Note: Descriptions are shown in the official language in which they were submitted.
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BACKGROUND OF THE INVENTION
(1) Field of the Invent_o
This invention relates to the chemical analysis of
substances, and more particularly, to a method and apparatus
for the automatic analysis of biological fluids.
(2) State of the Prior Art
In recent years, a number of automated systems have
been developed for carrying out quantitative chemical analyses
of fluid samples. Most of the commercially-available systems
utilize liquid reagents and require analyzer equipment having
intricate solution handling and transport capabilities. One
widely used system, shown in U.S. Patent 2,797,149, employs a
continuous-flow technique in which successive samples are
separated from one another by immiscible fluid segments such as
gas or air bubbles. Such a system is complex and expensive,
requires skilled operators, and necessitates a considerable
expenditure of time and effort in repetitive cleaning operations.
Another liquid analysis system is disclosed in U.S.
Patent No. 3~788,816, in which a turntable carries a plurality
of receptacles containing samples to be analyzed and a plurality
of tube modules which are adapted to receive preset volumes of
sample and reagent. Coaxially disposed relative to the turn-
table is a vertically movable rotary element comprising a
probe tip which serves to dispense reagents and to transfer
sample to a spectrophotometer.
U.S. Patent No. 3,883,308, to Matte, discloses liquid
analysis apparatus in which a plurality of sample containers
are carried on a circular support, a plurality of reagent cups
are supported on a second circular support, and an aspirator
is provided for transferring fluid from a sample container to
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a selected reagent cup. The bottom portions of the reagent
cups are transparent to facilitate a photometric reading
through the container.
As an alternative to liquid analysis systems, various
essentially-dry analytlcal elements have been adopted for
automated test procedures. Although these elements offer
substantial storage and handling conveniences, compared to
"wet-chemistry," they have enjoyed only limited success and have
been used primarily for qualitative and semi-quantitative test
purposes. Apparatus for use with integral analytical elements
in the form of continuous webs is shown in U.S. Patents 3,036,893
and 3,526,480. Since the reagents are contained on the web in a
predetermined sequence, the versatility of this apparatus is
quite limited.
Automatic slide handling apparatus is known in
clinical apparatus of the "wet-chemistry" type. In one such
apparatus, shown in U.S. Patent No. 3,574,064, glass slides are
fed from a single supply station onto a turntable. Slides
carried on the turntable are moved past a metering station, and
20 then through wash and incubation stations spaced around the
periphery of the turntable. Slides processed by the apparatus
are ejected from the turntable into a slide receiver adjacent
the slide supply station. There is no provision for automatic
analysis of the processed slides, and they must be manually
removed from the slide receiver for examination under a labora-
tory microscope.
U.S. Patent 3,904,372, discloses apparatus for
handling chromatographic plates in which plates are removed
from a supply magazine by a pick-up arm, placed in position
for spotting with an aliquot of fluid, and then transferred
by the pick-up arm to a liquid development tank. The pick-up
arm is pivotally mounted and utilizes a vacuum means to
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grip and hold the plates as they are transferred from the
magazine to the development tank.
Slide handling mechanisms are also known in the
photographic art. Representative of these rnechanisms is the
U.S. Patent to Costanza et al., No. 3,926,514. This patent
discloses a slide projector having a slide supply magazine
which is supported above a turntable. Slides are fed from
the magazine onto the turntable which moves the slides into
a position for projection; after projection, the turntable
1~ moves the slide into a receiving chamber where the slides are
collected for eventual restacking in the supply magazine. The
Costanza et al. slides and apparatus are not indicated as being
useful for performing radiometric analysis.
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SUMMARY OF THE INVENTION
This invention relates to a method and apparatus
for the automatic analysis of biological fluids in which
a fluid sample is metered onto a test slide which is analyzed
after an appropriate period of the incubation.
In accordance with the invention, there is provided
a slide supply means for receiving a stack of slides~ each slide
incorporating means to effect the analysis of a fluid sample.
