U.S. patent number RE31,150 [Application Number 06/296,780] was granted by the patent office on 1983-02-15 for apparatus for monitoring chemical reactions and employing moving photometer means.
This patent grant is currently assigned to Coulter Electronics, Inc.. Invention is credited to Guenter Ginsberg, Thomas Horne, Robert L. Kreiselman.
United States Patent |
RE31,150 |
Ginsberg , et al. |
February 15, 1983 |
Apparatus for monitoring chemical reactions and employing moving
photometer means
Abstract
Apparatus for measuring progressively the absorbance changes of
a large number of aliquots from a plurality of different samples.
The sample introduction, testing instructions, aliquot preparation,
reagent dispensing, absorbance measuring and data recording all can
be accomplished in a continuous mode of processing. Stat and batch
operation also can be accomplished. The aliquots are in an array of
cuvettes which is advanced slowly along a circular path. Photometer
means, preferably having several photometric detectors, are mounted
in fixed orientation on a common support that advances rapidly
along a similar circular path, such that radiation passing through
each of the cuvettes is monitored many times by a specific
photometric detector by the time that cuvette completes one circuit
of its path. The photometric detectors can operate at several
different wavelengths. Many different chemical reactions can be
monitored at the same time. The radiant energy passing through each
cuvette is received by the continuously moving photometer means, is
converted electrically into a digitized value proportional to
absorbance and is transmitted digitally from the moving assemblage
of photometric detectors, cuvettes and electrical components to a
stationary receiver. In one embodiment, the digital transmission is
in the form of a pulsed train of light signals. In another
embodiment, one or more slip rings transmit electric signals from
the moving assemblage to the stationary portion. Suitable drive
elements, sample and reagent storage and transfer mechanisms as
well as cuvette laundry means may be provided as part of the
complete apparatus.
Inventors: |
Ginsberg; Guenter (Miami,
FL), Horne; Thomas (Harpenden, GB2), Kreiselman;
Robert L. (Melbourne, FL) |
Assignee: |
Coulter Electronics, Inc.
(Hialeah, FL)
|
Family
ID: |
27404460 |
Appl.
No.: |
06/296,780 |
Filed: |
August 27, 1981 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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808166 |
Jun 20, 1977 |
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Reissue of: |
846337 |
Oct 28, 1977 |
04234538 |
Nov 18, 1980 |
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Current U.S.
Class: |
422/64;
250/208.3; 250/576; 356/222; 356/246; 356/435; 422/67 |
Current CPC
Class: |
G01N
21/253 (20130101); G01N 2201/0423 (20130101) |
Current International
Class: |
G01N
21/25 (20060101); G01N 021/24 (); G01N
001/14 () |
Field of
Search: |
;422/64,67 ;356/246,435
;23/23R ;250/432R ;364/497 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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844876 |
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Dec 1976 |
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BE |
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905301 |
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Sep 1962 |
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GB |
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1192008 |
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May 1970 |
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GB |
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Other References
Anderson, Analytical Biochemistry, 28, 545-562, (1969)..
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Primary Examiner: Serwin; Ronald E.
Attorney, Agent or Firm: Silverman, Cass & Singer,
Ltd.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This is a continuation-in-part of our application of the same title
Ser. No. 808,166 filed June 20, 1977, now abandoned.
Claims
What it is desired to secure by Letters Patent of the United States
is:
1. Apparatus for monitoring chemical reactions occurring in a
plurality of liquid or the like sample substantances carried
.[.in.]. .Iadd.by .Iaddend.a plurality of respective .[.cuvettes
whose wallS are at least to some extent capable of transmitting .].
