
2112 is a non-
disposable container that is permanently attached to the rotor 2111.
[0272] The illustrated rotor 2111 is a generally circular plate that is
fixedly
coupled to the axle 2113. The rotor 2111 can alternatively have other shapes.
The rotor
2111 preferably comprises a material that has a low density to keep the
rotational inertia
low and that is sufficiently strong and stable to maintain shape under
operating loads to
maintain close optical alignment. For example, the rotor 2111 can be comprised
of GE
brand ULTEM (trademark) polyetherimide (PEI). This material is available in a
plate form
that is stable but can be readily machined. Other materials having similar
properties can
also be used.
[0273] The size of the rotor 2111 can be selected to achieve the desired
centrifugal force. In some embodiments, the diameter of rotor 2111 is from
about 75
millimeters to about 125 millimeters, or more preferably from about 100
millimeters to
about 125 millimeters. The thickness of rotor 2111 is preferably just thick
enough to
support the centrifugal forces and can be, for example, from about 1.0 to 2.0
millimeter
thick.
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[0274] In an alternative embodiment, the fluid interface 2120 selectively
removes blood plasma from the sample eleinent 2112 after centrifuging. The
blood plasma
is then delivered to an analyte detection system for analysis. In one
einbodiment, the
separated fluids are removed from the sample element 2112 through the bottom
connector.
Preferably, the location and orientation of the bottom connector and the
container allow the
red blood cells to be removed first. One embodiment may be configured with a
red blood
cell detector. The red blood cell detector may detect when most of the red
blood cells have
exited the container by determining the haemostatic level. The plasina
remaining in the
container may then be diverted into the analysis chamber. After the fluids
have been
removed from the container, the top connector may inject fluid (e.g., saline)
into the
container to flush the systein and prepare it for the next sample.
[0275] FIGURES 22A to 23C illustrate another embodiment of a fluid handling
and analysis apparatus 140, which employs a removable, disposable fluid
handling cassette
820. The cassette 820 is equipped with a centrifuge rotor assembly 2016 to
facilitate
preparation and analysis of a sample. Except as further described below, the
apparatus 140
of FIGURES 22A-22C can in certain embodiments be similar to any of the other
embodiments of the apparatus 140 discussed herein, and the cassette 820 can in
certain
embodiments be similar to any of the embodiments of the cassettes 820
disclosed herein.
[0276] The removable fluid handling cassette 820 can be removably engaged
with a main analysis instrument 810. When the fluid handling cassette 820 is
coupled to
the main instruinent 810, a drive system 2030 of the main instrument 810 mates
with the
rotor assembly 2016 of the cassette 820 (FIGURE 22B). Once the cassette 820 is
coupled
to the main instrument 810, the drive systein 2030 engages and can rotate the
rotor
assembly 2016 to apply a centrifugal force to a body fluid sample carried by
the rotor
assembly 2016.
[0277] In some embodiments, the rotor assembly 2016 includes a rotor 2020
sample element 2448 (FIGURE 22C) for holding a sample for centrifuging. When
the rotor
2020 is rotated, a centrifugal force is applied to the sample contained within
the sample
element 2448. The centrifugal force causes separation of one or more
components of the
sample (e.g., separation of plasma from whole blood). The separated
component(s) can
then be analyzed by the apparatus 140, as will be discussed in further detail
below.
[0278] The main instrument 810 includes both the centrifuge drive system 2030
and an analyte detection system 1700, a portion of which protrudes from a
housing 2049 of
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the main instrument 810. The drive system 2030 is configured to releasably
couple with the
rotor assembly 2016, and can impart rotary motion to the rotor assembly 2016
to rotate the
rotor 2020 at a desired speed. After the centrifuging process, the analyte
detection system
1700 can analyze one or more components separated from the sainple carried by
the rotor
2020. The projecting portion of the illustrated detection system 1700 forms a
slot 2074 for
receiving a portion of the rotor 2020 carrying the sample element 2448 so that
the detection
system 1700 can analyze the sample or component(s) carried in the sample
element 2448.
[0279] To assemble the fluid handling and analysis apparatus 140 as shown in
FIGURE 22C, the cassette 820 is placed on the main instrument 810, as
indicated by the
arrow 2007 of FIGURES 22A and 22B. The rotor asseinbly 2016 is accessible to
the drive
system 2030, so that once the cassette 820 is properly mounted on the main
instrument 810,
the drive system 2030 is in operative engageiuent with the rotor assembly
2016. The drive
system 2030 is then energized to spin the rotor 2020 at a desired speed. The
spinning rotor
2020 can pass repeatedly through the slot 2074 of the detection system 1700.
[0280] After the centrifuging process, the rotor 2020 is rotated to an
analysis
position (see FIGURES 22B and 23C) wherein the sample element 2448 is
positioned
within the slot 2074. With the rotor 2020 and sample element 2448 in the
analysis position,
the analyte detection system 1700 can analyze one or more of the components of
the sample
carried in the sample element 2448. For example, the detection system 1700 can
analyze at
least one of the components that is separated out during the centrifuging
process. After
using the cassette 820, the cassette 820 can be removed from the main
instrument 810 and
discarded. Another cassette 820 can then be mounted to the main instrument
810.
[0281] With reference to FIGURE 23A, the illustrated cassette 820 includes the
housing 2400 that surrounds the rotor assembly 2016, and the rotor 2020 is
pivotally
connected to the housing 2400 by the rotor assembly 2016. The rotor 2020
includes a rotor
interface 2051 for driving engagement with the drive system 2030 upon
placement of the
cassette 820 on the main instrument 810.
[0282] In some embodiments, the cassette 820 is a disposable fluid handling
cassette. The reusable main instrument 810 can be used with any number of
cassettes 820
as desired. Additionally or alternatively, the cassette 820 can be a portable,
handheld
cassette for convenient transport. In these embodiments, the cassette 820 can
be manually
mounted to or removed from the main instrument 810. In some embodiments, the
cassette
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820 may be a non disposable cassette which can be permanently coupled to the
main
instrument 810.
[0283] FIGURES 25A and 25B illustrate the centrifugal rotor 2020, which is
capable of carrying a sample, such as bodily fluid. Thus, the illustrated
centrifugal rotor
2020 can be considered a fluid handling element that can prepare a sample for
analysis, as
well as hold the sample during a spectroscopic analysis. The rotor 2020
preferably
coinprises an elongate body 2446, at least one sample element 2448, and at
least one bypass
element 2452. The sample element 2448 and bypass element 2452 can be located
at
opposing ends of the rotor 2020. The bypass element 2452 provides a bypass
flow path that
can be used to clean or flush fluid passageways of the fluid handling and
analysis apparatus
140 without passing fluid through the sainple element 2448.
[0284] The illustrated rotor body 2446 can be a generally planar member that
defines a mounting aperture 2447 for coupling to the drive system 2030. The
illustrated
rotor 2020 has a somewhat rectangular shape. In alternative embodiments, the
rotor 2020 is
generally circular, polygonal, elliptical, or can have any other shape as
desired. The
illustrated shape can facilitate loading when positioned horizontally to
accommodate the
analyte detection system 1700.
[0285] With reference to FIGURE 25B, a pair of opposing first and second fluid
connectors 2027, 2029 extends outwardly from a front face of the rotor 2020,
to facilitate
fluid flow through the rotor body 2446 to the sample element 2448 and bypass
element
2452, respectively. The first fluid connector 2027 defines an outlet port 2472
and an inlet
port 2474 that are in fluid communication with the sample element 2448. In the
illustrated
embodiment, fluid channels 2510, 2512 extend from the outlet port 2472 and
inlet port
2474, respectively, to the sample element 2448. (See FIGURES 25E and 25F.) As
such,
the ports 2472, 2474 and channels 2510, 2512 define input and return flow
paths through
the rotor 2020 to the sample element 2448 and back.
[0286] With continued reference to FIGURE 25B, the rotor 2020 includes the
bypass element 2452 which permits fluid flow therethrough from an outlet port
2572 to the
inlet port 2574. A channel 2570 extends between the outlet port 2572 and the
inlet port
2574 to facilitate this fluid flow. The channel 2570 thus defines a closed
flow path through
the rotor 2020 from one port 2572 to the other port 2574. In the illustrated
embodiment,
the outlet port 2572 and inlet port 2574 of the bypass element 2452 have
generally the same
spacing therebetween on the rotor 2020 as the outlet port 2472 and the inlet
port 2474.
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[0287] One or more windows 2460a, 2460b can be provided for optical access
through the rotor 2020. A window 2460a proximate the bypass element 2452 can
be a
through-hole (see FIGURE 25E) that permits the passage of electromagnetic
radiation
through the rotor 2020. A window 2460b proxiinate the sample element 2448 can
also be a
similar through-hole which permits the passage of electromagnetic radiation.
Alternatively,
one or both of the windows 2460a, 2460b can be a sheet constructed of calcium
fluoride,
barium fluoride, germanium, silicon, polypropylene, polyethylene, combinations
thereof, or
any material with suitable transmissivity (i.e., transmittance per unit
thickness) in the
relevant wavelength(s). The windows 2460a, 2460b are positioned so that one of
the
windows 2460a, 2460b is positioned in the slot 2074 when the rotor 2020 is in
a vertically
orientated position.
[0288] Various fabrication techniques can be used to form the rotor 2020. In
some embodiments, the rotor 2020 can be formed by molding (e.g., compression
or
injection molding), machining, or a similar production process or combination
of
production processes. In some embodiments, the rotor 2020 is comprised of
plastic. The
coinpliance of the plastic material can be selected to create the seal with
the ends of pins
2542, 2544 of a fluid interface 2028 (discussed in further detail below). Non-
limiting
exemplary plastics for forming the ports (e.g., ports 2572, 2574, 2472, 2474)
can be
relatively chemically inert and can be injection molded or machined. These
plastics
include, but are not limited to, PEEK and polyphenylenesulfide (PPS). Although
both of
these plastics have high modulus, a fluidic seal can be made if sealing
surfaces are
produced with smooth finish and the sealing zone is a small area where high
contact
pressure is created in a very small zone. Accordingly, the materials used to
form the rotor
2020 and pins 2542, 2544 can be selected to achieve the desired interaction
between the
rotor 2020 and the pins 2542, 2544, as described in detail below.
[0289] The illustrated rotor assembly 2016 of FIGURE 23A rotatably connects
the rotor 2020 to the cassette housing 2400 via a rotor axle boss 2426 which
is fixed with
respect to the cassette housing and pivotally holds a rotor axle 2430 and the
rotor 2020
attached thereto. The rotor axle 2430 extends outwardly from the rotor axle
boss 2426 and
is fixedly attached to a rotor bracket 2436, which is preferably securely
coupled to a rear
face of the rotor 2020. Accordingly, the rotor assembly 2016 and the drive
system 2030
cooperate to ensure that the rotor 2020 rotates about the axis 2024, even at
high speeds.
The illustrated cassette 820 has a single rotor assembly 2016. In other
embodiments, the
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cassette 820 can have more than one rotor assembly 2016. Multiple rotor
assemblies 2016
can bg used to prepare (preferably simultaneously) and test multiple samples.
[0290] With reference again to FIGURES 25A, 25B, 25E and 25F, the sample
element 2448 is coupled to the rotor 2020 and can hold a sample of body fluid
for
processing with the centrifuge. The sainple element 2448 caii, in certain
embodiments, be
geiierally similar to other sample elements or cuvettes disclosed herein
(e.g., sample
elements 1730, 2112) except as further detailed below.
[0291] The sample element 2448 comprises a sample chamber 2464 that holds a
sample for centrifuging, and fluid channels 2466, 2468, which provide fluid
communication
between the chamber 2464 and the channels 2512, 2510, respectively, of the
rotor 2020.
Thus, the fluid channels 2512, 2466 define a first flow path between the port
2474 and the
chamber 2464, and the channels 2510, 2468 define a second flow path between
the port
2472 and the chamber 2464. Depending on the direction of fluid flow into the
sainple
element 2448, either of the first or second flow paths can serve as an input
flow path, and
the other can serve as a return flow path.
[0292] A portion of the sample chamber 2464 can be considered an
interrogation region 2091, which is the portion of the sample chamber through
which
electromagnetic radiation passes during analysis by the detection system 1700
of fluid
contained in the chamber 2464. Accordingly, the interrogation region 2091 is
aligned with
the window 2460b when the sample element 2448 is coupled to the rotor 2020.
The
illustrated interrogation region 2091 comprises a radially inward portion
(i.e., relatively
close to the axis of rotation 2024 of the rotor 2020) of the chamber 2464, to
facilitate
spectroscopic analysis of the lower density portion(s) of the body fluid
sample (e.g., the
plasma of a whole blood sample) after centrifuging, as will be discussed in
greater detail
below. Where the higher-density portions of the body fluid sample are of
interest for
spectroscopic analysis, the interrogation region 2091 can be located in a
radially outward
(i.e., further from the axis of rotation 2024 of the rotor 2020) portion of
the chamber 2464.
[0293] The rotor 2020 can temporarily or permanently hold the sample element
2448. As shown in FIGURE 25F, the rotor 2020 forms a recess 2502 which
receives the
sample element 2448. The sample element 2448 can be held in the recess 2502 by
frictional interaction, adhesives, or any other suitable coupling means. The
illustrated
sample element 2448 is recessed in the rotor 2020. However, the sample element
2448 can
alternatively overlie or protrude from the rotor 2020.
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[0294] The sainple element 2448 can be used for a predetermined length of
time, to prepare a predetennined amount of sample fluid, to perform a number
of analyses,
etc. If desired, the sample element 2448 can be reinoved from the rotor 2020
and then
discarded. Another sample element 2448 can then be placed into the recess
2502. Thus,
even if the cassette 820 is disposable, a plurality of disposable sample
elements 2448 can be
used with a single cassette 820. Accordingly, a single cassette 820 can be
used with any
number of sample eleinents as desired. Alternatively, the cassette 820 can
have a sample
eleinent 2448 that is pennaneiitly coupled to the rotor 2020. In some
embodiments, at least
a portion of the sainple element 2448 is integrally or monolithically formed
with the rotor
body 2446. Additionally or alternatively, the rotor 2020 can comprise a
plurality of sample
elements (e.g., with a record sample element in place of the bypass 2452). In
this
embodiment, a plurality of samples (e.g., bodily fluid) can be prepared
siinultaneously to
reduce sample preparation time.
[0295] FIGURES 26A and 26B illustrate a layered construction technique
which can be employed when fonning certain embodiments of the sample element
2448.
The depicted layered sainple element 2448 comprises a first layer 2473, a
second layer
2475, and a third layer 2478. The second layer 2475 is preferably positioned
between the
first layer 2473 and the third layer 2478. The first layer 2473 fonns an upper
chamber wall
2482, and the third layer 2478 forms a lower chamber wall 2484. A lateral wall
2490 of the
second layer 2475 defines the sides of the chamber 2464 and the fluid channels
2466, 2468.
