Note: Descriptions are shown in the official language in which they were submitted.
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f\UI01~AATED ANALYSIS INSrlaUNlENT SYSlEM
Max D. Lis~on
INTRODUCl-ION
The present invention relates generally to an automated analysis
instrurnent system and, more particularly, to an automated ins~rument for
the analysis of a selected constituent of a specimen sample by reacting a
reagent corresponding to the constituent with the sampleO The present
invention is particularly useful as an automated clinical chemistry analyzer
for determining the presence and levels of one or more selected constituents
in biological fluid samples.
E~ACKGROUND OF THE INVENTION
- Numerous automated clinical analyzers are known and widely used inhospital clinical laboratories. The majority of such analyzers can be
categorized into two distinct groups of either single-channel "batch" type
analyzers or multi-channel "profile" type analyzers. Batch type analyzers are
adapted to test for a single constituent in each of multiple samples loaded
into the instrument. An example of such an instrument is illustrated in U.S.
Patent No. 3,7489044 issued to the same inventor herein. By contrast, profile
type analyzers simul~aneously test for a fixed number of predetermined
different constituen~s in each of multiple samples loaded into the instrument.
Such testing for multiple constituents is generally accomplished by dividing
the sample and passing these portions through separate and discrete analysis
stations or channels lhence the designation "multichannel"). Each of these
analysis stations is generally dedicated to testing the sample for a particular
3~ constituent.
Both the batch and profile type analyzers generally utilize a liquid
reagent to react with the par~icular constituent being tested in the sample
and a photo-optical sys~em ~o read ~he optical absorbance of the sample which
corresponds t~ the level of the constituent in the sample. -
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Altho~l~h each of ~hese types of automa~ed analy7ers have received
wide acceptance in the clinical laboratory, certain drawbacl<s are associated
with their use. For example, although the ba~ch type analyzer is reliable due
to its simplicity, cost effec$ive for large number of samples and has a
relatively high test throughput rate, it is limited in the sense that it can only
be effectively utilized to perform a single constituent analysis at a time on a
rela~ively large number of samplesO In addition, such analyzers are not
capable of performing emergency "stat" tests due ~o their rela~ively long and
~ complex set~up time and their inherent inability to economically analyze a
single tes~ sample.
Profile type analyzers are similarly limited in their ability to perform
emergency "stat" tests. A further significant disadvantage found with profile
type analyæers is that although they can simul~aneously perform tests for
multiple constituents on the same sample, generally all of these tests must be
performed for every sample whether desired or not. This results in a waste
of both sample material and the reagents used in the unnecessary tests.
Fur~hermore, due to the fact ~hat multiple discrete and dedicated channels
are utilized in such an instrument, there is significant duplication of
numerous components which adds to the complexity and expense of the
overall instrumen~.
BRIE~ DESCRIPTION OF THE INVENTION
The automated analysis ins~rument system of the present invention
overcornes the above-described drawbacks ound with known analyzers by
providing a simple and accurate instrument that can perform ane or multiple
selected tests on a single specimen and which does not require any
appreciable test set-up time so ~hat it is available at any hour of the day for
either sta~ testing of emergency sarnples or for routine chemistries. The
unique design of the present invention incorporates extreme flexibility,
availability and simpli~ity oE operation with a high test throughput rate, low
per test cost and positive sample identification.
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Briefly stated, -the present invention is an
automat~d instrument system for analyzin~ the consti-
tuents o:E a specimen sample by reacting a reagent corre-
sponding to the selected constituent with the sample,
the analysis system comprising
cuvette means for retaining each sample and
reagent to be reacted in a discrete reaction compartment;
means for dispensing the reagent into ~e
cuvette compartment;
means for dispensing the sample into ~he
cuvette compar-tment;
a plurality of analysis stations separated by
predetermined spatial intervals; and
means for transporting the cuvette compartment
at a predetermined rate of advance to the analysis stations
whereby the time interval between the stations corresponds
to desired analysis period during the reaction time of
- the reagent.