.Iadd.sample support members, said sample substances and support
members being capable of producing an optical effect when exposed
to radiant .Iaddend.energy which comprises:
A. support means,
B. a rotor mounted on said support means for rotation thereon on an
axis,
C. a turntable mounted coaxially with the rotor for rotation
relative to said support means, a plurality of .[.radiant energy
transmissive cuvettes.]. .Iadd.sample support members
.Iaddend.mounted to the turntable and disposed in a circular
arrangement coaxially with said axis and adapted to have sample
substances producing chemical reactions carried .[.in.]. .Iadd.by
.Iaddend.at least some of said .[.cuvettes.]. .Iadd.sample support
members.Iaddend.,
D. first drive means for rotating the turntable on its axis in a
first program of rotation whereby the .[.cuvettes.]. .Iadd.sample
support members .Iaddend.describe an annular path as the turntable
rotates,
E. second drive means for rotating the rotor on said axis in a
second program of rotation in which the number of total revolutions
of the rotor for a given period of time is greater than the number
of revolutions of the turntable for the same period of time,
F. photometer means mounted on the rotor and defining at least one
beam path for radiant energy which extends at least .[.through.].
.Iadd.toward .Iaddend.said annular path such that the beam path
includes and traverses at least a portion of the sample substance
which may be contained in any of said .[.cuvettes.]. .Iadd.sample
support members .Iaddend.which intersects such beam path during
rotation of the turntable .Iadd.will be exposed to said beam when
so intersected and produce an optically changed beam leaving said
sample support member.Iaddend.,
G. the photometer means including means responsive to any radiant
energy projected along said beam path to produce electrical signals
as the .[.cuvettes.]. .Iadd.sample support members
.Iaddend.intersect the beam path, which signals are related to
chemical conditions of the sample substances, if any, which may be
contained in said .[.cuvettes.]. .Iadd.sample support
members.Iaddend., there being two radiant energy detectors and
means for dividing the beam path into two parts and directing the
parts through different strata of the .[.cuvettes.]. .Iadd.sample
support members.Iaddend.,
H. means for generating usable data from any such signals, and
I. means for coupling at most all of the electrical signals from
said photometer means to said data generating means.
2. In apparatus for monitoring chemical reactions, a plurality of
.[.cuvettes.]. .Iadd.sample support members .Iaddend.adapted to
have respective liquid or the like samples contained therein, the
chemical reaction of which it is desired to monitor, photometer
means including a beam path for radiant energy adapted to intersect
and .[.pass through .Iadd.and scan .Iaddend.all of the
.[.cuvettes.]. .Iadd.sample support members .Iaddend.to provide
respective electrical signals related to the chemical reactions
occurring in the respective .[.cuvettes.]. .Iadd.sample support
members.Iaddend., and means for generating data based upon and
responding to said signals, the invention comprising a photometric
detector means constructed and arranged as part of the photometer
means for generating the electrical signals and also means to cause
movement of both said .[.cuvettes.]. .Iadd.sample support members
.Iaddend.and photometer means relative to each other and also
relative to a reference location, said movement means
comprising:
first movable carrier means having the photometer means mounted
thereon and arranged to cause the beam path to trace a certain
first repetitive pattern during movement thereof,
second movable carrier means having the .[.cuvettes.]. .Iadd.sample
support members .Iaddend.mounted thereon and arranged to cause the
.[.cuvettes.]. .Iadd.sample support members .Iaddend.to trace a
certain second repetitive pattern during movement thereof, said
first and second movable carrier means both having drive means for
their independent moving,
the first and second repetitive patterns being geometrically
related to one another such that there is a significant portion of
each which coincide, such that when the photometer means moves
through said significant portion it will scan the .[.cuvettes.].
.Iadd.sample support members .Iaddend.which are simultaneously
located thereat and the photometric detector means will generate
the related electrical signals, the speed of movement of the first
carrier means being substantially greater than that of the second
carrier means to an extent that each .[.cuvette.]. .Iadd.sample
support member .Iaddend.moving through said coincident portion will
be scanned at least once by said beam path during its presence in
said coincident portion, said photometer means including means
providing an output proportional to the .[.transmittance.].
.Iadd.optical effect produced upon said beam by the
.Iaddend.scanning of the contents of each .Iadd.sample support
member .Iaddend.scanned,
photoemissive transmitter and photoresponsive receiver means
coupled to receive said output, said transmitter means being
mechanically connected for movement along with said photometer
means and said receiver means being stationary,
said first movable carrier means being movable about an axis and
said transmitter means being mounted proximate to said axis,
a plurality of photometric detectors being mounted to the said
first movable carrier means, each photometric detector providing
its own digital output, and
output routing and control means by which said digital output is
associated with respect to the originating .[.cuvette.].