[0296] The second layer 2475 can be formed by die-cutting a substantially
unifonn-thickness sheet of a material to form the lateral wall pattern shownn
in FIGURE
26A. The second layer 2475 can comprise a layer of lightweight flexible
material, such as a
polymer material, with adhesive disposed on either side thereof to adhere the
first and third
layers 2473, 2478 to the second layer 2475 in "sandwich" fashion as shown in
FIGURE
26B. Alternatively, the second layer 2475 can comprise an "adhesive-only"
layer formed
from a unifonn-thickness sheet of adhesive which has been die-cut to fonn the
depicted
lateral wall pattern.
[0297] However constructed, the second layer 2475 is preferably of uniform
thickness to define a substantially uniform thickness or path length of the
sample chamber
2464 and/or interrogation region 2091. This path length (and therefore the
thickness of the
second layer 2475 as well) is preferably between 10 microns and 100 microns,
or is 20, 40,
50, 60, or 80 microns, in various embodiments.
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[0298] The upper chamber wall 2482, lower chamber wall 2484, and lateral
wall 2490 cooperate to form the chamber 2464. The upper chamber wall 2482
and/or the
lower chamber wall 2484 can permit the passage of electromagnetic energy
therethrough.
Accordingly, one or both of the first and third layers 2473, 2478 comprises a
sheet or layer
of material which is relatively or highly transmissive of electromagnetic
radiation
(preferably infrared radiation or mid-infrared radiation) such as barium
fluoride, silicon,
polyethylene or polypropylene. If only one of the layers 2473, 2478 is so
transmissive, the
other of the layers is preferably reflective, to back-reflect the incoming
radiation beam for
detection on the same side of the sainple element 2448 as it was emitted. Thus
the upper
chamber wall 2482 and/or lower chamber wall 2484 can be considered optical
window(s).
These window(s) are disposed on one or both sides of the interrogation region
2091 of the
sample element 2448.
[0299] In one embodiment, sample eleinent 2448 has opposing sides that are
transmissive of infrared radiation and suitable for making optical
measurements as
described, for example, in U.S. Patent Application Publication No.
2005/0036146,
published February 17, 2005, titled SAMPLE ELEMENT QUALIFICATION, and hereby
incorporated by reference and made a part of this specification. Except as
further described
herein, the embodiments, features, systeins, devices, materials, methods and
techniques
described herein may, in some embodiments, be similar to any one or more of
the
embodiments, features, systems, devices, materials, methods and techniques
described in
U.S. Patent Application Publication No. 2003/0090649, published on May 15,
2003, titled
REAGENT-LESS WHOLE-BLOOD GLUCOSE METER; or in U.S. Patent Application
Publication No. 2003/0086075, published on May 8, 2003, titled DEVICE AND
METHOD
FOR IN VITRO DETERMINATION OF ANALYTE CONCENTRATIONS WITHIN
BODY FLUIDS; or in U.S. Patent Application Publication No. 2004/0019431,
published
on January 29, 2004, titled METHOD OF DETERMINING AN ANALYTE
CONCENTRATION IN A SAMPLE FROM AN ABSORPTION SPECTRUM, or in U.S.
Patent No. 6,652,136, issued on November 25, 2003 to Marziali, titled METHOD
OF
SIMULTANEOUS MDCING OF SAMPLES. In addition, the embodiments, features,
systems, devices, materials, methods and techniques described herein may, in
certain
embodiments, be applied to or used in connection with any one or more of the
embodiments, features, systems, devices, materials, methods and techniques
disclosed in
the above-mentioned U.S. Patent Applications Publications Nos. 2003/0090649;
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2003/0086075; 2004/0019431; or U.S. Patent No. 6,652,136. All of the above-
mentioned
publications and patent are hereby incorporated by reference herein and made a
part of this
specification.
[0300] With reference to FIGURES 23B and 23C, the cassette 820 can further
comprise the movable fluid interface 2028 for filling and/or removing sample
liquid from
the sample element 2448. In the depicted einbodiment, the fluid interface 2028
is rotatably
mounted to the housing 2400 of the cassette 820. The fluid interface 2028 can
be actuated
between a lowered position (FIGURE 22C) and a raised or filling position
(FIGURE 27C).
When the interface 2028 is in the lowered position, the rotor 2020 can freely
rotate. To
transfer sample fluid to the sample element 2448, the rotor 2020 can be held
stationary and
in a sample element loading positioii (see FIGURE 22C) the fluid interface
2028 can be
actuated, as indicated by the arrow 2590, upwardly to the filling position.
When the fluid
interface 2028 is in the filling position, the fluid interface 2028 can
deliver sample fluid
into the sample element 2448 and/or remove sample fluid from the sample
element 2448.
[0301] With continued reference to FIGURES 27A and 27B, the fluid interface
2028 has a main body 2580 that is rotatably mounted to the housing 2400 of the
cassette
820. Opposing brackets 2581, 2584 can be einployed to rotatably couple the
main body
2580 to the housing 2400 of the cassette 820, and permit rotation of the main
body 2580
and the pins 2542, 2544 about an axis of rotation 2590 between the lowered
position and
the filling position. The main instrument 810 can include a horizontally
moveable actuator
(not shown) in the form of a solenoid, pneumatic actuator, etc. which is
extendible through
an opening 2404 in the cassette housing 2400 (see FIG. 23B). Upon extension,
the actuator
strikes the main body 2580 of the fluid interface 2028, causing the body 2580
to rotate to
the filling position shown in FIGURE 27C. The main body 2580 is preferably
spring-
biased towards the retracted position (shown in FIGURE 23A) so that retraction
of the
actuator allows the main body to return to the retracted position. The fluid
interface 2028
can thus be actuated for periodically placing fluid passageways of the pins
2542, 2544 in
fluid communication with a sample element 24481ocated on the rotor 2020.
[0302] The fluid interface 2028 of FIGURES 27A and 23B includes fluid
connectors 2530, 2532 that can provide fluid communication between the
interface 2028
and one or more of the fluid passageways of the apparatus 140 and/or sampling
system
100/800, as will be discussed in further detail below. The illustrated
connectors 2530, 2532
are in an upwardly extending orientation and positioned at opposing ends of
the main body
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2580. The connectors 2530, 2532 can be situated in other orientations and/or
positioned at
other locations along the main body 2580. The main body 2580 includes a first
inner
passageway (not shown) which provides fluid communication between the
connector 2530
and the pin 2542, and a second inner passageway (not shown) which provides
fluid
communication between the connector 2532 and the pin 2544.
[0303] The fluid pins 2542, 2544 extend outwardly fiom the main body 2580
and can engage the rotor 2020 to deliver and/or remove sample fluid to or from
the rotor
2020. The fluid pins 2542, 2544 have respective pin bodies 2561, 2563 and pin
ends 2571,
2573. The pin ends 2571, 2573 are sized to fit within corresponding ports
2472, 2474 of
the fluid connector 2027 and/or the ports 2572, 2574 of the fluid connector
2029, of the
rotor 2020. The pin ends 2571, 2573 can be slightly chamfered at their tips to
enhance the
sealing between the pin ends 2571, 2573 and rotor ports. In soine
embodiinents, the outer
diameters of the pin ends 2573, 2571 are slightly larger than the inner
diaineters of the ports
of the rotor 2020 to ensure a tight seal, and the inner diameters of the pins
2542, 2544 are
preferably identical or very close to the inner diameters of the channels
2510, 2512 leading
from the ports. In other embodiments, the outer diameter of the pin ends 2571,
2573 are
equal to or less than the inner diameters of the ports of the rotor 2020.
[0304] The connections between the pins 2542, 2544 and the corresponding
portions of the rotor 2020, either the ports 2472, 2474 leading to the sample
element 2448
or the ports 2572, 2574 leading to the bypass element 2452, can be relatively
simple and
inexpensive. At least a portion of the rotor 2020 can be somewhat compliant to
help ensure
a seal is fonned with the pins 2542, 2544. Alternatively or additionally,
sealing members
(e.g., gaskets, 0-rings, and the like) can be used to inhibit leaking between
the pin ends
2571, 2573 and corresponding ports 2472, 2474, 2572, 2574.
[0305] FIGURES 23A and 23B illustrate the cassette housing 2400 enclosing
the rotor assembly 2016 and the fluid interface 2028. The housing 2400 can be
a modular
body that defines an aperture or opening 2404 dimensioned to receive a drive
system
housing 2050 when the cassette 820 is operatively coupled to the main
instrument 810. The
housing 2400 can protect the rotor 2020 from external forces and can also
limit
contamination of samples delivered to a sample element in the rotor 2020, when
the
cassette 820 is mounted to the main instrument 810.
[0306] The illustrated cassette 820 has a pair of opposing side walls 2041,
2043,
top 2053, and a notch 2408 for mating with the detection system 1700. A front
wal12045
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and rear wa112047 extend between the side walls 2041, 2043. The rotor assembly
2016 is
mounted to the inner surface of the rear wall 2047. The front wall 2045 is
configured to
mate with the main instrument 810 while providing the drive system 2030 with
access to
the rotor assembly 2016.
[0307] The illustrated front wa112045 has the opening 2404 that provides
access
to the rotor assembly 2016. The drive system 2030 can be passed through the
opening 2404
into the interior of the cassette 820 until it operatively engages the rotor
asseinbly 2016.
The opening 2404 of FIGURE 23B is configured to mate and tightly surround the
drive
system 2030. The illustrated opening 2404 is generally circular and includes
an upper
notch 2405 to permit the fluid interface actuator of the main instrument 810
to access the
fluid interface 2028, as discussed above. The opening 2404 can have other
configurations
suitable for adinitting the drive system 2030 and actuator into the cassette
820.
[0308] The notch 2408 of the housing 2400 can at least partially surround the
projecting portion of the analyte detection system 1700 when the cassette 820
is loaded
onto the main instrument 810. The illustrated notch 2408 defines a cassette
slot 2410
(FIGURE 23A) that is aligned with elongate slot 2074 shown in FIGURE 22C, upon
loading of the cassette 820. The rotating rotor 2020 can thus pass through the
aligned slots
2410, 2074. In some embodiments, the notch 2408 has a generally U-shaped axial
cross
section as shown. More generally, the configuration of the notch 2408 can be
selected
based on the design of the projecting portion of the detection systeni 1700.
[0309] Although not illustrated, fasteners, clips, mechanical fastening
assemblies, snaps, or other coupling means can be used to ensure that the
cassette 820
remains coupled to the main instrument 810 during operation. Alternatively,
the interaction
between the housing 2400 and the components of the main instrument 810 can
secure the
cassette 820 to the main instrument 810.
[0310] FIGURE 28 is a cross-sectional view of the main instrument 810. The
illustrated centrifuge drive system 2030 extends outwardly from a front face
2046 of the
main instrument 810 so that it can be easily mated with the rotor assembly
2016 of the
cassette 820. When the centrifuge drive system 2030 is energized, the drive
system 2030
can rotate the rotor 2020 at a desired rotational speed.
[0311] The illustrated centrifuge drive systein 2030 of FIGURES 23E and 28
includes a centrifuge drive motor 2038 and a drive spindle 2034 that is
drivingly connected
to the drive motor 2038. The drive spindle 2034 extends outwardly from the
drive motor
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2038 and forms a centrifuge interface 2042. The centrifuge interface 2042
extends
outwardly from the drive system housing 2050, which houses the drive motor
2038. To
impart rotary inotion to the rotor 2020, the centrifuge interface 2042 can
have keying
members, protrusions, notches, detents, recesses, pins, or other types of
structures that can
engage the rotor 2020 such that the drive spindle 2034 and rotor 2020 are
coupled together.
[0312] The centrifuge drive motor 2038 of FIGURE 28 can be any suitable
motor that can impart rotary motion to the rotor 2020. When the drive motor
2038 is
energized, the drive motor 2038 can rotate the drive spindle 2034 at constant
or varying
speeds. Various types of motors, including, but not limited to, centrifuge
motors, stepper
motors, spindle motors, electric motors, or any other type of motor for
outputting a torque
can be utilized. The centrifuge drive motor 2038 is preferably fixedly secured
to the drive
systein housing 2050 of the main instrument 810.
[0313] The drive motor 2038 can be the type of motor typically used in
personal
computer hard drives that is capable of rotating at about 7,200 RPM on
precision bearings,
such as a motor of a Seagate Model ST380011A hard drive (Seagate Technology,
Scotts
Valley, CA) or similar motor. In one embodiment, the drive spindle 2034 inay
be rotated at
6,000 rpm, which yields approximately 2,000 G's for a rotor having a 2.5 inch
(64
millimeter) radius. In another embodiment, the drive spindle 2034 may be
rotated at speeds
of approximately 7,200 rpm. The rotational speed of the drive spindle 2034 can
be selected
to achieve the desired centrifugal force applied to a sample carried by the
rotor 2020.
[0314] The main instrument 810 includes a main housing 2049 that defines a
chamber sized to accommodate a filter wheel assembly 2300 including a filter
drive motor
2320 and filter wheel 2310 of the analyte detection system 1700. The main
housing 2049
defines a detection system opening 3001 configured to receive an analyte
detection system
housing 2070. The illustrated analyte detection system housing 2070 extends or
projects
outwardly from the housing 2049.
[0315] The main instrument 810 of FIGURES 23C and 23E includes a bubble
sensor unit 321, a pump 2619 in the form of a peristaltic pump roller 2620a
and a roller
support 2620b, and valves 323a, 323b. The illustrated valves 323a, 323b are
pincher pairs,
although other types of valves can be used. When the cassette 820 is
installed, these
components can engage components of a fluid handling network 2600 of the
cassette 820,
as will be discussed in greater detail below.
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[0316] With continued reference to FIGURE 28, the analyte detection systein
housing 2070 surrounds and houses some of the internal components of the
analyte
detection system 1700. The elongate slot 2074 extends downwardly from an upper
face
2072 of the housing 2070. The elongated slot 2074 is sized and dimensioned so
as to
receive a portion of the rotor 2020. When the rotor 2020 rotates, the rotor
2020 passes
periodically through the elongated slot 2074. When a sample element of the
rotor 2020 is
in the detection region 2080 defined by the slot 2074, the analyte detection
system 1700 can
analyze material in the sample element.
[0317] The analyte detection system 1700 can be a spectroscopic bodily fluid
analyzer that preferably comprises an energy source 1720. The energy source
1720 can
generate an energy beam directed along a major optical axis X that passes
through the slot
2074 towards a sample detector 1745. The slot 2074 thus permits at least a
portion of the
rotor (e.g., the interrogation region 2091 or sample chamber 2464 of the
sample element
2448) to be positioned on the optical axis X. To analyze a sample carried by
the sample
element 2448, the sample element and sample caii be positioned in the
detection region
2080 on the optical axis X such that light emitted from the source 1720 passes
through the
slot 2074 and the sample disposed within the sample element 2448.
[0318] The analyte detection system 1700 can also comprise one or more lenses
positioned to transmit energy outputted from the energy source 1720. The
illustrated
analyte detection system 1700 of FIGURE 28 comprises a first lens 2084 and a
second lens
2086. The first lens 2084 is configured to focus the energy from the source
1720 generally
onto the sample element and material sample. The second lens 2086 is
positioned between
the sample element and the sample detector 1745. Energy from energy source
1720 passing
through the sample element can subsequently pass through the second lens 2086.