The present syst~m preferrably utilizes a dis-
posable cuvette belt which is formed from a thin plastic
film. A series of parallel discrete reaction chambers
may~e formed in this 1exible belt which transports the
reaction mixtures throught the instrument. Such a cuvette
beit provides a simple and highly flexible means for trans-
porting the reaction mixtures through the instrument in
such a manner that multiple photometer readings may be
m~de on each reaction mixture at selected time intervals
without the necessity of passing the mixture back through
an analysis station a second time. The disposable cuvette
belt also avoids the requixement for washing the reaction
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chambers which requlres adclitional harclware. Furthermore,
it provides compl.etely discrete handli.ng of the reaction
mixtures thereby avoiding the possibility of cross-con-
tamination which is associated with flow-thr~ugh cuvettes
and the possibility of incomplete washing of reusable
discrete reaction chambers whlch may lead to inaccurate
test results.
In conjunction with the cuvette belt~ the analyzer
of the present inve.ntion preferrably utilizes a unLque
photo-optical system employing fiber optical bundles or
similar light guides to transmit various wavelengths of
light to each analysis station from a single light source.
It ls to be noted that the t~rm "light" as used herein
should be considered in its broadest sense ~o inclu~e
both visible wavelengths and non~visible spectral ana~ysis
wavelengths.
In addition to sharing a single light source,
the photo-optical system may share common wavelengths
selecti~e filters at both the output and input sides of
the system. In this manner r a further reduction in the
cost and sc)mplexity of the system is achieved and ~he
reliability of the instrument is not degraded to the
samP extent when utili~ing a large numbex o~ photometers
as compared to uæing a separate light source ~n~ filter
combination for each photometer. Fur-thermore, in lar~e
part due to the fact
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that a single wavelength determining- light source/Eilter element for each
wavelength is used regardless of the analysis station where the reading is
physically being made, it is possible to obtain ex~remely preclse "~racking" or
correspondence between the spectral responses of the photometric readings
from each of the statis)ns. In this connection~ it has been found that a one
percent coefficient of variation can be achieved between the analysis station
photometer responses when read in milliabsorbance units carried to the fifth
decimal placeO Such precision is necessary7 for example, for comparing
kinetlc deltas (rates of change in spectral absorption) for high denslty "down"
rat~ reactions where very small changes must be measured in the presence of
strong absorbances.
In the preferred embodiment, eight analysis stations are located frorn 0
to 10 minutes of reaction incubation time along the cuvette track and tests
may be read at any or all of these s~ations. lEach fiber optic bundle can
transmit up to 150 pulses at each of seven separate wavelengtlls of` light to
all ei~ht read stations during each five second period in which a particular
cuvette is positioned in a progressive stepped manner at each o~ the read
2~ stations. However, due to the position-to-position transit time of theadvancing cuvettes, each cuvette is stationary for only about four seconds at
each read station. Hence, only approximately l 00 pulses are usable for
analysis purposes. ~ microprocessor selects two appropriate wavelengths for
conducting bichromatic analysis of the selected sample constituent at each of
the eight read stations. Absorbance measurements are then made at the
appropriate endpoint or op~imal zero order kinetic time periods. During
calculations, the microprocessor may determine that the sample should be
further dilutf d or flag the test result due to inherent sample absorhance (eOg~,
interferrin~ icterus, lipemia or hemolysis) tha~ could result in an inaccurate
test result with certain constituent analysesO
One of the principle features and advantages of the present invention is
that the multiple analysis sta~ions perrnit their positioning at read times thatare closely related to ~heoretical optimal kinetic and endpoint reaction read
times. Furthermore, each of the analysis stations is capable of utllizin~ any
combination of the seven wavelengths to analy~e the sample, thereby
avoiding the inherent disadvantages foulld with prior art dedicated analysis
tracks. For example, the multiple analysls stations allow read-time
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El.ex:ibil.lt~ for up to -ten m:inutes at any selected wave-
lenc3th wi.th kinetlc reactions which permit the m:icro-
processor to moni-tor th~se react:ions and select appropri-
ate zero order del-ta readings from a series of readings
obtained from the different analysis stations. Thi.s capa-
bility and flexibilit.y is also useful for sera blar~ing
determinations which may be utili~ed to correot substrate
depletion flag points in kinetic reactions so as -to proi~de
a larger useful range for the chemistry methodology used
and to sub-tract out chromogens naturally occuring in the
sample ln order to set zero levels for endpoint reac-~ions.