.Iadd.sample support member.Iaddend., and a chemical reaction test
result is obtainable for each .[.cuvette.]. .Iadd.sample support
member.Iaddend..
3. Apparatus according to claim 2 in which said output routing and
control means have one portion mounted for movement with said
photometer means carrier means and is coupled between said
photometric detectors and said transmitter means, and there is
another portion of said output routing and control means which is
coupled to said receiver means, is stationary and includes a master
control unit.
4. Apparatus according to claim 3 in which additional transmitter
means are coupled to said another portion and transmit to
additional receiver means that are coupled to said one portion and
are movable therewith for establishing two-way communications
between said portions.
5. Chemical reaction monitoring apparatus comprising:
A. .[.cuvette.]. .Iadd.sample support member .Iaddend.carrier
means,
B. photometer carrier means,
C. a plurality of photometers mounted on the photometer carrier
means and including a detector for search photometer and source
means of radiant energy also mounted on the photometer carrier
means projecting an energy beam to each said detector,
D. the .[.cuvette.]. .Iadd.sample support member .Iaddend.carrier
means adapted to have at least one .[.radiant energy transmissive
cuvette.]. .Iadd.sample support member responsive to radiant energy
.Iaddend.carried thereby and said .[.cuvette.]. .Iadd.sample
support member .Iaddend.adapted to .[.have a liquid.]. .Iadd.carry
a .Iaddend.sample .[.container therein.]. to enable a condition of
chemical reaction therein to be monitored,
E. means for moving the .[.cuvette.]. .Iadd.sample support member
.Iaddend.carrier means and the photometer carrier means in a
repetitious cycling movement relative to one another so that each
beam intersects and .[.passes through and cuvette.]. .Iadd.scans
said sample support member .Iaddend.repeatedly once each cycle,
F. means for generating signals relating to said condition and
responsive to the outputs of said detectors,
G. means for acquiring usable data from said signals and,
H. said signal generating means including A/D conversion circuitry
carried on said .[.rotor and rotating therewith.]. .Iadd.photometer
carrier means.Iaddend..
6. The apparatus as claimed in claim 5 in which said A/D conversion
circuitry is connected with each photometer carried on said
.[.rotor and rotating therewith.]. .Iadd.photometer carrier
means.Iaddend.. .[.7. Apparatus for measuring the absorbance of
chemical reactions occurring and/or occurred in a plurality of
liquid or the like sample substances carried respectively in a
plurality of cuvettes which comprises:
A. a support structure,
B. a horizontally disposed cuvette carrier having a plurality of
cuvettes disposed thereon in a circular array about a central
vertical axis, the cuvette carrier being mounted on the support
structure, the cuvettes having walls capable of transmitting
radiant energy,
C. a rotor horizontally disposed parallel with the cuvette carrier
and mounted for rotation on said axis,
D. a photometer secured to said rotor and including a source of
radiant energy of a type which said cuvettes are capable of
transmitting, a photoresponsive element aligned with the source of
radiant energy and adapted to receive a beam of radiant energy
emerging from said source, the source and photoresponsive element
being arranged such that the beam lies on a radius of the rotor
with one of the element and source located inside the circular
array and the other of said element and source located outside of
said circular array, the rotation of the rotor causing the beam to
describe a locus which is an annular disc,
E. the vertical relationship between the array of cuvettes and the
locus being such as to cause the disc to intersect the cuvettes at
a level where sample substances carried thereby will be traversed
by the beam,
F. means for driving the rotor in a rotary movement to cause the
beam to intersect all of the cuvettes in sequence, at least once
for each revolution of the rotor if the rotor is rotated more than
one revolution relative to said array and a proportionally lesser
number of times if the rotor is rotated less than a revolution
relative to said array,
G. the photoresponsive element being responsive to said beam to
produce an analog signal, the signal resulting when the beam passes
through a cuvette being related to the transmittance of said
cuvette plus the sample substance, if any, carried by said
cuvette,
H. means for producing data on the absorbance of the substances
through which the beam has passed during rotation of the rotor,
said data producing means being associated with the support
structure, being nonrotatable and being responsive to digital
information,
I. an A/D converter carried on said rotor and connected with the
photoresponsive element for converting the analog signals generated
by said photoresponsive element into digital information and
J. coupling means including a fixed portion carried by said support
structure and a rotary portion secured to said rotor, the rotary
portion being connected to the A/D converter to receive the output
thereof and the
fixed portion being connected to said data producing means..].