A third
lens 2090 is preferably positioned between a beam splitter 2093 and a
reference detector
2094. The reference detector 2094 is positioned to receive energy from the
beam splitter
2093.
[0319] The analyte detection system 1700 can be used to determine the analyte
concentration in the sample carried by the rotor 2020. Other types of
detection or analysis
systems can be used with the illustrated centrifuge apparatus or sample
preparation unit.
The fluid handling and analysis apparatus 140 is shown for illustrative
purposes as being
used in conjunction with the analyte detection system 1700, but neither the
sample
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preparation unit nor analyte detection system are intended to be limited to
the illustrated
configuration, or to be limited to being used together.
[0320] To assemble the fluid handling and analysis apparatus 140, the cassette
820 can be moved towards and installed onto the main instrument 810, as
indicated by the
arrow 2007 in FIGURE 22A. As the cassette 820 is installed, the drive system
2030 passes
through the aperture 2040 so that the spindle 2034 mates with the rotor 2020.
Simultaneously, the projecting portion of the detection system 1700 is
received in the notch
2408 of the cassette 820. When the cassette 820 is installed on the main
instrument 810,
the slot 2410 of the notch 2048 and the slot 2074 of the detection system 1700
are aligned
as shown in FIGURE 22C. Accordingly, when the cassette 820 and main instrument
810
are assembled, the rotor 2020 can rotate about the axis 2024 and pass through
the slots
2410, 2074.
[0321] After the cassette 820 is assembled with the main instrument 810, a
sainple can be added to the sample element 2448. The cassette 820 can be
connected to an
infusion source and a patient to place the system in fluid communication with
a bodily fluid
to be analyzed. Once the cassette 820 is connected to a patient, a bodily
fluid may be
drawn from the patient into the cassette 820. The rotor 2020 is rotated to a
vertical loading
position wherein the sample element 2448 is near the fluid interface 2028 and
the bypass
element 2452 is positioned within the slot 2074 of the detection system 1700.
Once the
rotor 2020 is in the vertical loading position, the pins 2542, 2544 of the
fluid interface 2028
are positioned to mate with the ports 2472, 2474 of the rotor 2020. The fluid
interface 2028
is then rotated upwardly until the ends 2571, 2573 of the pins 2542, 2544 are
inserted into
the ports 2472, 2474.
[0322] When the fluid interface 2028 and the sample element 2448 are thus
engaged, sample fluid (e.g., whole blood) is pumped into the sample eleinent
2448. The
sample can flow through the pin 2544 into and through the rotor channel 2512
and the
sample element channel 2466, and into the sample chamber 2464. As shown in
FIGURE
25C, the sample chamber 2464 can be partially or completely filled with sample
fluid. In
some embodiments, the sample fills at least the sample chamber 2464 and the
interrogation
region 2091 of the sample element 2448. The sample can optionally fill at
least a portion of
the sample element channels 2466, 2468. The illustrated sam.ple chamber 2464
is filled
with whole blood, although the sainple chamber 2464 can be filled with other
substances.
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After the sample element 2448 is filled with a desired amount of fluid, the
fluid interface
2028 can be moved to a lowered position to permit rotation of the rotor 2020.
[0323] The centrifuge drive system 2030 can then spin the rotor 2020 and
associated sample element 2448 as needed to separate one or more components of
the
sample. The separated component(s) of the sample may collect or be segregated
in a
section of the sample element for analysis. In the illustrated embodiment, the
sample
element 2448 of FIGURE 25C is filled with whole blood prior to centrifuging.
The
centrifugal forces can be applied to the whole blood until plasma 2594 is
separated from the
blood cells 2592. After centrifuging, the plasma 2594 is preferably located in
a radially
inward portion of the sample element 2448, including the interrogation region
2091. The
blood cells 2592 collect in a portion of the sample chainber 2464 which is
radially outward
of the plasina 2594 and interrogation region 2091.
[0324] The rotor 2020 can then be moved to a vertical analysis position
wherein
the sample eleinent 2448 is disposed within the slot 2074 and aligned with the
source 1720
and the sainple detector 1745 on the major optical axis X. When the rotor 2020
is in the
analysis position, the interrogation portion 2091 is preferably aligned with
the major optical
axis X of the detection system 1700. The analyte detection system 1700 can
analyze the
sample in the sample element 2448 using spectroscopic analysis techniques as
discussed
elsewhere herein.
[0325] After the sample has been analyzed, the sample can be removed from the
sample element 2448. The sample may be transported to a waste receptacle so
that the
sample element 2448 can be reused for successive sample draws and analyses.
The rotor
2020 is rotated from the analysis position back to the vertical loading
position. To empty
the sample element 2448, the fluid interface 2028 can again engage the sample
element
2448 to flush the sample element 2448 with fresh fluid (either a new sample of
body fluid,
or infusion fluid). The fluid interface 2028 can be rotated to mate the pins
2542, 2544 with
the ports 2472, 2474 of the rotor 2020. The fluid interface 2028 can pump a
fluid through
one of the pins 2542, 2544 until the sample is flushed from the sample element
2448.
Various types of fluids, such as infusion liquid, air, water, and the like,
can be used to flush
the sample element 2448. After the sample element 2448 has been flushed, the
sample
eleinent 2448 can once again be filled with another sample.
[0326] In an alternative embodiment, the sample element 2448 may be removed
from the rotor 2020 and replaced after each separate analysis, or after a
certain number of
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analyses. Once the patient care has terminated, the fluid passageways or
conduits may be
disconnected from the patient and the sample cassette 820 which has come into
fluid
contact with the patient's bodily fluid may be disposed of or sterilized for
reuse. The main
instrument 810, however, has not come into contact with the patient's bodily
fluid at any
point during the analysis and therefore can readily be connected to a new
fluid handling
cassette 820 and used for the analysis of a subsequent patient.
[0327] The rotor 2020 can be used to provide a fluid flow bypass. To
facilitate
a bypass flow, the rotor 2020 is first rotated to the vertical analysis/bypass
position wherein
the bypass elemeilt 2452 is near the fluid interface 2028 and the sample
eleinent 2448 is in
the slot 2074 of the analyte detection system 1700. Once the rotor 2020 is in
the vertical
analysis/bypass position, the pins 2542, 2544 can mate with the ports 2572,
2574 of the
rotor 2020. In the illustrated enlbodiment, the fluid interface 2028 is
rotated upwardly until
the ends 2571, 2573 of the pins 2542, 2544 are inserted into the ports 2572,
2574. The
bypass element 2452 can then provide a completed fluid circuit so that fluid
can flow
through one of the pins 2542, 2544 into the bypass element 2452, through the
bypass
element 2452, and then through the other pin 2542, 2544. The bypass element
2452 can be
utilized in this manner to facilitate the flushing or sterilizing of a fluid
system connected to
the cassette 820.
[0328] As shown in FIGURE 23B, the cassette 820 preferably includes the fluid
handling network 2600 which can be employed to deliver fluid to the sample
element 2448
in the rotor 2020 for analysis. The main instrument 810 has a number of
components that
can, upon installation of the cassette 820 on the main instrument 810, extend
through
openings in the front face 2045 of cassette 820 to engage and interact with
components of
the fluid handling network 2600, as detailed below.
[0329] The fluid handling network 2600 of the fluid handling and analysis
apparatus 140 includes the passageway 111 which extends from the connector 120
toward
and through the cassette 820 until it becomes the passageway 112, which
extends from the
cassette 820 to the patient connector 110. A portion llla of the passageway
111 extends
across an opening 2613 in the front face 2045 of the cassette 820. When the
cassette 820 is
installed on the main instrument 810, the roller pump 2619 engages the portion
l i la,
which becomes situated between the impeller 2620a and the impeller support
2620b (see
FIGURE 23C).
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[0330] The fluid handling network 2600 also includes passageway 113 which
extends from the patient connector 110 towards and into the cassette 820.
After entering
the cassette 820, the passageway 113 extends across an opening 2615 in the
front face 2045
to allow engagement of the passageway 113 with a bubble sensor 321 of the main
instrument 810, when the cassette 820 is installed on the main instrument 810.
The
passageway 113 then proceeds to the connector 2532 of the fluid interface
2028, which
extends the passageway 113 to the pin 2544. Fluid drawn from the patient into
the
passageway 113 can thus flow into and through the fluid interface 2028, to the
pin 2544.
The drawn body fluid can further flow from the pin 2544 and into the sample
element 2448,
as detailed above.
[0331] A passageway 2609 extends from the connector 2530 of the fluid
interface 2028 and is thus in fluid communication with the pin 2542. The
passageway 2609
branches to form the waste line 324 and the pump line 327. The waste line 324
passes
across an opening 2617 in the front face 2045 and extends to the waste
receptacle 325. The
pump line 327 passes across an opening 2619 in the front face 2045 and extends
to the
pump 328. When the cassette 820 is installed on the main instrument 810, the
pinch valves
323a, 323b extend through the openings 2617, 2619 to engage the lines 324,
327,
respectively.
[0332] The waste receptacle 325 is mounted to the front face 2045. Waste fluid
passing from the fluid interface 2028 can flow through the passageways 2609,
324 and into
the waste receptacle 325. Once the waste receptacle 325 is filled, the
cassette 820 can be
removed from the main instrument 810 and discarded. Alternatively, the filled
waste
receptacle 325 can be replaced with an empty waste receptacle 325.
[0333] The pump 328 can be a displacement pump (e.g., a syringe pump). A
piston control 2645 can extend over at least a portion of an opening 2621 in
the cassette
face 2045 to allow engagement with an actuator 2652 when the cassette 820 is
installed on
the main instrument 810. When the cassette 820 is installed, the actuator 2652
(FIGURE
23E) of the main instrument 810 engages the piston control 2645 of the pump
328 and can
displace the piston control 2645 for a desired fluid flow.
[0334] It will be appreciated that, upon installing the cassette 820 of FIGURE
23A on the main instrument 810 of FIGURE 23E, there is formed (as shown in
FIGURE
23E) a fluid circuit similar to that shown in the sampling unit 200 in FIGURE
3. This fluid
circuit can be operated in a manner similar to that described above in
connection with the
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apparatus of FIGURE 3 (e.g., in accordance with the methodology illustrated in
FIGURES
7A-7J and Table 1).
[0335] FIGURE 24A depicts another embodiment of a fluid handling network
2700 that can be employed in the cassette 820. The fluid handling network 2700
can be
generally similar in structure and function to the network 2600 of FIGURE 23B,
except as
detailed below. The network 2700 includes the passageway 111 which extends
from the
connector 120 toward and through the cassette 820 until it becomes the
passageway 112,
which extends from the cassette 820 to the patient connector 110. A portion
111a of the
passageway 111 extends across an opening 2713 in the front face 2745 of the
cassette 820.
When the cassette 820 is installed on the main instrurnent 810, a roller puinp
2619 of the
main instrument 810 of FIGURE 24B can engage the portion 111a in a manner
similar to
that described above with respect to FIGURES 23B-23C. The passageway 113
extends
from the patient connector 110 towards and into the cassette 820. After
entering the
cassette 820, the passageway 113 extends across an opening 2763 in the front
face 2745 to
allow engagement with a valve 2733 of the main instrument 810. A waste line
2704
extends from the passageway 113 to the waste receptacle 325 and across an
opening 2741
in the front face 2745. The passageway 113 proceeds to the connector 2532 of
the fluid
interface 2028, which extends the passageway 113 to the pin 2544. The
passageway 113
crosses an opening 2743 in the front face 2745 to allow engagement of the
passageway 113
with a bubble sensor 2741 of the main instrument 810 of FIGURE 24B. When the
cassette
820 is installed on the main instrument 810, the pinch valves 2732, 2733
extend through
the openings 2731, 2743 to engage the passageways 113, 2704, respectively.
[0336] The illustrated fluid handling network 2700 also includes a passageway
2723 which extends between the passageway 111 and a passageway 2727, which in
turn
extends between the passageway 2723 and the fluid interface 2028. The
passageway 2727
extends across an opening 2733 in the front face 2745. A pump line 2139
extends from a
pump 328 to the passageways 2723, 2727. When the cassette 820 is installed on
the main
instrument 810, the pinch valves 2716, 2718 extend through the openings 2725,
2733 in the
front face 2745 to engage the passageways 2723, 2727, respectively.
[0337] It will be appreciated that, upon installing the cassette 820 on the
main
instrument 810 (as shown in FIGURE 24A), there is formed a fluid circuit that
can be
operated in a manner similar to that described above, in connection with the
apparatus of
FIGS. 9-10.
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[0338] In view of the foregoing, it will be furtlier appreciated that the
various
embodiments of the fluid handling and analysis apparatus 140 (comprising a
main
instrument 810 and cassette 820) depicted in FIGURES 22A-28 can serve as the
fluid
handling and analysis apparatus 140 of any of the sampling systeins
100/300/500, or the
fluid handling system 10, depicted in FIGURES 1-5 herein. In addition, the
fluid handling
and analysis apparatus 140 of FIGURES 22A-28 can, in certain embodiments, be
similar to
the apparatus 140 of FIGURES 1-2 or 8-10, except as further described above.
SECTION V - METHODS FOR DETERMINING ANALYTE CONCENTRATIONS
FROM SAMPLE SPECTRA
[0339] This section discusses a nuinber of computational methods or algorithms
which may be used to calculate the concentration of the analyte(s) of interest
in the sainple
S, and/or to compute other measures that may be used in support of
calculations of analyte
concentrations. Any one or combination of the algorithms disclosed in this
section may
reside as program instructions stored in the memory 212 so as to be accessible
for execution
by the processor 210 of the fluid handling and analysis apparatus 140 or
analyte detection
system 334 to compute the concentration of the analyte(s) of interest in the
sample, or other
relevant measures.
[0340] Several disclosed embodiments are devices and methods for analyzing
material sample measurements and for quantifying one or more analytes in the
presence of
interferents. Interferents can comprise components of a material sample being
analyzed for
an analyte, where the presence of the interferent affects the quantification
of the analyte.
Thus, for example, in the spectroscopic analysis of a sample to determine an
analyte
concentration, an interferent could be a compound having spectroscopic
features that
overlap with those of the analyte. The presence of such an interferent can
introduce errors
in the quantification of the analyte. More specifically, the presence of
interferents can affect
the sensitivity of a measurement technique to the concentration of analytes of
interest in a
material sample, especially when the system is calibrated in the absence of,
or with an
unknown amount of, the interferent.
[0341] Independently of or in combination with the attributes of interferents
described above, interferents can be classified as being endogenous (i.e.,
originating within
the body) or exogenous (i.e., introduced from or produced outside the body).
As example of
these classes of interferents, consider the analysis of a blood sample (or a
blood component
sample or a blood plasma sample) for the analyte glucose. Endogenous
interferents include
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those blood components having origins within the body that affect the
quantification of
glucose, and may include water, heinoglobin, blood cells, and any other
component that
naturally occurs in blood. Exogenous interferents include those blood
components having
origins outside of the body that affect the quantification of glucose, and can
include iteins
administered to a person, such as medicaments, drugs, foods or herbs, whether
administered
orally, intraveiiously, topically, etc.