It has been found wi-th th~ five second cuvette
advance rate menti.oned above that adequat~ time is ~ro-
vided for sample, reagent and diluent dispensin~0 mixing
of the reaction mixture and photometry operations~ This
zuvette ~elt advance rate results in the capability of pro-
viding 720 test per hour. Since the same optical analysis
may be performed on a particular sample up to ei~ht times
as the sample cuvette moves through the instrument, it is
~0 not necessary to hold work up at any one sta-tion until a
particular test is completed Hence, although the tes-ting
is performed methodically, i-t is accomplished a-t optimum
speed to provide high ~ou~hpu~ ~ithout compromising test
accuracy and reliability. Furthermore, since th~ micro-
processor will print Ollt a test result as soon as it is
completed resardless of the status of other tests being
performed by the instrument which may require more ~ime~
stat results are obtained as soon as possible.
Another important feature of the presen~ in~ent-
ion is that it may ~e adapted to eficlently utili~.e dry
reagents, preferably in tablet form Such t~blet~ ~re
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dropped into the cuvette by the operati.on oE a tablet
dispenser mounted on a ro-tating carousel which hvlds a
large number of tablets in a recldy state.
Such tabletted reagen-ts are always ready for
use so that there is no warm-up or set-up time necessary
for stat testing. Since tablet dispensers for ~umerous
chemistries can be held in a simple, mechanîcal carous~l
which, under micropr~cessor control, will rotate the
approp.ria-te dispenser in-to
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position over the cuve-t-te ~nd clrop a tab:Le-t, i-t is not
necessary :Eor the operator to select, measure or miY~ reagents
ancl the valving, tuhing and o-ther plumhing needs of the
system are yreatly recluce~. Furthermore, since the reagen~
tablet is only reconstituted when needed for a particular
analysis and then in only a precise amount for that par-
ticular test, there is no waste of reagent. Hence~ unlike
profile analyzers, only the particular tests desired and
selected are conducted by the instrument, thereby eliminating
.10 reagen-t and sample waste~
Furthermore, dry reagents inherently have a sig-
nificantly longer stabili.ty life over reconstituted liquid
reagents and, hence, do not require removal from th~
instrumen-t for storage and refrlgeration ~hen not in use
An added benefit i.s that the analyzer is not lsckecl into
a fixed test foremat with inflexible analyzer hardware.
Tablet dispensers for new chemistries can simply be in-
serted into reagent carousel and, after the microprocéssor
. so-ftware is electronically updated with the new test data,
they are ready to be conducted by the instrumen~.
Another significant advantage of the automatea
analysis system of the present invention is -that it per-
mits the çffective use of a micropæ~cessor-controlled
loading and transfer assembly ~or presenting to the anal~
yzer containers having the samples to be tested~
Such a loading and transfer assembly can be
adapted to identify the sample as it is presentea to the
analyzer and feed this infor~ati.on to -the microprocessor
controlling the dispensing of the rea~en-ts so tllat the
desired tests are performed on the sample. In additionr
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since such an assembly perm:i.ts u-tilizat:ion of the
sarne containe.r in which the sample was collected
(i.e., in the case of bloocl samples, the "Vacutainex"
tube which is commonly used to draw the sera specimen) t
the identification of the sample is positive without the
possibility of intervening human error in the transfer or
loading of the sample into the analyzer.
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Other features and advantages of the present irlvention will become
apparent to those skilled in the art when viewing ~he attached drawings taken
in conjunction with the following description of the preferred embodiment of
the invention.