.[.8. The apparatus as claimed in claim 7 in which the coupling
means comprise a slip ring device located at said axis..]. .[.9.
The apparatus as claimed in claim 7 in which the cuvette carrier is
also mounted for rotation on said axis and drive means are provided
to rotate said carrier slower than
the rotor..]. 10. Apparatus for monitoring chemical reactions
occurring in a plurality of liquid or the like sample substances
carried in a plurality of respective cuvettes whose walls are at
least to some extent capable of transmitting radiant energy which
comprises:
A. support means,
B. a rotor mounted on said support means for rotation thereon on an
axis,
C. a turntable mounted coaxially with the rotor for rotation
relative to said support means, a plurality of
radiant-energy-transmissive cuvettes mounted to the turntable and
disposed in a circular arrangement coaxially with said axis and
adapted to have sample substances producing chemical reactions
carried in at least some of said cuvettes,
D. first drive means for rotating the turntable on its axis in a
first program of rotation whereby the cuvettes describe an annular
path as the turntable rotates,
E. second drive means for rotating the rotor on said axis in a
second program of rotation in which the number of total revolutions
of the rotor for a given period of time is greater than the number
of revolutions of the turntable for the same period of time,
F. said photometer means are mounted on said rotor and comprise a
plurality of photometers spaced about said rotor circumferentially,
each photometer having structure defining a beam path for radiant
energy disposed radially relative to the axis of said rotor such
that all beam paths will extend through said annular path and the
cuvettes will intersect all of the beam paths as said rotor rotates
and each beam path will traverse at least a portion of the sample
substance which may be contained in said cuvettes during rotation
of said rotor,
G. each photometer including independent means responsive to its
radiant energy beam projected along its respective path to produce
electrical signals as the cuvettes pass through the beam, which
signals are related to chemical conditions of the sample
substances, if any, with regard to all of the beam paths, said
means to produce electrical signals of each photometer include an
analog to digital converter,
H. means for generating usable data concerning the absorbance of
the sample substances from any such signals, said data generating
means comprising the following elements in series connection: a
digital multiplexer having its inputs coupled to the output of each
said converter, means for presenting the digital data concerned
with absorbance into serial bit order, and data bit transmitter
means, such elements being mounted to said rotor, and said data
generating means further comprising the following elements
structurally mounted to said support means and connected in series:
a data bit receiver, series bit to parallel bit order logic
communication means, and a master control unit, and
I. means for coupling all of the electrical signals from said
photometer
means to said data generating means. 11. The apparatus as claimed
in claim 10 in which the data generating means comprise at least a
computing device and the coupling means include receiving structure
carried on the support means and providing a fixed communication
link between the computing device and the photometers and
transmitting structure carried on the rotor and providing a
rotating communication link between the computing device
and the photometers. 12. Apparatus for monitoring chemical
reactions occurring in a plurality of liquid samples carried in a
plurality of respective cuvettes which comprises:
A. support means,
B. a generally planar carrier mounted on said support means and
having a plurality of radiant-energy-transmissive cuvettes disposed
thereon in a generally circular array and adapted to have liquid
samples producing chemical reactions respectively held in said
cuvettes, each cuvette having a portion freely protruding from said
carrier and all cuvettes thereby defining an annular ring
projecting from said carrier,
C. a rotor mounted on said support means for rotation on an axis
which coincides generally with the center of said circular array
and there being drive means for rotating the rotor in a movement
parallel to the plane of the carrier,
D. a plurality of photometers mounted on the rotor and each being
radially arranged relative to the axis and including source means
of radiant energy and a radiant-energy-responsive element spaced
apart whereby to define a beam path therebetween, including at
least an A/D converter connected to each photometer to process said
electrical signals of the radiant-energy-responsive element of said
photometer mounted on the rotor,
E. the rotor and carrier being arranged in proximity so that the
annular ring is located in the beam paths whereby during rotation