[0342] Independently of or in combination with the attributes of interferents
described above, interferents can coinprise coinponents which are possibly but
not
necessarily present in the saniple type under analysis. In the example of
analyzing sainples
of blood or blood plasma drawn from patients who are receiving medical
treatment, a
medicament such as acetaminophen is possibly, but not necessarily present in
this sample
type. In contrast, water is necessarily present in such blood or plasma
samples.
[0343] To facilitate an understanding of the inventions, embodiments are
discussed herein where one or more analyte concentrations are obtained using
spectroscopic
measurements of a sample at wavelengths including one or more wavelengths that
are
identified with the analyte(s). The embodiments disclosed herein are not meant
to limit,
except as claimed, the scope of certain disclosed inventions which are
directed to the
analysis of measurements in general.
[0344] As an example, certain disclosed methods are used to quantitatively
estimate the concentration of one specific compound (an analyte) in a mixture
from a
measurement, where the mixture contains compounds (interferents) that affect
the
measurement. Certain disclosed embodiments are particularly effective if each
analyte and
interferent component has a characteristic signature in the measurement, and
if the
measurement is approximately affme (i.e., includes a linear component and an
offset) with
respect to the concentration of each analyte and interferent. In one
embodiment, a method
includes a calibration process including an algorithm for estimating a set of
coefficients and
an offset value that permits the quantitative estimation of an analyte. In
another
embodiment, there is provided a method for modifying hybrid linear algorithm
(HLA)
methods to accommodate a random set of interferents, while retaining a high
degree of
sensitivity to the desired component. The data employed to accommodate the
random set of
interferents are (a) the signatures of each of the members of the family of
potential
additional components and (b) the typical quantitative level at which each
additional
component, if present, is likely to appear.
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[0345] Certain methods disclosed herein are directed to the estimation of
analyte concentrations in a material sample in the possible presence of an
interferent. In
certain embodiments, any one or combination of the methods disclosed herein
may be
accessible and executable processor 210 of system 334. Processor 210 may be
connected to
a computer network, and data obtained from system 334 can be transmitted over
the
network to one or more separate computers that implement the methods. The
disclosed
methods can include the manipulation of data related to sample measurements
and other
information supplied to the methods (including, but not liinited to,
interferent spectra,
sample population models, and threshold values, as described subsequently).
Any or all of
this information, as well as specific algorithms, may be updated or changed to
improve the
method or provide additional infonnation, such as additional analytes or
interferents.
[0346] Certain disclosed methods generate a "calibration constant" that, when
nlultiplied by a measurement, produces an estimate of an analyte
concentration. Both the
calibration constant and measurement can comprise arrays of numbers. The
calibration
constant is calculated to minimize or reduce the sensitivity of the
calibration to the presence
of interferents that are identified as possibly being present in the sample.
Certain methods
described herein generate a calibration constant by: 1) identifying the
presence of possible
interferents; and 2) using information related to the identified interferents
to generate the
calibration constant. These certain methods do not require that the
information related to
the interferents includes an estimate of the interferent concentration - they
merely require
that the interferents be identified as possibly present. In one embodiment,
the method uses a
set of training spectra each having known analyte concentration(s) and
produces a
calibration that minimizes the variation in estimated analyte concentration
with interferent
concentration. The resulting calibration constant is proportional to analyte
concentration(s)
and, on average, is not responsive to interferent concentrations.
[0347] In one embodiment, it is not required (though not prohibited either)
that
the training spectra include any spectrum from the individual whose analyte
concentration
is to be determined. That is, the term "training" when used in reference to
the disclosed
methods does not require training using measurements from the individual whose
analyte
concentration will be estimated (e.g., by analyzing a bodily fluid sample
drawn from the
individual).
[0348] Several terms are used herein to describe the estimation process. As
used
herein, the term "Sample Population" is a broad term and includes, without
limitation, a
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large number of samples having measurements that are used in the computation
of a
calibration - in other words, used to train the method of generating a
calibration. For an
embodiment involving the spectroscopic determination of glucose concentration,
the
Sample Population measurements can each include a spectrum =(analysis
measurement) and
a glucose concentration (analyte measurement). In one embodiment, the Sample
Population
measurements are stored in a database, referred to herein as a "Population
Database."
[0349] The Sample Population may or may not be derived from measurements
of material sainples that contain interferents to the measurement of the
analyte(s) of
interest. One distinction made herein between different interferents is based
on whether the
interferent is present in both the Sample Population and the sample being
measured, or only
in the sample. As used herein, the term "Type-A interferent" refers to an
interferent that is
present in both the Sample Population and in the material sample being
measured to
determine an analyte concentration. In certain methods it is assumed that the
Sample
Population includes only interferents that are endogenous, and does not
include any
exogenous interferents, and thus Type-A interferents are endogenous. The
number of Type-
A interferents depends on the measurement and analyte(s) of interest, and may
number, in
general, from zero to a very large number. The material sasnple being
measured, for
example sample S, may also include interferents that are not present in the
Sample
Population. As used herein, the term "Type-B interferent" refers to an
interferent that is
either: 1) not found in the Sample Population but that is found in the
material sample being
measured (e.g., an exogenous interferent), or 2) is found naturally in the
Sample
Population, but is at abnormally high concentrations in the material sample
(e.g., an
endogenous interferent). Examples of a Type-B exogenous interferent may
include
medications, and examples of Type-B endogenous interferents may include urea
in persons
suffering fiom renal failure. In the example of mid-IR spectroscopic
absorption
measurement of glucose in blood, water is found in all blood sainples, and is
thus a Type-A
interferent. For a Sample Population made up of individuals who are not taking
intravenous
drugs, and a material sample taken from a hospital patient who is being
administered a
selected intravenous drug, the selected drug is a Type-B interferent.
[0350] In one embodiment, a list of one or more possible Type-B Interferents
is
referred to herein as forming a "Library of Interferents," and each
interferent in the library
is referred to as a "Library Interferent." The Library Interferents include
exogenous
interferents and endogenous interferents that may be present in a material
sample due, for
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example, to a medical condition causing abnormally high concentrations of the
endogenous
interferent.
[0351] In addition to components naturally found in the blood, the ingestion
or
injection of some medicines or illicit drugs can result in very high and
rapidly changing
concentrations of exogenous interferents. This results in problems in
measuring analytes in
blood of hospital or emergency room patients. An example of overlapping
spectra of blood
coinponents aiid medicines is illustrated in FIGURE 29 as the absorption
coefficient at the
same concentration and optical pathlength of pure glucose and three spectral
interferents,
specifically mannitol (cheinical forinula: hexa.ne-1,2,3,4,5,6-hexaol), N
acetyl L cysteine,
dextran, and procainamide (chemical formula: 4-amino-N-(2-
diethylaininoethyl)benzamid).
FIGURE 30 shows the logaritlun of the change in absorption spectra from a
Sample
Population blood composition as a function of wavelength for blood containing
additional
likely concentrations of components, specifically, twice the glucose
concentration of the
Sample Population and various amounts of mannitol, N acetyl L cysteine,
dextran, and
procainamide. The presence of these components is seen to affect absorption
over a wide
range of wavelengths. It can be appreciated that the determination of the
concentration of
one species without a priori knowledge or independent measurement of the
concentration of
other species is problematic.
[0352] One method for estimating the concentration of an analyte in the
presence of interferents is presented in flowchart 3100 of FIGURE 31 as a
first step (Block
3110) where a measurement of a sample is obtained, a second step (Block 3120),
where the
obtained measurement data is analyzed to identify possible interferents to the
analyte, a
third step (Block 3130) where a model is generated for predicting the analyte
concentration
in the presence of the identified possible interferents, and a fourth step
(Block 3140) where
the model is used to estimate the analyte concentration in the sample from the
measurenlent. Preferably the step of Block 3130 generates a model where the
error is
minimized for the presence of the identified interferents that are not present
in a general
population of which the sample is a member.
[0353] The method Blocks 3110, 3120, 3130, and 3140 may be repeatedly
performed for each analyte whose concentration is required. If one measurement
is sensitive
to two or more analytes, then the methods of Blocks 3120, 3130, and 3140 may
be repeated
for each analyte. If each analyte has a separate measurement, then the methods
of Blocks
3110, 3120, 3130, and 3140 may be repeated for each analyte.
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[0354] An einbodiment of the method of flowchart 3100 for the determination
of an analyte from spectroscopic measurements will now be discussed. Further,
this
embodiment will estimate the amount of glucose concentration in blood sample
S, without
limit to the scope of the inventions disclosed herein. In one embodiment, the
measurement
of Block 3110 is an absorbance spectrum, CS(~1), of a measurement sample S
that has, in
general, one analyte of interest, glucose, and one or more interferents. In
one embodiment,
the methods include generating a calibration constant ic(k;) that, when
inultiplied by the
absorbance spectrum Cs(k1), provides an estimate, gest, of the glucose
concentration gs.
[0355] As described subsequently, one einbodiinent of Block 3120 includes a
statistical coinparison of the absorbance spectrum of sample S with a spectrum
of the
Sample Population and combinations of individual Library Interferent spectra.
After the
analysis of Block 3120, a list of Library Interferents that are possibly
contained in sample S
has been identified and includes, depending on the outcome of the analysis of
Block 3120,
either no Library Interferents, or one or more Library Interferents. Block
3130 then
generates a large number of spectra using the large number of spectra of the
Sample
Population and their respective known analyte concentrations and known spectra
of the
identified Library Interferents. Block 3130 then uses the generated spectra to
generate a
calibration constant matrix to convert a measured spectrum to an analyte
concentration that
is the least sensitive to the presence of the identified Library Interferents.
Block 3140 then
applies the generated calibration constant to predict the glucose
concentration in sample S.
[0356] As indicated in Block 3110, a measurement of a sample is obtained. For
illustrative purposes, the measurement, CsQ;), is assumed to be a plurality of
measurements
at different wavelengths, or analyzed measurements, on a sample indicating the
intensity of
light that is absorbed by sample S. It is to be understood that spectroscopic
measureinents
and computations may be performed in one or more domains including, but not
limited to,
the transmittance, absorbance and/or optical density domains. The measurement
Cs(X;) is an
absorption, transmittance, optical density or other spectroscopic measurement
of the sample
at selected wavelength or wavelength bands. Such measurements may be obtained,
for
example, using analyte detection system 334. In general, sample S contains
Type-A
interferents, at concentrations preferably within the range of those found in
the Sample
Population.
[0357] In one embodiment, absorbance measurements are converted to
pathlength normalized measurements. Thus, for example, the absorbance is
converted to
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optical density by dividing the absorbance by the optical pathlength, L, of
the measurement.
In one embodiment, the pathlength L is measured from one or more absorption
measureinents on known compounds. Thus, in one embodiment, one or more
measurements of the absorption through a sample S of water or saline solutions
of known
concentration are made and the pathlength, L, is computed from the resulting
absorption
measurement(s). In another embodiment, absorption measurements are also
obtained at
portions of the spectruin that are not appreciably affected by the analytes
and interferents,
and the analyte measurement is supplemented with an absorption measurement at
those
wavelengths.
[0358] Some methods are "pathlength insensitive," in that they can be used
even
when the precise pathlength is not known beforehand. The sample can be placed
in the
sample chainber 903 or 2464, sample element 1730 or 2448, or in a cuvette or
other sainple
container. Electromagnetic radiation (in the mid-infrared range, for example)
can be
emitted from a radiation source so that the radiation travels through the
sample chamber. A
detector can be positioned where the radiation emerges, on the other side of
the sample
chamber from the radiation source, for example. The distance the radiation
travels through
the sample can be referred to as a "pathlength." In some einbodiments, the
radiation
detector can be located on the same side of the sample chamber as the
radiation source, and
the radiation can reflect off one or more internal walls of the sample chamber
before
reaching the detector.
[0359] As discussed above, various substances can be inserted into the sample
chamber. For example, a reference fluid such as water or saline solution can
be inserted, in
addition to a sample or samples containing an analyte or analytes. In some
embodiinents, a
saline reference fluid is inserted into the sample chamber and radiation is
emitted through
that reference fluid. The detector measures the amount and/or characteristics
of the
radiation that passes through the sample chamber and reference fluid without
being
absorbed or reflected. The measurement taken using the reference fluid can
provide
information relating to the pathlength traveled by the radiation. For example,
data may
already exist from previous measurements that have been taken under similar
circumstances. That is, radiation can be emitted previously through sample
chambers with
various known pathlengths to establish reference data that can be arranged in
a "look-up
table," for example. With reference fluid in the sample chamber, a one-to-one
correspondence can be experimentally established between various detector
readings and
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various pathlengths, respectively. This correspondence can be recorded in the
look-up
table, wliich can be recorded in a computer database or in electronic memory,
for example.
[0360] One method of determining the radiation pathlength can be
accomplished with a thin, empty sample chamber. In particular, this approach
can
determine the thickness of a narrow sample chamber or cell with two reflective
walls.
(Because the chamber will be filled with a sample, this same thickness
corresponds to the
"pathlength" radiation will travel through the sample). A range of radiation
wavelengths
can be emitted in a continuous maslner through the cell or sample chamber. The
radiation
can enter the cell and reflect off the interior cell walls, bouncing back and
forth between
those walls one or multiple times before exiting the cell and passing into the
radiation
detector. This can create a periodic interference pattern or "fringe" with
repeating maxima
and minima. This periodic pattern can be plotted where the horizontal axis is
a range of
wavelengths and the vertical axis is a range of transmittance, measured as a
percentage of
total transmittance, for example. The maxima occur when the radiation
reflected off of the
two internal surfaces of the cell has traveled a distance that is an integral
multiple N of the
wavelength of the radiation that was transmitted without reflection.
Constructive
interference occurs whenever the wavelength is equal to 2b/N, where "b" is the
thickness
(or pathlength) of the cell. Thus, if AN is the number of maxima in this
fringe pattern for a
given range of wavelengths k1 k2, then the thickness of the cell b is provided
by the
following relation: b = AN / 2(k1- k2). This approach can be especially useful
when the
refractive index of the material within the sample chamber or fluid cell is
not the same as
the refractive index of the walls of the cell, because this condition improves
reflection.
[0361] Once the pathlength has been determined, it can be used to calculate or
determine a reference value or a reference spectrum for the interferents (such
as protein or
water) that may be present in a sample. For example, both an analyte such as
glucose and
an interferent such as water may absorb radiation at a given wavelength. When
the source
emits radiation of that wavelength and the radiation passes through a sample
containing
both the analyte and the interferent, both the analyte and the interferent
absorb the radiation.
The total absorption reading of the detector is thus fully attributable to
neither the analyte
nor the interferent, but a combination of the two. However, if data exists
relating to how
much radiation of a given wavelength is absorbed by a given interferent when
the radiation
passes through a sample with a given pathlength, the contribution of the
interferent can be
subtracted from the total reading of the detector and the remaining value can
provide
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information regarding concentration of the analyte in the sample. A similar
approach can
be taken for a whole spectrum of wavelengths. If data exists relating to how
inuch radiation
is absorbed by an interferent over a range of wavelengths when the radiation
passes through
a sample with a given pathlength, the interferent absorbance spectrum can be
subtracted
from the total absorbance spectrum, leaving only the analyte's absorbance
spectrum for that
range of wavelengths. If the interferent absorption data is taken for a range
of possible
pathlengths, it can be helpful to determine the pathlength of a particular
sample chamber
first so that the correct data can be found for samples measured in that
sample chamber.