DE~SCRIPTION OF THE DRAWINGS
Figure 1 is a ~op schema~ic view of an automa~ed analysis instrument
system constructed in accordance with an embodiment of the present
nventlon;
Figure 2 is a partial perspective view of the analysis system of Figure 1
showing many of the important operational features thereof;
Figure 3 is a partial schematic representation of a preferred photo-
optical system utilized with the analysis system of Figures I and 2; and
Fi~ure 4 is a diagram of a typical kinetic analysis reaction showing a
preferred utiiization of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
E;!eferring to Figures 1 and 2, an automated analysis instrument system
10 is shown in which is constructed in accordance with an embodiment of the
present invention. In this embodiment~ the systern is configured as clinical
analy7er for the testing of constituents in biological fluids, such as blood
samples.
The system generally comprises the following elements:
A. A disposable reaction cuvette supply 20 consisting of a continuous
cuvette belt 22 having a series of parallel discrete reaction
compartments 24 formed in a spaced relationship therein.5
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B. A single continuous cuvette track 30 having a main transport belt 32
disposed therein which engages indexing holes 26 formed in cuvet~e belt
22 and advances the reaction compartment 24 at a predetermined rate
of advance through the instrument.
C. A series o~ tabletted reagent dispensers 40 located in a rotatabledispenser carousel 42 which is adapted to bring the correct reagent
dispenser 40 to solid reagent dispensing poin~ "SRD" where a single
reagent tablet 44 is dropped into a reaction compartment.
D. A diluent and/or liquid reagent dispenser 50 is located adjacent to
carousel 42 for adding sufficient diluent 52 for reagent tablet 44
dissolution and/or or dispensin~ a liquid reagent into the reaction
compartment 24 at point "LDD".
E. A sample loading and transfer carousel assembly 60 is located
downstream of the reagent and diluent dispensers. This carousel
assembly comprises a loading carousel 62 into which patient samples 70
are randomly loaded; a transfer carousel 64 which acce~ats the patient
samples 70 from loadin~ carousel 62, identifies the patient sample by
means of a bar code reader 66 which reads a bar code label 72 placed on
the patient sample container and continuously feeds the patient samples
into the system; and finally, an unloading carousel 6~ receives the
patient samples 70 after testing ancl stores them in an organi7ed
manner in the event that the~ must later be located and retrieved.
F:. Sampler 8û Ior dispensing sample into the reaction compartments 24 at
point "Sl)" is loca~ed adjacent to transier carousel 64. This sampler is
designed to aspirate 2 to 20 ,ul of patient sample 70 from its container
in the ~ransfer carousel and dispense it into a reaction compartment 24
every five seconds.
G. Ei~ht photometric analysis stations 90 are located at points "SAll'
through "5A8" along the cuvette track 30. These analysis stations are
connected by individual optical guides 92 and 94 to photo-optical
system lO0. This sys~em is illustrated in FiglJre 3 and is described in
detail below.
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Turnin~ now to the detailed opera1ion of the instIurnellt system, a
phlehotomist draws a patient blood sample 70 which is positively iden~ified by
a bar code label 72 placed on the container in which ~he sample is drawn.
After centrifu~ing the sample to separate the sera, the sample along with as
many others as desired is placed in loading carousel 62 which is then placed
into the instrumen~ loading and transfer carousel assernbly 60. For
emergency stat tes~ing, the patient sample 70 may be loaded directly into
one of the empty san7ple receiving slo~s 65 of transfer carousel 647 or may be
exchanged with a sample container already loaded in -transfer carousel 64
prior to bar cocle rèader 66.
The loading carousel is ~hen automatically indexed to a position where
the patient sample 70 is transferred into an empty sample receiving slot 65 of
transfer carousel 64. The transfer carousel 64 then indexes around to bar
code reader 66 which identifies the patient sample. This sample identity is
fed to an instrument control microprocessor ~ns~t shown) which correlates this
information with the test requisition for this sample which has already been
entered into the instrument computer system by the laborats)ry technician.