A sample supply means includes a plurality of fluld containers,
and a metering means is adapted to deposit predetermined quanti-
ties of fluid onto slides successively moved into a metering
position. A slide transporting means is adapted to remove a
slide from a slide stack, move the slide to the metering posi-
tion, and deliver the slide to a conveyor means cooperating with
an incubator means. An analysis means senses a characteristic
of the slide resulting from the fluid deposited thereon, after
an appropriate period of incubation.
The invention is particularly suitable for use in
performing analyses of blood sera in which the serum is
dispensed onto a test slide of the type which is formed as a
multilayer element containing the necessary reagents for reaction
with components of the serum. However, this invention is not
limited to use with ~ust such test slides, nor is it limited
to just the analysis of blood sera, as other fluids can be used
with apparatus of the type disclosed.
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BRIEF DESCRIPTION OF THE` DRAWINGS
FIG. 1 is a perspective vi.ew of appârâtus constructed
in accordânce with the invention;
FIG. 2 is a fragmentâry top plan view of the sample
tray;
FIG. 3 is a fragmentary elevational view of the sample
tray and the drive mechanism therefor;
FIG. 4 is a top plan view of the slide supply table
and showing a portion of the slide transfer mechanism;
FIG. 5 is a vertical sectional view of the slide
supply table, the slide ejector mechanism and a portion of
the slide transfer mechanism;
FIG. 6 is a top plan view of the slide transfer
mechanism;
FIG. 7 is a fragmentary elevational view, partially
sectioned, of the slide transfer mechanism and the drive means
therefor;
FIG. 8 is a fragmentary elevational view of the
sample tray, metering device, and the slide transfer mechanism
which is shown in the elevated position;
FIG. 9 is a top plan view of the incubator, with
parts broken away to show the incubator rotor, the slide
holding means in the rotor, and elements of the radiometer;
FIG. 10 is an elevational view of the incubator and
the incubator drive means;
FIG. 11 is a fragmentary view of the incubator
rotor, laid out in a straight line to show the slide loading
mechanism,
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FIG. 12 is an elevational view Or the rotor, as viewed
in FIG. 11.
FIG. 13 is an enlarged sectional view, taken along
line 13-13 in FIG. 11; and
FIG. 14 is a schematic diagram of the apparatus of
this invention and the controls therefor.
DESCRIPTION O~ THE PREFERRED EMBODIMENTS
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In accordance with one embodiment of the invention,
there is shown in FIG. 1 a chemical analyzer 20 which comprises
a sample tray 22, a reagent supply table 24, a metering device
26, a slide transfer mechanism 28, and incubators 30, 32. As
will be discussed in more detail hereinafter, analyzer 20 is
adapted to select a test slide from supply table 24 9 transport
the slide to metering device 26 where a drop of biological fluid
is placed thereon, and then deposit the slide in one of the
incubators 30, 32. Analysis means (shown in FIG. 9) is adapted
to ~a~e a radiometric reading of the slide after it has been in
the incubator for an appropriate period of time.
Sample tray 22 is shown in detail in FIGS. 2 and 3.
Tray 22 comprises a circular, generally flat top plate 35 which
has a plurality of slots 36 formed around the periphery thereof;
slots 36 are adapted to receive cups 37 which contain a biological
fluid to be tested. Slots 36 are numbered 1-35 to provide a
means for identifying the position of each of the samples to be
analyzed. At the start of each test operation, tray 22 is
mounted on the analyzer with the "home" position, designated 57,
directly under metering device 26. As shown in FIGS. 2 and 3, a
generally circular cover member 55 extends over the cups 37.
Tray 22 is removably mounted on a carrier plate 40 by means of
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clips 42 which are movable in a radial direction to engage
and disengage pins 43 on carrier plate 40. Sample tray 22
is rotated by a stepping motor 50 which transmits power
through reduction gearing 52 to a drive shaft 54 journaled
in base plate 56 of the analyzer; drive shaft 54 is fixed
to carrier plate 40. An encoder wheel 58, carried on shaft
54, cooperates ~7ith photocells 59 to provide a means of
locating a particular position in the sample tray.