[0362] This same process can be applied iteratively or simultaneously for
multiple interferents and/or multiple analytes. For example, the water
absorbance spectrum
and the protein absorbance spectruin can both be subtracted to leave behind
the glucose
absorbance spectrum.
[0363] The pathlength can also be calculated using an isosbestic wavelength.
An isosbestic wavelength is one at which all components of a sample have the
same
absorbance. If the components (and their absorption coefficients) in a
particular sample are
known, and one or multiple isosbestic wavelengths are known for those
particular
components, the absorption data collected by the radiation detector at those
isosbestic
wavelengths can be used to calculate the pathlength. This can be advantageous
because the
needed information can be obtained from multiple readings of the absorption
detector that
are taken at approximately the same time, with the same sample in place in the
sample
chamber. The isosbestic wavelength readings are used to determine pathlength,
a.nd other
selected wavelength readings are used to determine interferent and/or analyte
concentration.
Thus, this approach is efficient and does not require insertion of a reference
fluid in the
sample chamber.
[0364] In some embodiments, a method of determining concentration of an
analyte in a sample can include inserting a fluid sample into a sample
container, emitting -
radiation from a source through the container and the fluid sample, obtaining
total sample
absorbance data by measuring the amount of radiation that reaches the
detector, subtracting
the correct interferent absorbance value or spectrum from the total sainple
absorbance data,
and using the remaining absorbance value or spectrum to determine
concentration of an
analyte in the fluid sample. The correct interferent absorbance value can be
determined
using the calculated pathlength.
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[0365] The concentration of an analyte in a sample can be calculated using the
Beer-Lambert law (or Beer's Law) as follows: If T is transmittance, A is
absorbance, Po is
initial radiant power directed toward a sample, and P is the power that
emerges from the
sainple and reaches a detector, then T = P / Po, and A = -log T=1og (Po / P).
Absorbance is
directly proportional to the concentration (c) of the light-absorbing species
in the sample,
also known as an analyte or an interferent. Thus, if e is the molar
absorptivity (1/M 1/cm),
b is the patli length (cm), and c is the concentration (M), Beer's Law can be
expressed as
follows: A = e b c. Thus, c= A/(e b).
[0366] Referring once again to flowchart 3100, the next step is to determine
which Library Interferents are present in the sample. In particular, Block
3120 indicates that
the measureineiits are analyzed to identify possible interferents. For
spectroscopic
measurements, it is preferred that the determination is made by comparing the
obtained
measurement to interferent spectra in the optical density domain. The results
of this step
provide a list of interferents that may, or are likely to, be present in the
sample. In one
embodiment, several input parameters are used to estimate a glucose
concentration gest from
a measured spectrum, C. The input parameters include previously gathered
spectrum
measurement of samples that, like the measurement sample, include the analyte
and
combinations of possible interferents from the interferent library; and
spectrum and
concentration ranges for each possible interferent. More specifically, the
input parameters
are:
[0367] Library of Interferent Data: Library of Interferent Data includes, for
each of "M" interferents, the absorption spectrum of each interferent,
IF ={IF1, IF2, ..., IFM}, where m= 1, 2, ..., M; and a maximum
concentration for each interferent, Tmax {Tmaxl, Tmax2, ...,
Tmaxm}; and
[0368] Samnle Population Data: Sample Population Data includes
individual spectra of a statistically large population taken over the
same wavelength range as the sample spectrum, Csi, and an analyte
concentration corresponding to each spectrum. As an example, if
there are N Sample Population spectra, then the spectra can be
represented as C={Cl, C2, ..., CN}, where n= 1, 2, ..., N, and the
analyte concentration corresponding to each spectrum can be
represented as g={gl, g2, ..., gN}.
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[0369] Preferably, the Sample Population does not have any of the M
interferents present, and the material sample has interferents contained in
the Sample
Population and none or more of the Library Interferents. Stated in terms of
Type-A and
Type-B interferents, the Sample Population has Type-A interferents and the
material
sample has Type-A and may have Type-B interferents. The Sample Population Data
are
used to statistically quantify an expected range of spectra and analyte
concentrations. Thus,
for example, for a systein 10 or 334 used to determine glucose in blood of a
person having
unlciiown spectral characteristics, the spectral measurements are preferably
obtained from a
statistical sample of the population.
[0370] The following discussion, which is not meant to limit the scope of the
present disclosure, illustrates embodiments for measuring more than one
analyte using
spectroscopic techniques. If two or more analytes have non-overlapping
spectral features,
then a first embodiment is to obtain a spectrum corresponding to each analyte.
The
measurements may then be analyzed for each analyte according to the method of
flowchart
3100. An alternative embodiment for analytes having non-overlapping features,
or an
embodiment for analytes having overlapping features, is to make one
measurement
comprising the spectral features of the two or more analytes. The measurement
may then be
analyzed for each analyte according to the method of flowchart 3100. That is,
the
measurement is analyzed for each analyte, with the other analytes considered
to be
interferents to the analyte being analyzed for.
INTERFERENT DETERMINATION
[0371] One embodiment of the method of Block 3120 is shown in greater detail
with reference to the flowchart of FIGURE 32. The method includes fonning a
statistical
Sample Population model (Block 3210), assembling a library of interferent data
(Block
3220), comparing the obtained measurement and statistical Sample Population
model with
data for each interferent from an interferent library (Block 3230), performing
a statistical
test for the presence of each interferent from the interferent library (Block
3240), and
identifying each interferent passing the statistical test as a possible
Library Interferent
(Block 3250). The steps of Block 3220 can be performed once or can be updated
as
necessary. The steps of Blocks 3230, 3240, and 3250 can either be performed
sequentially
for all interferents of the library, as shown, or alternatively, be repeated
sequentially for
each interferent.
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[0372] One embodiment of each of the methods of 13Ioclks 3210, 3220, 3230,
3240, and 3250 are now described for the example of identifying Library
Interferents in a
sample from a spectroscopic measurement using Sample Population Data and a
Library of
Interferent Data, as discussed previously. Each Sample Population spectrum
includes
measurements (e.g., of optical density) taken on a sample in the absence of
any Library
Interferents and has an associated known analyte concentration. A statistical
Sample
Population model is formed (Block 3210) for the range of analyte
concentrations by
coinbining all Sample Population spectra to obtain a mean matrix and a
covariance matrix
for the Sample Population. Thus, for example, if each spectrum at n different
wavelengths
is represented by an n x 1 matrix, C, then the mean spectrum, , is a n x 1
matrix with the
(e.g., optical density) value at each wavelength averaged over the range of
spectra, and the
covariance matrix, V, is the expected value of the deviation between C and
as V = E((C-
) (C- )T). The matrices and V are one model that describes the statistical
distribution of
the Sample Population spectra.
[0373] In another step, Library Interferent information is assembled (Block
3220). A number of possible interferents are identified, for example as a list
of possible
medications or foods that might be ingested by the population of patients at
issue or
measured by system 10 or 334, and their spectra (in the absorbance, optical
density, or
transmission domains) are obtained. In addition, a range of expected
interferent
concentrations in the blood, or other expected sample material, are estimated.
Thus, each of
M interferents has spectrum IF and maximum concentration Tmax. This
information is
preferably asseinbled once and is accessed as needed.
[0374] The obtained measurement data and statistical Sample Population model
are next compared with data for each interferent from the interferent library
(Block 3230) to
perform a statistical test (Block 3240) to determine the identity of any
interferent in the
mixture (Block 3250). This interferent test will first be shown in a rigorous
mathematical
formulation, followed by a discussion of FIGURES 33A and 33B which illustrates
the
method.
[0375] Mathematically, the test of the presence of an interferent in a
measurement proceeds as follows. The measured optical density spectrum, CS, is
modified
for each interferent of the library by analytically subtracting the effect of
the interferent, if
present, on the measured spectrum. More specifically, the measured optical
density
spectrum, CS, is modified, wavelength-by-wavelength, by subtracting an
interferent optical
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density spectrum. For an interferent, M, having an absorption spectrum per
unit of
interferent concentration, IFM, a modified spectrum is given by C's(T) = Cs -
IFM T, where
T is the interferent concentration, which ranges from a minimum value, Tmin,
to a
maximum value Tinax. The value of Tmin may be zero or, alternatively, be a
value between
zero and Tmax, such as some fraction of Tmax.
[0376] Next, the Mahalanobis distance (MD) between the modified spectrum
C's (T) and the statistical model ( , V) of the Sample Population spectra is
calculated as:
[0377] MD2 (Cs (T t),N-; P~ (CS - (T IFm) - )T V -1 (Cs- (T IFm) - )
Eq. (1)
[0378] The test for the presence of interferent IF is to vary T from Tmin to
Tmax (i.e., evaluate C'S (T) over a range of values of T) and determine
wliether the
minimum MD in this interval is in a predetermined range. Thus for exalnple,
one could
determine whether the minimum MD in the interval is sufficiently small
relative to the
quantiles of a x2 random variable with L degrees of freedom (L = number of
wavelengths).
[0379] FIGURE 33A is a graph 3300 illustrating the steps of Blocks 3230 and
3240. The axes of graph 3300, OD; and ODj, are used to plot optical densities
at two of the
many wavelengths at which measurements are obtained. The points 3301 are the
measurements in the Sample Population distribution. Points 3301 are clustered
within an
ellipse that has been drawn to encircle the majority of points. Points 3301
inside ellipse
3302 represent measurements in the absence of Library Interferents. Point 3303
is the
sample measurement. Presumably, point 3303 is outside of the spread of points
3301 due
the presence of one or more Library Interferents. Lines 3304, 3307, and 3309
indicate the
measurement of point 3303 as corrected for increasing concentration, T, of
three different
Library Interferents over the range from Tmin to Tmax. The three interferents
of this
example are referred to as interferent #1, interferent #2, and interferent #3.
Specifically,
lines 3304, 3307, and 3309 are obtained by subtracting from the sample
measurement an
amount T of a Library Interferent (interferent #1, interferent #2, and
interferent #3,
respectively), and plotting the corrected sample measurement for increasing T.
[0380] FIGURE 33B is a graph further illustrating the method of FIGURE 32.
In the graph of FIGURE 33B, the squared Mahalanobis distance, MD2 has been
calculated
and plotted as a function of t for lines 3304, 3307, and 3309. Referring to
FIGURE 33A,
line 3304 reflects decreasing concentrations of interferent #1 and only
slightly approaches
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points 3301. The value of MD2 of line 3304, as shown in FIGURE 33B, decreases
slightly
and then increases with decreasing interferent #1 concentration.
[0381] Referring to FIGURE 33A, line 3307 reflects decreasing concentrations
of interferent #2 and approaches or passes through many points 3301. The value
of MD2 of
line 3307, as shown in FIGURE 33B, shows a large decrease at some interferent
#2
concentration, then increases. Referring to FIGURE 33A, line 3309 has
decreasing
concentrations of interferent #3 and approaches or passes through even more
points 3303.
The value of MD2 of line 3309, as shown in FIGURE 33B, shows a still larger
decrease at
some interferent #3 concentration.
[0382] In one embodiment, a threshold level of MD2 is set as an indication of
the presence of a particular interferent. Thus, for example, FIGURE 33B shows
a line
labeled "original spectrum" indicating MD2 when no interferents are subtracted
from the
spectrum, ald a line labeled "95% Threshold", indicating the 95% quantile for
the chi2
distribution with L degrees of freedom (where L is the number of wavelengths
represented
in the spectra). This level is the value which should exceed 95% of the values
of the MD2
metric; in other words, values at this level are uncommon, and those far above
it should be
quite rare. Of the three interferents represented in FIGURES 33A and 33B, only
interferent
#3 has a value of MD 2 below the threshold. Thus, this analysis of the sample
indicates that
interferent #3 is the most likely interferent present in the sample.
Interferent #1 has its
minimum far above the threshold level and is extremely unlikely to be present;
interferent
#2 barely crosses the threshold, making its presence more likely than
interferent #1, but still
far less likely to be present than interferent #1.
[0383] As described subsequently, information related to the identified
interferents is used in generating a calibration constant that is relatively
insensitive to a
likely range of concentration of the identified interferents. In addition to
being used in
certain methods described subsequently, the identification of the interferents
may be of
interest and may be provided in a manner that would be usefiil. Thus, for
example, for a
hospital based glucose monitor, identified interferents may be reported on
display 141 or be
transmitted to a hospital computer via communications link 216.
CALIBRATION CONSTANT GENERATION EMBODIMENTS
[0384] Once Library Interferents are identified as being possibly present in
the
sample under analysis, a calibration constant for estimating the concentration
of analytes in
the presence of the identified interferents is generated (Block 3130). More
specifically, after
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Bloclc 3120, a list of possible Library Interferents is identified as being
present. One
embodiment of the steps of Block 3120 are shown in the flowchart of FIGURE 34
as Block
3410, where synthesized Sample Population measurements are generated, Block
3420,
where the synthesized Sample Population measurements are partitioned in to
calibration
and test sets, Block 3430, where the calibration are is used to generate a
calibration
constant, Block 3440, where the calibration set is used to estimate the
analyte concentration
of the test set, Block 3450 where the errors in the estimated analyte
concentration of the test
set is calculated, and Block 3460 where an average calibration constant is
calculated.
[0385] One embodiment of each of the methods of Blocks 3410, 3420, 3430,
3440, 3450, and 3460 are now described for the exanlple of using identifying
interferents in
a sample for generating an average calibration constant. As indicated in Block
3410, one
step is to generate synthesized Sainple Population spectra, by adding a random
concentration of possible Library Interferents to each Sample Population
spectrum. The
spectra generated by the method of Block 3410 are referred to herein as an
Interferent-
Enhanced Spectral Database, or IESD. The IESD can be fornled by the steps
illustrated in
FIGURES 35-38, where FIGURE 35 is a schematic diagram 3500 illustrating the
generation of Randomly-Scaled Single Interferent Spectra, or RSIS; FIGURE 36
is a graph
3600 of the interferent scaling; FIGURE 37 is a schematic diagram illustrating
the
combination of RSIS into Combination Interferent Spectra, or CIS; and FIGURE
38 is a
schematic diagram illustrating the combination of CIS and the Sample
Population spectra
into an IESD.
[0386] The first step in Block 3410 is shown in FIGURES 35 and 36. As shown
schematically in flowchart 3500 in FIGURE 35, and in graph 3600 in FIGURE 36,
a
plurality of RSIS (Block 3540) are formed by combinations of each previously
identified
Library Interferent having spectrum IF,,, (Block 3510), multiplied by the
maximum
concentration Tmaxm (Block 3520) that is scaled by a random factor between
zero and one
(Block 3530), as indicated by the distribution of the random number indicated
in graph
3600. In one embodiment, the scaling places the maximum concentration at the
95th
percentile of a log-normal distribution to produce a wide range of
concentrations with the
distribution having a standard deviation equal to half of its mean value. The
distribution of
the random numbers in graph 3600 are a log-normal distribution of =100, 6=50.