~0
The control microprocessor then begins the advance of the cuvette
supply reel 20 and belt 22 into cuvette track 30 in response to this sample
identification. This cuvette supply advance is accomplished by loading belt
34 which threads the cuvette belt into main transport belt 32. If bar code
reader 66 detects that there are no further samples to be tested, the control
microprocessor will activate cuv~tte bel1t cutter 28 which divides cuvette
belt 22 into sec tions 29 having a number of reaction compar~ments
corresponding to the number of analysis reactions to be performed at a given
~ime. This procedure rriinimizes waste for sin~le tests or stat situations. In
aLdditiosl, the cuvette belt cutter 28 may also be periodically operated during
continuous operation of the instrument in order to prevent the length of the
cuvette belt lwhich must be disposed of) from becoming unmanageable.
As it is fed into the instrument, the cuvette belt 22 enters a water bath
l 2 which will maintain the reagent and sample reaction m ixture at a
prede termined incubation temperature. This reac tion ternperature is
generally either 30 degrees C or 37 degrees C.
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For the sake of simplicity, it should also be noted th~ in Figure i, each
circular cuvette posi~lon point 25 along cuve~te track 3Q represents a five
second period. In other words, every five seconds the control rnicroprocessor
will step a particular cuvette reac~ion cornpartment 24 to the next circular
position along the cuvette track 30.
.
During the time that the ~ransfer carousel 64 is indexing the sample 70
between the bar code reader 66 and its position where sampler 80 aspirates a
portion thereof, an appropriate rea~en~ is added at either point "SRD" or
"LDD" to the reaction cornpartment that is timed by the control
microprocessor to receive the sample. The microprocessor causes the proper
reagerl~ to be dispensed from one of the thirty-two different table~ed
reagent dispensers 40 that can be accommodated by dispenser carousel 42, or
the multiple liquid reagents that can be accommodated by diluent/liquid
reagent dispenser S0, in response to the patient sample identification by bar
code reader 66.
If a tabletted reagent is dispensed, sufficient diluent for tablet
dissolution is added there~o a~ point "LDD" and an ultrasonic horn 14 is
utilized to provide 45 seconds of high energy ultra-sound to completely brea
up and dissolve the reagent tablet. In the preferred embodiment, this rea~ent
mixture has a volume of 200~1.
After this reconstitutiun o:E the reagent in the predetermined amount of
diluent, the reaction compar~merrt is passed to a reagent quality control
analysis station at point "SAl". Here each reagent mixture is
photometrically analyzed to veri:Ey proper reagent dispensing and dlssolution.
Furthermore, the microprocessor can also utilize this reading to adjust ~or
any minor variation in reagent amount and resulting coneentration that may
exist :~rom tablet to tablet.
Next, the reaction compartment 24 is transpor~ed to point "SD" where
sampler 80 will dispense the appropriate patient sample into the reaction
cornpartment 24. As noted above, the main transport belt 32 of cuvette
track 30 is carefully synchronized with the reagent dispensers and the
sarnpler to insure ~hat the proper reac$ion mixture is obtained as ordered by
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the control microprocessor Since sarnpler 80 is the only non-discrete
element of the analysis system, its probe is flushed with additional diluent to
prevent contamlnation and carry-over bel ween samples. In the preferred
embodirnent, the final reaction volume is 300,ul.
The next analysis station is the sample blanking station located at point
"SA2". It has been found desirable to dispense an amount of each patient
sample into a reaction compartment without a reagent being added ~o obtain
a sample blank. This sample blank value may be obtained at this analysis
station or any of the following six analysis stations as required.
A second reagent dispenser 54 may be located Iurther down the cwette
track 30 for multiple or triggered reaction capability. For example, such a
reagent dispenser would be useful in conducting CKM~ constituent analyses.
At the end of the cuvette track 30, a cu~/ette sealer 16 is located to
seal $he tops of the cuvette reaction compartments aEter testing for
convenient and sanitary disposal of the samples. After passing through the
cuvette sealer 16, the cuvette belt 22 is stripped off of the main transpor~
belt 32 by an unloading belt 3~ wh;ch removes the tested cuvettes from the
water bath 12 and automatically discards them into disposal bin 18.