of the rotor each beam path will be intercepted by substantially
all cuvettes for each rotation of the rotor,
F. the radiant-energy-responsive elements adapted to generate
electrical signals respectively related to the absorbtivity of the
liquids, if any, contained in the cuvettes which intercept the said
beam paths during rotation of said rotor,
G. means for generating usable data from said signals relating to
the chemical reactions, if any, in the respective cuvettes, and
H. means for coupling the electrical signals from the rotating
photometers to said data generating means. .Iadd. 13. The chemical
reaction monitoring apparatus as claimed in claim 6 in which the
photometers are arranged so that the beams thereof lie on radii of
a circle having an axis and in which the cycling relative movement
is rotary about said axis. .Iaddend..Iadd. 14. The chemical
reaction monitoring apparatus as claimed in claim 13 in which there
is a plurality of sample support members comprising cuvettes
arranged in a circle on said cuvette carrier means coaxially
relative to said photometer carrier means and the relative movement
causes each of the cuvettes to be scanned by all of the beams
sequentially. .Iaddend..Iadd. 15. The chemical reaction monitoring
apparatus as claimed in claim 13 in which the photometer carrier
means is a rotor and during the relative movement at least the
rotor rotates on said axis. .Iaddend..Iadd. 16. The apparatus as
claimed in claim 5 or 6, in which the said carrier has a plurality
of openings arranged in a circle and said sample support members
are removably engaged in said openings. .Iaddend. .Iadd. 17. The
apparatus as claimed in claim 5 or 6 in which at least one of said
sample support members comprises at least one well capable of
transmission of said radiant energy for impingement of said sample
substance and measurement of the resulting interaction by said
detector. .Iaddend. .Iadd. 18. Apparatus for measuring chemical
reactions occurring and/or occurred in a plurality of liquid or the
like sample substances carried respectively by a plurality of
sample support members which comprises:
A. a support structure,
B. a horizontally disposed sample support member carrier having a
plurality of sample support members disposed thereon in a circular
array about a central vertical axis, the sample support member
carrier being mounted on the support structure,
C. a rotor horizontally disposed parallel with the sample support
member carrier and mounted for rotation on said axis,
D. a photometer secured to said rotor and including source means of
radiant energy of a type which said sample support members are
capable of modifying, a photoresponsive element having a fixed
geometric relation with the source means of radiant energy and
adapted to receive a beam of radiant energy emerging from said
source means but after modification through impingement upon a
sample support member, the source means and photometer being
arranged such that at least the portion of the beam between the
source means and the circular array is rectilinear and lies on a
radius of the rotor, the rotation of the rotor causing the beam to
describe a locus which is an annular disc,
E. the vertical relationship between the array of sample support
members and the locus being such as to cause the disc to intersect
the sample support members at a level where sample substances
carried thereby will be scanned by the beam and will cause said
modification of said beam including at least an optical change
therein,
F. means for driving the rotor in a rotary movement to cause the
beam to intersect all of the sample support members in sequence at
least once for each rotation of the rotor if the rotor is rotated
more than one revolution relative to said array and a
proportionally lesser number of times if the rotor is rotated less
than a revolution relative to said array,
G. the photoresponsive element being responsive to said beam after
modification to produce an analog signal, the signal resulting when
the beam impinges against a sample support member and being related
to optical modification caused by said sample support member and
the chemical reaction of the sample substance, if any carried by
said sample support member,
H. means for producing data on the chemical reaction of the sample
subsbtances which the beam has scanned during rotation of the
rotor, said data producing means being associated with the support
structure, being nonrotatable and beng responsive to digital
information,
I. an A/D converter carried on said rotor and connected with the
photoresponsive element for converting the analog signals generated
by said photoresponsive element into digital information and
J. coupling means including a fixed portion carried by said support
structure and a rotary portion secured to said rotor, the rotary
portion being connected to the A/D converter to receive the output
thereof and the fixed portion being connected to the said data
producing means.