[0387] Once the individual Library Interferent spectra have been multiplied by
the random concentrations to produce the RSIS, the RSIS are combined to
produce a large
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population of interferent-only spectra, the CIS, as illustrated in FIGURE 37.
The individual
RSIS are combined independently and in random coinbinations, to produce a
large family
of CIS, with each spectrum witllin the CIS consisting of a random combination
of RSIS,
selected from the full set of identified Library Interferents. The metliod
illustrated in
FIGURE 37 produces adequate variability with respect to each interferent,
independently
across separate interferents.
[0388] The next step combines the CIS and replicates of the Sample Population
spectra to form the IESD, as illustrated in FIGURE 38. Since the Interferent
Data and
Sample Population spectra may have been obtained at different pathlengths, the
CIS are
first scaled (i.e., multiplied) to the same pathlength. The Sainple Population
database is
then replicated M times, where M depends on the size of the database, as well
as the
nuinber of interferents to be treated. The IESD includes M copies of each of
the Sample
Population spectra, where one copy is the original Sainple Population Data,
and the
remaining M-1 copies each have an added random one of the CIS spectra. Each of
the IESD
spectra has an associated analyte concentration from the Sample Population
spectra used to
form the particular IESD spectrum.
[0389] In one embodiment, a 10-fold replication of the Sanlple Population
database is used for 130 Sample Population spectra obtained from 58 different
individuals
and 18 Library Interferents. Greater spectral variety among the Library
Interferent spectra
requires a smaller replication factor, and a greater number of Library
Interferents requires a
larger replication factor.
[0390] The steps of Blocks 3420, 3430, 3440, and 3450 are executed to
repeatedly combine different ones of the spectra of the IESD to statistically
average out the
effect of the identified Library Interferents. First, as noted in Block 3420,
the IESD is
partitioned into two subsets: a calibration set and a test set. As described
subsequently, the
repeated partitioning of the IESD into different calibration and test sets
improves the
statistical significance of the calibration constant. In one embodiment, the
calibration set is
a random selection of some of the IESD spectra and the test set are the
unselected IESD
spectra. In a preferred embodiment, the calibration set includes approximately
two-thirds of
the IESD spectra.
[0391] In an alternative embodiment, the steps of Blocks 3420, 3430, 3440, and
3450 are replaced with a single calculation of an average calibration constant
using all
available data.
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[0392] Next, as indicted in Block 3430, the calibration set is used to
generate a
calibration constant for predicting the analyte concentration from a sample
measurement.
First an analyte spectrum is obtained. For the embodiment of glucose
determined from
absorption measurements, a glucose absorption spectrum is indicated as G. The
calibration
constant is then generated as follows. Using the calibration set having
calibration spectra C
= {'G1, G2, ... , 'G} and corresponding glucose concentration values {gi, g2,
... , gõ
}, then glucose-free spectra C,'= 'C2, ... , 'C;,} can be calculated as: 'G} =
'Cj - ao g; .
Next, the calibration constant, x, is calculated from C' and aG, according to
the following 5
steps:
1) 0' is deconlposed into C' = Ac Ae. B,., that is, a singular value
decomposition,
where the A-factor is an orthonormal basis of column space, or span, of G;
2) A(,, is truncated to avoid overfitting to a particular column rank r, based
on the
sizes of the diagonal entries of A (the singular values of C~). The selection
of r
involves a trade-off between the precision and stability of the calibration,
with a
larger r resulting in a more precise but less stable solution. In one
embodiment,
each spectrum C includes 25 wavelengths, and r ranges from 15 to 19;
3) The first r columns of A.. are taken as an orthonormal basis of span( C');
4) The projection from the background is found as the product P.. = AC. AC, T
, that is
the orthogonal projection onto the span of C', and the complementary, or
nulling
projection P,.1 = 1- P,,,, which forms the projection onto the complementary
subspace C'l, is calculated; and
5) The calibration vector x is then found by applying the nulling projection
to the
absorption spectrum of the analyte of interest: icR,,W = P(~l aG and
normalizing: ic
= KRAW /(xRAW ,VG ), where the angle brackets (,) denote the standard inner
(or
dot) product of vectors. The normalized calibration constant produces a unit
response for a unit PG spectral input for one particular calibration set.
[0393] Next, the calibration constant is used to estimate the analyte
concentration in the test set (Block 3440). Specifically, each spectrum of the
test set (each
spectrum having an associated glucose concentration from the Sample Population
spectra
used to generate the test set) is multiplied by the calibration vector x from
Block 3430 to
calculate an estimated glucose concentration. The error between the calculated
and known
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glucose concentration is then calculated (Block 3450). Specifically, the
measure of the error
can include a weighted value averaged over the entire test set according to
1/rins2.
[0394] Blocks 3420, 3430, 3440, and 3450 are repeated for many different
random conibinations of calibration sets. Preferably, Blocks 3420, 3430, 3440,
and 3450
are repeated are repeated Ilundreds to thousands of times. Finally, an average
calibration
constant is calculated from the calibration and error from the many
calibration and test sets
(Block 3460). Specifically, the average calibration is computed as weighted
average
calibration vector. In one embodiment the weighting is in proportion to a
normalized rms,
such as the xaõe = K , * rms2/E(rins2) for all tests.
[0395] With the last of Block 3130 executed according to FIGURE 34, the
average calibration constant xa,,e is applied to the obtained spectrum (Block
3140).
[0396] Accordingly, one embodiment of a method of computing a calibration
constant based on identified interferents can be summarized as follows:
1. Generate synthesized Sample Population spectra by adding the RSIS to raw
(interferent-free) Sample Population spectra, thus forming an Interferent
Enhanced
Spectral Database (IESD) -- each spectrum of the IESD is synthesized from one
spectrum of the Sample Population, and thus each spectrum of the IESD has at
least
one associated known analyte concentration
2. Separate the spectra of the IESD into a calibration set of spectra and a
test set of
spectra
3. Generate a calibration constant for the calibration set based on the
calibration set
spectra and their associated known correct analyte concentrations (e.g., using
the
matrix manipulation outlined in five steps above)
4. Use the calibration constant generated in step 3 to calculate the error in
the
corresponding test set as follows (repeat for each spectrum in the test set):
a. Multiply (the selected test set spectrum) x (average calibration constant
generated in step 3) to generate an estimated glucose concentration
b. Evaluate the difference between this estimated glucose concentration and
the
known, correct glucose concentration associated with the selected test
spectrum to generate an error associated with the selected test spectrum
5. Average the errors calculated in step 4 to arrive at a weighted or average
error for
the current calibration set - test set pair
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6. Repeat steps 2 through 5 n times, resulting in 72 calibration constants and
n average
errors
7. Compute a "grand average" error from the n average errors and an average
calibration constant from the n calibration constants (preferably weighted
averages
wherein the largest average errors and calibration constants are discounted),
to
arrive at a calibration constant wllich is minimally sensitive to the effect
of the
identified interferents
EXAMPLE 1
[0397] One example of certain methods disclosed herein is illustrated with
reference to the detection of glucose in blood using mid-IR absorption
spectroscopy. Table
2 lists 10 Library Interferents (each having absorption features that overlap
with glucose)
and the corresponding maxiinuin concentration of each Library Interferent.
Table 2 also
lists a Glucose Sensitivity to Interferent without and with training. The
Glucose Sensitivity
to Interferent is the calculated change in estimated glucose concentration for
a unit change
in interferent concentration. For a highly glucose selective analyte detection
technique, this
value is zero. The Glucose Sensitivity to Interferent without training is the
Glucose
Sensitivity to Interferent where the calibration has been detennined using the
methods
above without any identified interferents. The Glucose Sensitivity to
Interferent with
training is the Glucose Sensitivity to Interferent where the calibration has
been determined
using the methods above with the appropriately identified interferents. In
this case, least
improvement (in terms of reduction in sensitivity to an interferent) occurs
for urea, seeing a
factor of 6.4 lower sensitivity, followed by three with ratios from 60 to 80
in improvement.
The remaining six all have seen sensitivity factors reduced by over 100, up to
over 1600.
The decreased Glucose Sensitivity to Interferent with training indicates that
the methods are
effective at producing a calibration constant that is selective to glucose in
the presence of
interferents.
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Glucose Glucose
Library Maximum Sensitivity to Sensitivity to
Interferent Concentration Interferent Interferent
w/o training w/ training
Sodium Bicarbonate 103 0.330 0.0002
Urea 100 -0.132 0.0206
Ma esiuin Sulfate 0.7 1.056 -0.0016
Naproxen 10 0.600 -0.0091
Uric Acid 12 -0.557 0.0108
Salicylate 10 0.411 -0.0050
Glutathione 100 0.041 0.0003
Niacin 1.8 1.594 -0.0086
Nicotinamide 12.2 0.452 -0.0026
Chlo ro ainide 18.3 0.334 0.0012
Table 2. Rejection of 10 interfering substances
EXAMPLE 2
[0398] Another example illustrates the effect of the metllods for 18
interferents.
Table 3 lists of 18 interferents and maximum concentrations that were modeled
for this
example, and the glucose sensitivity to the interferent without and with
training. The table
summarizes the results of a series of 1000 calibration and test simulations
that were
performed both in the absence of the interferents, and with all interferents
present. FIGURE
39 shows the distribution of the R.M.S. error in the glucose concentration
estimation for
1000 trials. While a number of substances show significantly less sensitivity
(sodium
bicarbonate, magnesium sulfate, tolbutamide), others show increased
sensitivity (ethanol,
acetoacetate), as listed in Table 3. The curves in FIGURE 39 are for
calibration set and the
test set both without any interferents and with all 18 interferents. The
interferent produces a
degradation of performance, as can be seen by comparing the calibration or
test curves of
FIGURE 39. Thus, for example, the peaks appear to be shifted by about 2 mg/dL,
and the
width of the distributions is increased slightly. The reduction in height of
the peaks is due
to the spreading of the distributions, resulting in a modest degradation in
performance.
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Library Cone. Glucose Sensitivity Glucose Sensitivity to
Interferent (mg/dL) to Interferent w/o Interferent w/
training training
1 Urea 300 -0.167 -0.100
2 Ethanol 400.15 -0.007 -0.044
3 Sodiuin Bicarbonate 489 0.157 -0.093
4 Acetoacetate Li 96 0.387 0.601
H drox but c Acid 465 -0.252 -0.101
6 Magnesium Sulfate 29.1 2.479 0.023
7 Na roxen 49.91 0.442 0.564
8 Salicylate 59.94 0.252 0.283
9 Ticarcillin Disodium 102 -0.038 -0.086
Cefazolin 119.99 -0.087 -0.006
11 Chlo ro amide 27.7 0.387 0.231
12 Nicotinamide 36.6 0.265 0.366
13 Uric Acid 36 -0.641 -0.712
14 Ibu rofen 49.96 -0.172 -0.125
Tolbutamide 63.99 0.132 0.004
16 Tolazamide 9.9 0.196 0.091
17 Bilirubin 3 -0.391 -0.266
18 Acetamino hen 25.07 0.169 0.126
Table 3. List of 18 Interfering Substances with maximum concentrations and
Sensitivity with respect to interferents, with/without training
EXAMPLE 3
[0399] In a third example, certain methods disclosed herein were tested for
measuring glucose in blood using mid-IR absorption spectroscopy in the
presence of four
interferents not normally found in blood (Type-B interferents) and that may be
common for
patients in hospital intensive care units (ICUs). The four Type-B interferents
are mannitol,
dextran, n-acetyl L cysteine, and procainamide.
[0400] Of the four Type-B interferents, mamiitol and dextran have the
potential
to interfere substantially with the estimation of glucose: both are spectrally
similar to
glucose (see FIGURE 1), and the dosages employed in ICUs are very large in
comparison
to typical glucose levels. Mannitol, for example, may be present in the blood
at
concentrations of 2500 mg/dL, and dextran may be present at concentrations in
excess of
5000 mg/dL. For comparison, typical plasma glucose levels are on the order of
100 - 200
mg/dL. The other Type-B interferents, n-acetyl L cysteine and procainamide,
have spectra
that are quite unlike the glucose spectrum.
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[0401] FIGURES 40A, 40B, 40C, and 40D each have a graph showing a
comparison of the absorption spectruin of glucose with different interferents
taken using
two different techniques: a Fourier Transform Infrared (FTIR) spectrometer
having an
interpolated resolution of 1 cm'1 (solid lines with triangles); and by 25
finite-bandwidth IR
filters having a Gaussian profile and full-width half-maximuin (FWHM)
bandwidth of 28
cm 1 corresponding to a bandwidth that varies from 140 nm at 7.08 m, up to
279 nm at 10
m (dashed lines with circles). Specifically, the figures show a comparison of
glucose with
mannitol (FIGURE 40A), with dextran (FIGURE 40B), with n-acetyl L cysteine
(FIGURE
40C), and with procainamide (FIGURE 40D), at a concentration level of 1 mg/dL
and path
length of 1 m. The horizontal axis in FIGURES 40A-40D has units of wavelength
in
inicrons ( m), ranging from 7 in to 10 m, and the vertical axis has
arbitrary units.
[0402] The central wavelength of the data obtained using filter is indicated
in
FIGURES 40A, 40B, 40C, and 40D by the circles along each dashed curve, and
corresponds to the following wavelengths, in microns: 7.082, 7.158, 7.241,
7.331, 7.424,
7.513, 7.605, 7.704, 7.800, 7.905, 8.019, 8.150, 8.271, 8.598, 8.718, 8.834,
8.969, 9.099,
9.217, 9.346, 9.461, 9.579, 9.718, 9.862, and 9.990. The effect of the
bandwidth of the
filters on the spectral features can be seen in FIGURES 40A-40D as the
decrease in the
sharpness of spectral features on the solid curves and the relative absence of
sharp features
on the dashed curves.
[0403] FIGURE 41 shows a graph of the blood plasma spectra for 6 blood
samples taken from three donors in arbitrary units for a wavelength range
froin 7 m to 10
m, where the symbols on the curves indicate the central wavelengths of the 25
filters. The
6 blood samples do not contain any mannitol, dextran, n-acetyl L cysteine, and
procainamide - the Type-B interferents of this Example, and are thus a Sample
Population.
Three donors (indicated as donor A, B, and C) provided blood at different
times, resulting
in different blood glucose levels, shown in the graph legend in mg/dL as
measured using a
YSI Biochemistry Analyzer (YSI Incorporated, Yellow Springs, OH). The path
length of
these samples, estimated at 36.3 m by analysis of the spectrum of a reference
scan of
saline in the same cell immediately prior to each sample spectrum, was used to
normalize
these measurements. This quantity was taken into account in the computation of
the
calibration vectors provided, and the application of these vectors to spectra
obtained from
other equipment would require a similar pathlength estimation and
normalization process to
obtain valid results.