As referred to above, all eight analysis stations are connected via light
guides 92~ 94 to photo optical system lO0. The principal elements of this
system are shown in Figure 3. The photo-optical system comprises a single
light source lOl for generating selected wavelengths of light. The output of
light source 101 is focused by fixe~ focusing lens 102 onto the multiple
wavelength selective filters disposed about the circumference of rotary
source filter wheel 103. The rotation oE source filter wheel l~3 is regulated
by the instrument control microprocessor through double shafted motor 104.
The output from source filter wheel 103 is sequentially transn~itted through
separate light guides 92 to each of the analysis s~ations.
At the analysis stations, the filtered light energy is passed through the
reaction cornpartment 24 containing the mixture to be analyzed, and the
output of the analysis stations is then passed back to the photo-optical
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system I00 via separate ligh~ guides 94. At this point7 a second filter wheel
107, which preferabiy is identical to and synchroni~ed with source fil~er
wheel 103, in~ercepts the outputs of light ~uid~s g4 be~ore this output is
directed to a separate photodetector ~ube 109 for each analysis station. A
reflector 108 may be utilize~ to focus the output of filter wheel 107 on
photodetector tubes 109. In the represen~ation of Figure 37 only one set of
light guides ~2, 94 and one photodetector ~ube is shown for simplicity,
although it is to be understood that eight oE these elements (one for each
analysis station) are required.
The outputs of photodetec~or tubes 109 are monltored by the control
microprocessor and appropriate wavelength output values for each analysis
reaction at each analysis station is stored by the microprocessor. When the
reaction is cornpleted, the microprocessor will utilize this stored information
to calculate the concentration of the selected sample constituent and provide
this result to the instrument operator.
As can be seen from Figure 3, each filter wheel has seven diEferent
wavelength selective filters 105 disposed about its circumference. In
addition, an opaque blank 106 is located thereon in order to establish the
residual "dark curren~" level of the electronics. Hence, great flexibility is
provided by permit~ing any one or combination of ~he seven wavelengths to
be read at any analysis station for any sample during the four second analysis
period. In that filter wheels 103, 107 are rotated at thirty revolutions per
second in the preferred embodiment9 thirty readings at a particular
wavelength rn~y be made each second which can then be averaged to provide
a highly accurate Einal value by the microprocessor.
Figure 4 illustrates a typical kinetic zero delta reaction which will help
~o illustrate ~he analytical ~bilities of the present invention. The vertical
axis of the graph is in increasin~ absorbance units while the hori~ontal axis isin increasing time units, Erom 0 to 10 minutes. The reading times of analysis
station point "SA~" through "5A8l' as the sample is transported through the
instrument are shown along this horizontal axis. The actual continuous
absorption curve for the kinetic reaction ~such as for a CPK test) is labeled
.
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In such kine~ic analysis, the linear portion of this absorbance curve
between points A-B are usable to calculate the level of the constituent being
analy~ed. However; these points are not Eixed and will vary from sample to
sample and constituent to constituent. Hence~ in order to determine the
linear portion of the absorptlon curve, the microprocessor will compare the
deltas (rate cf change in absorp~ion or the slope of curve C) of adjacen~
analysis stations for the selected wavelengths used in the analysis (usually
two for bichromatic testin~3. When two or more of these deltas between
three or more stations become approximately the same ~or the rate of change
there between become approximately zero, hence, the term "deita zeroi')9
curve C will be linear at these points and -the resulting absorption values may
be used to accurately calculate the cs)nstituent level in question.
From thls example, the grea~ flexlbility and analytical power of the
present invention in providing multiple analysis stations that are staggered in
read time along with the capability of u tilizing any combination of seven
different analysis wavelengths at each station can be appreciated.
2() Although particular configurations and features of th~ present invention
have been discussed in connection with the above-described preferred
embodiment thereof, it should be that those skilled in the art may make
various changes, modifications and substitutions thereto without departing
from the spirlt of the inven~ion as defined by the followin~ claims. For
example, it should be evident from the above discussion that an instrument
constructed in accordance with the present invention could be adapted for
analyzing a wide range of different specirnen types where it is required that
such specimens be reacted for differing, predetermined periods OI tirne and
~hat analytical readings be ta!cen durin~ ~r at the end of these time periods.