Reagents for use in the analyzer are carried on
reagent supply table 24, shown in FIGS. 4 and 5. Table 24
comprises a plurality of cartridge holders 60 which are
secured to table 24 by screws 61. Mounted within holders
60 are cartridges 62 each of which contains a stack of test
slides 63 suitable for use in the apparatus of this inven-
tion. Supply table 24 is rotatably mounted on a shaft 64
which is driven by motor 66 through a Geneva drive 67 to
move a selected cartridge into the feed position adjacent
arm 90.
A highly preferred form of slide for use with the
sub~ect invention is described in Belgian Patent No. 801,402,
granted on January 2, 1974. The slides disclosed in the
Belgian patent are formed as a multilayer element containing
the necessary reagents for reaction with components oE a
biological fluid, such as blood serum, deposited thereon.
Certain reactions colorimetrically produce a change in
optical density which is sensed by a radiometer, the amount
of light reflected from the element varying in accordance
with the reaction and being indicative oE the amount of a
particular component present in the fluid.
The invention can also be used with other forms
of slides, as for example, the slide disclosed in commonly-
assigned U.S. Pat. No. 4,053,381, granted on October 11,
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1977. This patent describes a slide, or -test element, of
the type which is used to potentiometrically designate the
activity of ions in a liquid test solution by the use of
electrodes.
Slides 63 are fed from cartridges 62 by an ejector
mechanism 65 which includes a pusher element 68 slidably
mounted on tracks 69 fixed to base plate 56. Pusher element
68 is driven by a crank 73 which is pinned to element 68 at 74
and is mounted for pivotal movement about a pin 76 fixed to
motor mount 77. A motor 78 is adapted to rotate a roller 80
which rides in slot 81 on crank 73 and serves to oscillate
crank 73 to push a slide out at the desired time.
Slide 63 is delivered by ejector mechanism 65 to
arm 90 of the transfer mechanism 28 shown in FIGS. 6 and 7.
Arm 90 comprises a pair of rails 91 and 92, rail 91 having
a groove 93 formed on an inner face 97 and rail 92 having
a groove 94 formed on its inner face 98; grooves 93 and 94
are adapted to receive slide 63 in a close-fitting relation-
ship such that the slide will be accurately positioned
relative to metering device 26. Springs 95 and 96 serve
as a gripping means to hold the slide in arm 90. A motor
110 acts through gear 111 which drives Geneva gear 112 on
drive shaft 113 to intermittently rotate a plate 114 which
carries arm 90 thereon. A motor 120, connected to an
eccentric 122 which is coupled to a collar 124 on shaft
113, is adapted to raise and lower table 114 and the arm
90 during the metering operation, described below.
Movement of a slide 63 from the supply table to a
metering position is accomplished by rotating arm 90 through
180 . Prior to moving the slide into the metering position,
however, a cup 37 from sample tray 22 must be brought into
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engagement with metering device 26. As shown in FIG. 8,
a pair of jaws 140, 141 are provided to liEt cup 37 into
engagement with a metering head 142. Jaws 140, 141 are
pivotally mounted respectively at 143, 144, and the jaws
are biased away from each other by a spring means, not
shown. As the jaws are moved toward the sample tray 22
by a power means of a conventional type, not shown, the
jaws will move in a generally straight line through open-
ings 145 in plate 146 until notched portions 147, 148, are
extended through openings 145; at this point the jaws are
biased to the open position, shown in phantom in FIG. 3.
On the return stroke, jaws 140, 141, will be cammed inward-
ly to engage a flange 149 on cup 37 and lift the cup into
engagement with head 142. After each metering operation,
jaws 140, 141 are lowered to return the cup to the sample
tray 22; the jaws remain in the position shown in FIG. 3
until a new sample cup 37 is advanced into the metering
position. As cup 37 is moved upwardly by jaws 140, 141,
a cup cap 38 is engaged by plate 35 which results in the
cap being pulled off to expose a metering tip 39 on the cup.