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[0404] Next, random amounts of each Type-B interferent of this Example are
added to the spectra to produce mixtures that, for example could make up an
Interferent
Enhanced Spectral. Each of the Sample Population spectra was coinbined with a
random
amount of a single interferent added, as indicated in Table 4, which lists an
index number
N, the Donor, the glucose concentration (GLU), interferent concentration
(conc(IF)), and
the interferent for each of 54 spectra. The conditions of Table 4 were used to
form
combined spectra including each of the 6 plasma spectra was combined with 2
levels of
each of the 4 interferents.
N Donor GLU conc(IF) IF
1 A 157.7 N/A
.......... .......................... .....__..... _.........__._.._...._..
_.... __._w......... ................... ..._............. .................
_............ _...................... .._......... .........................
2 A 382 N/A
3 B 122 N/A
...... ..._ ............................. ................. ..........
__............ _........... .............................
_....................... ............ ..... _........ _.............
__......... _.._..................... _.......... ....................
4 B 477.3 N/A
C 199.7 N/A
. ...................................................................._...-
_.._...... ..._.........._........................ ...... ...
_............................. ..... ___-__._..... ................ ..........
_......._....... _...
6 C 399 N/A
7 A 157.7 1001.2 Mannitol
. ................. .......................
_._._._._........_._..................... .... _... .............. _._....
_.................... ................ _..................... _........
__._............. __.................... ............
,.......
8 A 382 2716.5 Mannitol
9 A 157.7 1107.7 Mannitol
...... _------- _......._...................
_...__..._.................................................... ...........
___.......... _........ _...... _..._..................... _......_.._.......
A 382 1394.2 Mannitol
11 B 122 2280.6 Mannitol
........ __.......... ._...__ ........... ......... _.__....._..............
...... ._.._..._.............. _.... _..__ ._....... _.................
__...... _..._.... __............... _....._............. _..._...
12 B 477.3 1669.3 Mannitol
13 B 122 1710.2 Mannitol
_.....
...................................... .... .............................
......._..._......_.............. ___...... ....................
................ _._....... . ..............
.___.................................
14 B 477.3 1113.0 Mannitol
C 199.7 1316.4 Mannitol
.......... _.__._..._..._ _...... ._._.... _.... .... ....... ......_
................................... ....._.......
_..._.........T...__................_.._..___.._._...__..._.__.__.._.
16 C 399 399.1 Mannitol
17 C 199.7 969.8 Mannitol
..... __._ ...... .............. _..... ...... _.. ..._.............
._...__._._..............._........ _.. ...... _.._........... __..........
__.- .._.............. _._............................ _.
18 C 399 2607.7 Mannitol
19 A 157.7 8.8 N Acetyl L Cysteine
... .................. _.............. ............ ..u._..
................... .... _......... _..._ ._......................... _.....
........
A 382 2.3 N Acetyl L Cysteine
21 A 157.7 3.7 N Acetyl L Cysteine
........... _... __ .................
__.._....._.._.....__._...__..................... ___......................
..... _
22 A 382 8.0 N Acetyl L Cysteine
23 B 122 3.0 N Acetyl L Cysteine
.. __.......... _.... _____ ............ ._........ _._._
24 B 477.3 4.3 N Acetyl L Cysteine
B 122 8.4 N Acetyl L Cysteine
26 B 477.3 5.8 N Acetyl L Cysteine
27 C 199.7 7.1 N Acetyl L Cysteine
.. .......
28 C 399 8.5 N Acetyl L Cysteine
29 C 199.7 4.4 N Acetyl L Cysteine
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..._................. .................... ._.... ......... _......
._..._._._..._._...._.____..__...
30 C 399 4.3 N Acetyl L Cysteine
31 A 157.7 4089.2 Dextran
_.......... _.. ..... _....._~__..
32 A 382 1023.7 Dextran
33 A 157.7 1171.8 Dextran
........................ ._......_..... .._...___......... .... _........... .
.......... _..... _. ..... _............
.........-
34 A 382 4436.9 Dextran
35 B 122 2050.6 Dextran
. ............. _._....... _._..... ............................... _.
.................. .......... ._..__................... ._.... _......
_.............. _...... _......... _..... _..__..... _.............. ..... _
36 B 477.3 2093.3 Dextran
37 B 122 2183.3 Dextran
...... _........ __...._ .............. ....... ._......... __..__....
_...._............._........m......... ....... ._........ _... .......... -
...._........ .._........... ....___...__............ ......_..___......
_........
38 B 477.3 3750.4 Dextran
39 C 199.7 2598.1 Dextran
......... ..._._ ......................... .........
.......................... ................ ..-...... ......................
.._..-_............. ..._.......... _..._....... _................... __......
_..... _.............. _.......... _............ .......
40 C 399 2226.3 Dextran
41 C 199.7 2793.0 Dextran
............. .................. ...... ......__................... _.
.._.........._.,.............. _........ .......... ._...... .......
...................... _............. _..........
_._...__.........................
..................
42 C 399 2941.8 Dextran
43 A 157.7 22.5 Procainamide
........... ............. _.... ........ ..........._.......................
............... ......................................... ................
.__.... . ...__................................... _...... . ....
................................ . _..........
44 A 382 35.3 Procainamide
45 A 157.7 5.5 Procainamide
._......... ._.. .... .._...... ._ ......... _.... _._.............._........
........ _..._ ........ .................... ._....... ....................
_._....... ............................................
46 A 382 7.7 Procainamide
47 B 122 18.5 Procainamide
.............._.......
........... ............. ...._._........ ............_...........
....__..................................._................... ...-
............ _._...... ....... ........... _.............. ..__..........
_.._........... ......
48 B 477.3 5.6 Procainamide
49 B 122 31.8 Procainamide
_ ....................... _......... _ ..... __............ _..........
_......... ._........ ..._.........._........_._.......... _...
_.._........... _........ _.._.............. ..... _..._._..............
...............
_..
50 B 477.3 8.2 Procainamide
51 C 199.7 22.0 Procainamide
............. ...................__..... ........
.._._........._......____............ ........_.._._.....................
_..... . .... _.......... _.... _.._......._.._......_...............
_................ ................. _......
52 C 399 9.3 Procainamide
53 C 199.7 19.7 Procainamide
__ ............ ._.......... ...__.......... _._..... __....... __..._.. -
................. _....... _......... ......... _...... ._.__........_
54 C 399 12.5 Procainamide
Table 4. Interferent Enhanced Spectral Database for Example 3.
[0405] FIGURES 42A, 42B, 42C, and 42D. coiltain spectra formed from the
conditions of Table 4. Specifically, the figures show spectra of the Sample
Population of 6
samples having random amounts of mannitol (FIGURE 42A), dextran (FIGURE 42B),
n-
acetyl L cysteine (FIGURE 42C), and procainamide (FIGURE 42D), at a
concentration
levels of 1 mg/dL and path lengths of 1 m.
[0406] Next, calibration vectors were generated using the spectra of FIGURES
42A-42D, in effect reproducing the steps of Block 3120. The next step of this
Example is
the spectral subtraction of water that is present in the sample to produce
water-free spectra.
As discussed above, certain methods disclosed herein provide for the
estimation of an
analyte concentration in the presence of interferents that are present in both
a sample
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population and the measurement sample (Type-A interferents), and it is not
necessary to
remove the spectra for interferents present in Sample Population and sample
being
measured. The step of removing water from the spectrum is thus an alternative
embodiment
of the disclosed methods.
[0407] The calibration vectors are shown in FIGURES 43A-43p for mannitol
(FIGURE 43A), dextran (FIGURE 43B), n-acetyl L cysteine (FIGURE 43C), and
procainamide (FIGURE 43D) for water-free spectra. Specifically each one of
FIGURES
43A-43D compares calibration vectors obtained by training in the presence of
an
interferent, to the calibration vector obtained by training on clean plasma
spectra alone. The
calibration vector is used by computing its dot-product with the vector
representing
(pathlength-normalized) spectral absorption values for the filters used in
processing the
reference spectra. Large values (whether positive or negative) typically
represent
wavelengths for which the corresponding spectral absorbance is sensitive to
the presence of
glucose, while small values generally represent wavelengths for which the
spectral
absorbance is insensitive to the presence of glucose. In the presence of an
interfering
substance, this correspondence is somewhat less transparent, being modified by
the
tendency of interfering substances to mask the presence of glucose.
[0408] The similarity of the calibration vectors obtained for minimizing the
effects of the two interferents n-acetyl L cysteine and procainamide, to that
obtained for
pure plasma, is a reflection of the fact that these two interferents are
spectrally quite distinct
from the glucose spectrum; the large differences seen between the calibration
vectors for
minimizing the effects of dextran and mannitol, and the calibration obtained
for pure
plasma, are conversely representative of the large degree of similarity
between the spectra
of these substances and that of glucose. For those cases in which the
interfering spectrum is
similar to the glucose spectrum (that is, mannitol and dextran), the greatest
change in the
calibration vector. For those cases in which the interfering spectrum is
different from the
glucose spectrum (that is, n-acetyl L cysteine and procainamide), it is
difficult to detect the
difference between the calibration vectors obtained with and without the
interferent.
[0409] It will be understood that the steps of methods discussed are performed
in one embodiment by an appropriate processor (or processors) of a processing
(i.e.,
computer) system executing instructions (code segments) stored in appropriate
storage. It
will also be understood that the disclosed methods and apparatus are not
limited to any
particular implementation or programming technique and that the methods and
apparatus
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may be implemented using any appropriate techniques for implementing the
functionality
described herein. The methods and apparatus are not limited to any particular
programming
language or operating system. In addition, the various coinponents of the
apparatus may be
included in a single housing or in multiple housings that communication by
wire or wireless
communication.
[0410] Further, the interferent, analyte, or population data used in the
metllod
may be updated, changed, added, removed, or otherwise modified as needed.
Thus, for
example, spectral information and/or concentrations of interferents that are
accessible to the
metllods may be updated or changed by updating or changing a database of a
program
implementing the method. The updating may occur by providing new computer
readable
media or over a computer network. Other changes that may be made to the
methods or
apparatus include, but are not limited to, the adding of additional analytes
or the changing
of population spectral information.
[0411] One embodiment of each of the methods described herein may include a
computer program accessible to and/or executable by a processing systein,
e.g., a one or
more processors and memories that are part of an embedded system. Thus, as
will be
appreciated by those skilled in the art, embodiments of the disclosed
inventions may be
embodied as a method, an apparatus such as a special purpose apparatus, an
apparatus such
as a data processing system, or a carrier medium, e.g., a computer program
product. The
carrier medium carries one or more computer readable code segments for
controlling a
processing system to iinplement a method. Accordingly, various ones of the
disclosed
inventions may take the form of a method, an entirely hardware embodiment, an
entirely
software embodiment or an embodiment combining software and hardware aspects.
Furthermore, any one or more of the disclosed methods (including but not
limited to the
disclosed methods of measurement analysis, interferent determination, and/or
calibration
constant generation) may be stored as one or more computer readable code
segments or
data compilations on a carrier medium. Any suitable computer readable carrier
medium
may be used including a magnetic storage device such as a diskette or a hard
disk; a
memory cartridge, module, card or chip (either alone or installed within a
larger device); or
an optical storage device such as a CD or DVD.
[0412] In view of the foregoing, certain disclosed embodiments comprise an
apparatus for analyzing the coinposition of bodily fluid. This apparatus
includes a first
fluid passageway, at least one pump, an analyte detection system, and a fluid
sensor.
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[0413] The first fluid passageway (such as, without limitation, the passageway
112 aiid/or the passageway 113) has a patient end configured to provide fluid
communication with a bodily fluid within a patient. Where the first fluid
passageway
comprises the passageway 112, the patient end can comprise the end or region
of the
passageway 112 which is nearest the patient P, such as the patient connector
110/1100/1200, or any other suitable interface with any intervening fluid
passageways or
fluid network between the first fluid passageway and the patient P.
Alternatively the
patient end can comprise the connector 230; or the end of the connector 110
opposite the
apparatus 140; or the end of the sampling assembly 220 adjacent the connector
1100/1200
when employed as shown in FIGURES 11 or 12. The patient end of the first fluid
passageway of certain embodiments can provide the apparatus with fluid
conununication to
the bodily fluid within the patient indirectly, where an intervening tube or
passageway, such
as the catheter 11, I.V. tubing, or other fluid handling apparatus, is
positioned between the
first fluid passageway and the patient to provide a fluid handling link
between the patient
and the first fluid passageway.
[0414) In some embodiments the apparatus also includes a second fluid
passageway (such as, without limitation, the passageway 113) in fluid
communication with
the first fluid passageway via a junction between the first and second fluid
passageways
with the fluid sensor configured to sense the arrival of bodily fluid near the
junction of the
first and second fluid passageways. Thus, in several embodiments, the junction
of the first
and second fluid passageways can be the junction of the passageways 112 and
113 as
depicted in any of FIGURES 3, 5, 6A, 6B, 7A-7J, or 9.
[0415] The at least one pump is coupled to the first fluid passageway and has
an
infusion mode and a sample draw mode. In the infusion mode (an example of
which is
described herein in reference to FIGURE 7A), the pump is operable to deliver
infusion fluid
to the patient through the patient end of the first fluid passageway. In the
sample draw
mode (an example of which is described herein in reference to FIGURE 7C), the
pump is
operable to draw a sample of the bodily fluid from the patient through the
patient end of the
first fluid passageway. The at least one pump can comprise any of the pumps
discussed
herein, including pumps 203 and 328, pump roller 1005a, and displacement pump
905. In
certain embodiments, the apparatus comprises at least one pump having both the
infusion
mode and the sample draw modes. In certain other embodiments, the at least one
pump of
the apparatus comprises two unidirectional or single-mode pumps, wherein one
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unidirectional or single-mode pump provides the infusion mode and a second
unidirectional
or single-mode pump provides the sample draw mode.
[0416] The analyte detection system is accessible via the first fluid
passageway
such that the analyte detection system can receive at least one component of
the drawn
sainple of bodily fluid and determine the concentration of at least one
analyte. For
example, in certain embodiments, the analyte detection system receives the
bodily fluid
(e.g., blood) in its whole state and determines the concentration of at least
one analyte. For
another example, in certain embodiments, the analyte detection system receives
plasma (a
component) separated from a whole blood drawn sample and determines the
concentration
of at least one analyte. In certain embodiments, the analyte detection system
detennines the
analyte concentration in the component under analysis, in the drawn sample, in
the patient,
or in a combination of one or more of the component, drawn sample, and
patient. The
analyte detection system is generally positioned at a distance (e.g., one foot
to eight feet),
from the patient end of the first fluid passageway. Some embodiments of the
analyte
detection system include analyte detection systems 334 and 1700, described
herein.
Alternatively, the analyte detection system can comprise any suitable optical,
spectroscopic,
enzymatic (e.g. glucose), reagent-based (e.g., TPH or heart condition
markers), and/or
electrochemical (e.g., pH) analyte detection system.