.Iaddend..Iadd. 19. The apparatus as claimed in claim 18 in which a
plurality of photometers is secured to said rotor, the source means
and said photometers being related in such a manner as to produce a
separate beam of radiant energy for each photometer, there being a
separate photoresponsive element individual to each photometer
adapted to receive one of said beams emerging from said source
means but after modification through infringement upon a sample
support member, all of the beams lying on radii of the rotor and
being rectilinear between the source means and said array, the
rotation of the rotor causing all of the beams to describe a locus
which is an annular disc, the disc intersecting all of the sample
support members at a level where sample substances carried thereby
will cause modificatfion of all of said beams including at least
optical changes therein, each photoresponsive element being
responsive to its respective beam to produce analog signals, each
photoresposive element having an A/D converter carried on the rotor
for converting its analog signals to digital information and the
coupling means being arranged to transmit all of said digital
information to said data producing means. .Iaddend..Iadd. 20. The
apparatus as claimed in claim 19 in which the sample support member
carrier is also mounted for rotation on said axis and drive means
are provided to rotate said sample support member carrier slower
than said rotor..Iaddend. .Iadd. 21. The apparatus as claimed in
claim 20 in which the rotation of the sample support member is a
stepping action and the dwell periods of said stepping action occur
when there is a sample support member aligned with each beam.
.Iaddend..Iadd. 22. The apparatus as claimed in claim 18 in which
the coupling means comprise a slip ring device located at said
axis. .Iaddend..Iadd. 23. The apparatus as claimed in claim 19 in
which the coupling means comprise a slip ring device located at
said axis. .Iaddend..Iadd. 24. The apparatus as claimed in claim 18
in which the sample support member carrier is also mounted for
rotation on said axis and drive means are provided to rotate said
sample support member carrier slower than said rotor. .Iaddend.
Description
BACKGROUND OF THE INVENTION
This invention relates to apparatus for monitoring repeatedly the
absorption of electromagnetic radiation by a plurality of specimens
occurring during a period of time. More particularly, this
invention concerns an apparatus by which each of a plurality of
samples provides a plurality of aliquots which can be subjected to
chemical reaction with different reagents. The absorbance of each
aliquot repeatedly is measured during a predetermined reaction
time. The inputting of the samples, obtaining their aliquots,
selecting and adding of reagents, and the absorbance measuring all
can be effected in a continuous mode as well as a stat and a batch
mode of operation. The term "aliquot" as employed herein is a noun
meaning a portion of a sample.
Apparatus described hereinafter would be well suited for the
measurement of kinetic reactions such as useful in enzyme analysis
as well as end point measurement. Many chemical reactions require
from a few seconds to many minutes to be completed and, during such
kinetic reaction time, it is often important to observe the
progress of the reaction by making measurements several times. One
form of measurement is ascertaining the absorbance of
electromagnetic radiation of a particular wavelength by the
analyte. Typically, enzyme reaction measurements have been
accomplished by batch handling methods and apparatuses requiring a
considerable amount of preparation and manipulation by the
laboratory technician. The nature of the process cannot help but
result in relatively low throughput. Examples of batch operating
enzyme analyzers are disclosed in Wood et al U.S. Pat. No.
3,344,702 and Liston U.S. Pat. No. 3,748,044, the latter having
automated the aliquot preparation and reagent dispensing, but being
limited to a single chemistry determination for all of the aliquots
in the batch being processed.
In contrast to the batch mode a more efficient method is the
continuous mode in which the apparatus can remain operating as long
as there are samples to be tested, with old samples and their
tested aliquots being "replaced" by new samples and their aliquots
without interruption of the operation of the testing apparatus.
Such continuous operation is well known in biological chemistry
testing systems and is taught, for example, in Jones U.S. Pat. No.
3,799,744 and Hoskins et al U.S. Pat. No. 3,883,305, in which
separate chemistry tests can be made for several different aliquots
from the same sample.
A disadvantage of such systems is that they are capable of making
only a single photometric measurement on a given aliquot and even
if an attempt is made to achieve measurement of kinetic reaction
by, for example two time-separated measurements, these must be
effected on different aliquots of the same sample. Thus, these
systems are not designed to measure kinetic reactions by multiple
point observations on a single aliquot.