Caps 38 drop into holes 151 in plate 40. (See FIG. 8.)
When cup 37 is in position on metering head 142
and slide 63 is located under the cup, a pendant drop is
formed on the metering tip 39 of the cup 37. A metering
device, such as that disclosed in U.S. Pat. No. 4,041,995,
granted on August 16, 1977, and assigned to the assignee
of the subject invention, is one form of metering apparatus
and cup which is suitable for operation with this invention.
As noted in U.S. Pat. No. 4,041,995, a pendant drop can be
formed by pressurizing the air above the fluid in cup 37.
To "touch-off" the pendant drop into test slide 63, motor
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120 is actuated to elevate table 114 and arm 90 of the
transfer mechanism 28. (The elevated position is shown in
solid lines in FIG. 8.) After the drop has been deposited
on slide 63, motor 120 moves table 114, arm 90, and slide 63
to a lowered position (shown in phantom in FIG. 8); then
motor 110 is actuated to rotate the table 90 to a position
where the slide can be delivered to one of the incubators.
When arm 90 is positioned adjacent one of the incu-
bators 30, 32, motor 125, acting through a crank mechanism
126, moves a pusher member 127 along grooves 93, 94, to push
slide 63 through a slot 168 in incubator housing 170. (See
FIG. 11.)
An incubator of a suitable type is shown in FIGS.
9-13; incubator 32 preferably is generally similar to incu-
bator 30, and thus, only incubator 30 will be described in
detail. Incubator housing 170 is formed of a good insulating
material and comprises a pair of end walls 171, 172, joined
by a cylindrical wall 173. Affixed to a ring 174 on wall
171 is a heating element 175 which may be of the type in
which high resistance wires are embedded in silicone rubber.
Located within housing 170 is a conveyor 180 which is adapted
to receive slides 63 on a loading station 182 (FIG. 12) and
to advance the slides through the incubator housing.
Conveyor 180 comprises a rotor 184 which is mounted
for rotation about an axis 185. Rotor 184 is continuously
driven by means of a motor 190 which drives a gear 191 on
rotor shaft 192 through a belt 193. Spaced around the periph-
ery of rotor 184 are a plurality of slide holding members 200
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which are adapted to capture a slide from loading station 182,
move the slide to a sensing position spaced axially from the
loading station, and move the slide to a discharge chute 240
after analysis of the slide has been completed. (See FIG. 11.)
Each of the members 200 is generally C-shaped and comprises a
pair of legs 201, 204, ~oined by a cross member 203. A pin
205 fixed to member 200 ad~acent leg 204 is adapted to move
axially within the confines of slots 210 formed in an outer
ring 211 of rotor 184. As best shown in FIG. 13, the lower
portion of member 200 slides on a pressure plate 215 which is
biased against member 200 by a circular spring 217 seated in
an inner ring 220 of rotor 184.
Slide handling members 200 are axially moved on
rotor 184 by the action of cam means 225, 226, which are adapted
to engage pins 205 on members 200. Cam means 225 comprises a
blade 227 which is pivotally mounted at 228 and ls movable
between the solid-line position shown in FIG. 11 and the phantom
line position shown in the same figure. Blade 227 is connected
through linkage 230 to a solenoid 231 which, upon actuation,
moves the blade into the solid-line position (FIG. 11); a
return spring 232 biases the blade away from the solid-line
position. Elements of cam means 226 are generally similar to,
and cooperate together in the same manner as, those ~ust
described for cam means 225.
When rotor 184 is moving from right to left, as viewed
in FIG. 11, and solenoid 231 has been actuated, pin 205 of the
selected member 200 will be engaged by blade 227 and the member
will be moved axially toward wall 172. If a slide 63 is held
by the member 200, it will be discharged into duct 234 of the
discharge chute 240 as member 200 passes thereover; the member 200
will then engage a new slide 63 on loading station 182 (FIG. 12j
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and will be moved into a sensing position by cam means 226.