[0417] The fluid sensor is located at or near the patient end of the first
fluid
passageway and spaced from the analyte detection system. The fluid sensor is
configured
to sense a property of the fluid within the first fluid passageway. In some
embodiments, the
fluid sensor is located between the patient end of the first fluid passageway
and the analyte
detection system. In various embodiments, the fluid sensor can comprise a
colorimetric
sensor, a hemoglobin sensor, a hematocrit sensor, a pressure sensor, a bubble
sensor, a
dilution sensor, or a combination thereof. Examples of such sensors are
discussed herein,
including colorimetric sensor 311, hemoglobin sensor 1003, pressure sensors
and sensor
units 317, 507, 1011, and 1102, and bubble sensors and sensor units 314a,
314b, 321, 505,
1001 a, 1001 b, and 1001 c. A dilution sensor compatible with certain
embodiments
described herein provides a signal indicative of the dilution of the fluid
within the first fluid
passageway. In certain embodiments, this signal from the dilution sensor is
used to indicate
that the system can discontinue drawing body fluid from the patient and can
draw a sample
of the body fluid to the analyzer. The fluid sensor of certain embodiments is
useful for
detecting the arrival of body fluid in the first fluid passageway, or for
identifying the type
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and/or condition of the fluid in proximity to the fluid sensor to facilitate
directing the fluid
to one or more appropriate locations in the system. For example, in certain
embodiments,
one or more signals from the fluid sensor are used to indicate that the system
can
discontinue drawing body fluid from the patient and can draw a sample of the
body fluid to
the analyzer, thereby facilitating directing a drawn blood sample to the
analyte detection
system forsubsequent analysis of one or more desired blood analytes, as
discussed herein.
In some embodiments, the fluid sensor is located in a near-patient module
(e.g., the patient
connector 110 or the sampling assembly 220) located on the first fluid
passageway between
the patient end and the analyte detection systein. The near-patient module can
be spaced
from the analyte detection system.
[0418] Certain disclosed embodiments comprise fluid-handling methods which
are executable with, for example, any of the embodiments described above of
the apparatus
for analyzing the compositions of bodily fluid. Certain such methods include
providing a
first fluid passageway and an analyte detection system, infusing an infusion
fluid to a
patient, drawing or otherwise obtaining a body fluid from the patient, sensing
a property of
fluid within the first fluid passageway, and determining a concentration of at
least one
analyte in the fluid within the first fluid passageway. The first fluid
passageway has a
patient end and provides access to the analyte detection system. The infusion
fluid is
infused to the patient through the patient end, and the body fluid is drawn
from the patient
through the patient end. Properties of the fluid within the first fluid
passageway are sensed
at a sensing location at or near the patient end and spaced from the analyte
detection
system. In certain embodiments, the fluid within the first fluid passageway
comprises the
body fluid alone, while in other embodiments, the fluid within the first fluid
passageway
comprises the body fluid mixed with another fluid (e.g., infusion fluid). In
some
embodiments, the fluid-handling method further comprises providing a second
fluid
passageway in fluid communication with the first fluid passageway via a
junction between
the first and second passageways and sensing the arrival of the body fluid
near the junction
of the first and second fluid passageways.
[0419] In various embodiments, sensing a property of the fluid within the
first
fluid passageway comprises sensing the color, the hemoglobin content, the
hematocrit, the
dilution, the pressure of the fluid within the first fluid passageway, the
presence of one or
more bubbles in the first fluid passageway, detecting the arrival of body
fluid in the first
fluid passageway, or a combination thereof. In certain embodiments, sensing a
property of
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the fluid within the first fluid passageway comprises sensing a property of
the infusion fluid
or the body fluid within the first fluid passageway. In certain embodiments,
determining
the concentration of at least one analyte in the fluid within the first fluid
passageway
comprises determining the concentration of at least one analyte in at least
one component of
the body fluid. In certain embodiments, the property of the fluid within the
first fluid
passageway is sensed by a fluid sensor, which can be located at or near the
patient end of
the first fluid passageway, or on the first fluid passageway between the
patient end and the
analyte detection system.
[0420] Other disclosed embodiments comprise a sampling asseinbly to be used
with a main analyzer (such as, without limitation, the fluid handling and
analysis apparatus
140 or the analyte detection system 334) which is configured to sense an
analyte in a body
fluid drawn or otherwise obtained from a patient through a first fluid
passageway (e.g., the
passageway 112 and/or the passageway 113). The first fluid passageway extends
from the
main analyzer toward the patient. The assembly (which, in certain embodiments
can
comprise the sampling assembly 220 or the patient connector 110) includes an
instrument
portion (such as, without limitation, the instrument portion 813 or a sensing
module). The
instruinent portion includes at least one sensor and is preferably separate
from the main
analyzer and removably engaged with the first fluid passageway. The at least
one sensors
of the instrument portion is in sensing engagement with the first fluid
passageway such that
the at least one sensors can sense a property of a fluid within the first
fluid passageway.
[0421] Still other disclosed embodiments comprise a body fluid analysis system
including a main analyzer (such as, without limitation, the fluid handling and
analysis
apparatus 140 or the analyte detection system 334) and a sampling assembly
(e.g., the
sampling assembly 220 or the patient connector 110). The main analyzer is
configured to
measure an analyte in a sample of body fluid drawn or otherwise obtained from
a patient, or
in one or more components of such a drawn sample of body fluid. The sampling
assembly
is in communication with the main analyzer and includes a first fluid
passageway (such as,
without limitation, the passageway 112 and/or the passageway 113) and an
instrument
portion or sensing module (which, in one embodiment, can comprise the
instrtnnent portion
813). The first fluid passageway extends from the main analyzer and has a
patient end
spaced from the main analyzer. The instrument portion is removably engaged
with the first
fluid passageway and is located on the first fluid passageway spaced from the
main
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analyzer. The instrument portion has at:least one sensor in sensing engagement
witli the
first fluid passageway.
[0422] Other disclosed embodiments comprise a sampling assembly for use
with a main analyzer (such as, without limitation, the fluid handling and
analysis apparatus
140 or analyte detection system 334) which is configured to sense an analyte
in a body fluid
drawn or otlierwise obtained from a patient through a first fluid passageway
(e.g., the
passageway 112 and/or the passageway 113). The first fluid passageway has a
patient end
located at a distance from the main analyzer and an interface region where the
first fluid
passageway meets the main analyzer. The sampling assembly (such as, without
limitation,
the sampling assembly 220 or the patient connector 110) includes an instrument
portion or
sensing module (which can comprise the instrument portion 813) which includes
at least
one sensor and is removably engaged with the first fluid passageway between
the patient
end and the interface region of the first fluid passageway. The sensor engages
the first fluid
passageway such that it can sense a property of a fluid within the first fluid
passageway. In
certain embodiments, the fluid within the first fluid passageway comprises the
body fluid
alone while in other embodiments, the fluid within the first fluid passageway
co2nprises the
body fluid mixed with another fluid (e.g., the infusion fluid).
[0423] In some embodiments, the sampling assemblies disclosed above can also
include a second fluid passageway (such as, without limitation, the passageway
113) in
fluid communication with the first fluid passageway via a passageway junction
(e.g., the
junction 829). The instrument portion or the sampling assembly removably
engages both
the first and second fluid passageways at or near the passageway junction. One
or more of
the at least one sensor of the instrument portion or the sampling assembly can
be located
between the passageway junction and a patient end of the first fluid
passageway, or between
the junction and the interface region of the passageway.
[0424] The at least one sensor of the sampling assemblies discussed above can
comprise any one or more of the following, in various embodiments: dlution
sensor,
colorimetric sensor 311, henloglobin sensor 1003, pressure sensors and sensor
units 317,
507, 1011, and 1102, and bubble sensors and sensor units 314a, 314b, 505,
1001b, and
1001 c. The at least one sensor can be configured to detect the arrival of, or
a property of,
drawn body fluid in the first fluid passageway, or to identify the type and/or
condition of
the fluid next to the fluid sensor to facilitate directing the fluid to the
appropriate location
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or locations in the system for, e.g., subsequent analysis of one or more
desired blood
analytes in the analyte detection system, as discussed herein.
[0425] The junction of the first and second fluid passageways of the above-
described embodiments of the sampling assembly or body fluid analysis system
cazi be the
junction of the passageways 112 and 113 as depicted in any of FIGURES 3, 5,
6A, 6B, 7A-
7J, or 9.
[0426] Where the first fluid passageway comprises the passageway 112, the
patient end can comprise the end or region of the passageway 112 which is
nearest the
patient P, such as the patient connector 110/1100/1200, or any other suitable
interface with
any intervening fluid passageways or fluid networlc between the first fluid
passageway and
the patient P. Alternatively the patient end can comprise the connector 230;
or the end of
the connector 110 opposite the apparatus 140; or the end of the sampling
assembly 220
adjacent the connector 1100/1200 when employed as shown in FIGURES 11 or 12.
The
patient end of the first fluid passageway can provide fluid communication with
the bodily
fluid within the patient indirectly, where an intervening tube or passageway,
such as the
catheter 11, I.V. tubing, or other fluid handling apparatus, is positioned
between the first
fluid passageway and the patient to provide a fluid handling link between the
patient and
the first fluid passageway.
[0427] The instrument portion, in some einbodiments of the sampling assembly
or body fluid analysis. system discussed above, can include at least one first
valve portion
(such as, without limitation, 312, 313, 316, and/or 613) in operative
engagement with the
first fluid passageway. An instrument portion including such a first valve
portion can also
include a second valve portion (such as, without limitation, 312, 313, 316,
and/or 613) in
operative engagement with a second fluid passageway connected to the first
fluid
passageway.
[0428] Certain disclosed embodiments comprise methods of handling body fluid
which are executable with, for example, any of the embodiments described above
of the
sampling assembly or body fluid analysis system. In certain embodiments, the
body fluid is
within a first fluid passageway extending from and in fluid communication with
a main
analyzer. In certain embodiments, a method includes removably engaging the
first fluid
passageway with a sensing module separate from the main analyzer and sensing a
property
of the body fluid within the first fluid passageway with at least one sensor
of the sensing
module. In some embodiments the method further includes injecting gas into the
first fluid
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passageway or a second fluid passageway in fluid communication with the first
fluid
passageway using the sensing module. In some embodiments the method includes
directing
the body fluid from the first fluid passageway into a second fluid passageway
using the
sensing module. Some embodiments further include directing the body fluid with
at least
one valve portion of the sensing module. In some embodiments, sensing includes
sensing
the arrival of the body fluid in the first fluid passageway. In various
einbodiinents, sensing
comprises sensing the color, the hemoglobin content, the hematocrit, the
dilution, and/or
the pressure of the body fluid; and/or sensing the presence of bubbles in the
first fluid
passageway.
[0429] One advantage of some einbodiinents of the apparatus and methods
disclosed herein (including the sampling assembly 220 and patient connector
100, and
methods of use thereof) is limiting blood damage. More particularly, when a
sample or
volume of blood is drawn or otherwise obtained from the patient for sensing by
the one or
more sensors of the sampling assembly or instrument portion, the sample passes
through
the passageway 112 from the patient end to reach the instrument portion, where
it is
stopped, preferably well short of the analyte detection system 334 or
apparatus 140. At
least a first portion of this initial sample is then diverted and passed along
to the system 334
or apparatus 140 for analysis, and a second portion (e.g., having a volunze
larger than a
volume of the first portion) is returned to the patient via the passageway 112
(e.g., by one or
more valves). In certain embodiments in which this returned blood travels only
a relatively
short distance to the sampling assembly 220 or patient connector 110 (e.g.,
where the
distance traveled by the second portion is shorter than the distance traveled
by the first
portion), rather than all the way to the system 334 or apparatus 140, damage
to the returned
blood is diminished. For example, this returned blood is much less likely to
coagulate or to
have lysed (incurred damage to the red blood cells) as a result of the shorter
distance
traveled in returning to the patient. Limiting coagulation prevents the
formation of clots
which can restrict the flow of blood, and maintaining the integrity of red
blood cells
prevents loss of the blood's oxygen transport functions. These benefits result
in overall
improved status of the patient as compared to patients analyzed by systems
that require
returning blood to travel longer distances (e.g. all the way to the analyte
detection system
and back to the patient). Accordingly, certain of the above-described
apparatus and
methods can be considered apparatus and methods for limiting damage to
returned blood.
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[0430] Reference throughout this specification to "one embodiment" or "an
embodiment" means that a particular feature, structure or characteristic
described in
connection with the embodiment is included in at least one embodiment. Thus,
appearances
of the phrases "in one embodiment" or "in an embodiment" in various places
throughout
this specification are not necessarily all referring to the same embodiment.
Furthermore, the
particular features, structures or characteristics may be combined in any
suitable manner, as
would be apparent to one of ordinary skill in the art from this disclosure, in
one or more
embodiments.
[0431] Similarly, it should be appreciated that in the above description of
embodiments, various features of the inventions are sometimes grouped together
in a single
embodiment, figure, or description thereof for the purpose of streamlining the
disclosure
and aiding in the understanding of one or more of the various inventive
aspects. This
method of disclosure, however, is not to be interpreted as reflecting an
intention that any
claim require more features than are expressly recited in that claim. Rather,
as the following
claims reflect, inventive aspects lie in a combination of fewer than all
features of any single
foregoing disclosed embodiment. Thus, the claims following the Detailed
Description are
hereby expressly incorporated into this Detailed Description, with each claim
standing on
its own as a separate embodiment.
[0432] Further information on analyte detection systems, sample elements,
algorithms and methods for computing analyte concentrations, and other related
apparatus
and methods can be found in U.S. Patent Application Publication No.
2003/0090649,
published May 15, 2003, titled REAGENT-LESS WHOLE BLOOD GLUCOSE METER;
U.S. Patent Application Publication No. 2003/0178569, published September 25,
2003,
titled PATHLENGTH-INDEPENDENT METHODS FOR OPTICALLY DETERMINING
MATERIAL COMPOSITION; U.S. Patent Application Publication No. 2004/0019431,
published January 29, 2004, titled METHOD OF DETERMINING AN ANALYTE
CONCENTRATION IN A SAMPLE FROM AN ABSORPTION SPECTRUM; U.S. Patent
Application Publication No. 2005/0036147, published February 17, 2005, titled
METHOD
OF DETERMINING ANALYTE CONCENTRATION IN A SAMPLE USING
INFRARED TRANSMISSION DATA; and U.S. Patent Application Publication No.
2005/0038357, published on February 17, 2005, titled SAMPLE ELEMENT WITH
BARRIER MATERIAL. The entire contents of each of the above-mentioned
publications
are hereby incorporated by reference herein and are made a part of this
specification.
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[0433] A number of applications, publications and external documents are
incorporated by reference herein. Any conflict or contradiction between a
statement in the
bodily text of this specification and a statement in any of the incorporated
documents is to
be resolved in favor of the statement in the bodily text.
[0434] Although the invention(s) presented herein have been disclosed in the
context of certain preferred embodiments and examples, it will be understood
by those
skilled in the art that the invention(s) extend beyond the specifically
disclosed embodiments
to other alternative embodiments and/or uses of the invention(s) and obvious
modifications
and equivalents thereof. Thus, it is intended that the scope of the
invention(s) herein
disclosed should not be limited by the particular embodiments described above,
but should
be determined only by a fair reading of the claims that follow.
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