In the event a slide is not properly engaged by a member 200,
the slide will be pushed by the member 20 into a second duct
235 of discharge chute 240. Slides passing through chute 240
are collected, for disposal, in receptacle 241 (See FIG. 10.)
As each slide 63 enters incubator 30, it is moved
from the loading station 182 to a sensing position adjacent
wall 171. Scanning of the slides is achieved by an analysis
means, or radiometer, 250 (FIG. 9) which contains an energiz-
ing source 252, for example an incandescent bulb of suitable
radiation, and a sensor 254 for detecting light reflected from
the slide and directed to the detector by a planar mirror 255
and lens 256, 257.
The provision of two channels for the analysis of
test slides significantly increases the number and type of
tests which can be performed by the disclosed analyzer. The
multi-channel capability is achieved through the use of two
separate incubator and analysis means together with a slide
t~ansfer mechanism which can deposit slides in either of the
incubators. One possible arrangement would be to use incu-
bator 30 for glucose tests and incubator 32 for BUN tests.
To perform both tests, slide transfer mechanism 28 would
receive a first test slide having the proper reagents for
testing glucose, move the slide to the metering position
where a drop of fluid would be dispensed onto the slide, and
then deposit the slide ln incubator 30; the same operation
would be repeated for a BUN test slide which would be depos-
ited in incubator 32. It would also be possible to perform
rate analysis in one of the incubators and end-point analysis
in another. Further, it will be apparent that one of the in-
cubators could be used to process slides of the type disclosed
in the aforesaid U.S. Pat. No. 4,053,381, in which case the
slides would be analyzed by an electrometer, not shown.
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Operation of analyzer 20 can best be described by
reference to ~IG. 1 and to the schematic diagram shown in FIG.
14. Cups 37 containing fluid to be analyzed are loaded by the
operator into sample tray 22, with a partlcular sample being
located according to a numbered position on the tray. Tray 22
is placed on the machine with the home position 57 Or the tray
located directly under the metering device 26. Cartridges of
test slides are loaded into supply table 24 such that slides
for a particular test are ln an identifiable position~ e.g.,
slides measuring glucose in positions A and B (~IG. 14) and
slides for measuring BUN in positions C and D. Input data 400,
which includes calibration values, sample identification, and
the desired tests for each fluid sample, is keyed into a com-
puter, designated 401. Output signals from the computer are
applied to control center 402 which provides input signals
(dotted lines in FIG. 14) to the analyzer components to control
their operation at the appropriate time in the machine cycle.
Computer 400 may take any of the various forms known in the art
which include commercially available programmable minicomputers
and programmable microprocessors. The instructions and method
of programming such computers is well known in the art, and
thus, no further explanation is considered necessary here.
To start the analysis, slide e~ector 65 loads a test
slide 63 from cartridge A into transfer arm 90 of the slide
transfer mechanism 28. As arm 90 is being moved toward the
metering position, ~aws 140, 141, pick up a sample cup 37 from
tray 22 and raise it into engagement with the metering head 142.
When the test slide 63 in arm 90 is located directly below
metering tip 39 of the cup 37 in the metering de~ice, a pendant
drop is formed on the cup tip; arm 90 is then elevated to
effect contact between the drop and the slide, causing the drop
to be transferred to the slide. Arm 90 remains in the elevated
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position for an appropriate length of time and is then lowered
and rotated to a position ad~acent one of the incubators 30,
32, where the slide is delivered to the loading station 182
of the selected incubator. Slide 63 is moved into the incuba-
tor conveyor, as described above, and after an appropriate
incubation time, a radiometric reading of the slide is taken.
The results of the reading are transmitted to the computer
which per~orms the necessary calculations, according to a stored
program, to arrive at a concentration for a particular sample.
This information, along with sample identification, is then
transmitted to a display or print-out device 403.
The invention has been defined in detail with reference
to certain preferred embodiments thereof, but it will be under-
stood that variations and modifications can be effected within
the spirit and scope of the invention.