Recently published Greaves et al U.S. Pat. No. 3,966,322 discloses
a specimen investigating apparatus suitable for measuring kinetic
reactions in a continuous operations mode. Greaves et al teaches
that illumination of the plurality of specimens, which are
circumferentially mounted in cuvettes around the periphery of a
turntable, originates from a single non-rotating light source that
projects a beam of light vertically down the axis of the hollow
shaft of the turntable. Optical elements then divert and direct the
light beam radially outward toward one of the specimens holding
cuvettes and to a radially inwardly reflected or directed return
path that terminates with a vertically down-the-axis output to a
fixed light detector. The optical elements providing this tortuous
path for the light beam are mounted for rotation around the same
axis but at a higher speed than the specimen turntable. With only
one light source and one optical train, only one specimen can be
monitored at any one instant and each specimen is monitored only
once per revolution of the optical train.
Greaves et al as well as another apparatus which has been described
recently that is similar to Greaves et al has two disadvantages.
The light source for this type of device comprises a tungsten or
similar lamp having a filament. The light source remains fixed
while the optical elements of the train rotate. The orientation of
the lamp filament with respect to the optical elements of the train
will change with rotation, exacerbated by precession and the
intersection of the light beam with the photodetector at the end of
the long optical path will change similarly. The obvious sources of
error then become the following:
(1) The light input varies because light emitted from different
parts of the lamp filament is nonuniform and the optical elements
of the train look at different parts of the filament at different
times.
(2) The output from the photodetector varies because it has
different response in different areas of its sensitive surface and
the incident energy beam impinges varying areas of this surface at
different times.
Another prior art device is disclosed in DeMendez et al U.S. Pat.
No. 3,829,221 in which a single light source and photoresponsive
detector rotate in unison. The cuvettes are necessarily stationary.
This enables only batch methods of measurement of absorbance using
a single wavelength.
SUMMARY OF THE INVENTION
The present invention seeks to reduce the limitations found in the
prior art, while at the same time to provide increased measuring
accuracy and testing versatility, especially for monitoring kinetic
reactions. Apparatus is provided which operates in the continuous
mode and in which photometer means preferably comprising a
plurality of photometric detectors, (but which can comprise a
single photometer) continuously scan an array of cuvettes that is
being indexed at a slower speed around a preferably circular path.
As employed herein, "index" is a verb which encompasses both
stepping and continuous or smooth movement.
In one embodiment, the photometer means include a plurality of
radiation sources and radiation detectors of the photoresponsive
type that are respectively mated. Each source is aligned with its
associated detector in a fixed orientation that is maintained at
all times during rotaton of the rotor which carries the photometer
means, the axis of alignment lying on a radius of the rotor and
also lying on a radius of a cuvette-carrying turntable that is
mounted for rotation coaxial with the rotor. The axis of alignment
is such as to intersect a circular array of circumferentially
arranged cuvettes mounted on the turntable, there being a clear
space between each source and its associated detector through which
the circular array of cuvettes passes without mechanical
interference.
In another embodiment, the photometer means comprise a single
rotating radiation source in the center of the rotor which radiates
its beams of radiation to an array of axially arranged detectors
spaced around the rotor. The photometer means define radial optical
trains including a clear area, these trains sweep circular areas
concentric with the array of cuvettes carried by the turntable
about the axis where the single light source is positioned. The
cuvettes pass through the clear area of each train; the alignment
of the light source relative to its associated detector never
changes because the light source is fixed relative to all of the
optical trains. On this account during one rotation of the rotor
and its detectors there will be a plurality of scannings of each
curvette, specifically, each of the photometers will scan every
cuvette. For example, if there are eight photometric detectors each
cuvette will be scanned eight times and there will be provided
eight measurements of absorbance. This, of course is true for both
of the embodiments mentioned, that is, where there is a single
light source or a plurality thereof. The cuvette turntable will
normally be moving at a very slow speed, enabling the aliquots to
be loaded and unloaded continuously, say of the order of a fraction
of a revolution a minute. The rotor carrying the photometer means
on the other hand will be rotating at a relatively higher speed,
say of the order of 500 to 1000 revolutions per minute. The amount
of information which can be gathered in a very short time is
clearly quite voluminous. When it is appreciated that the
photometric detectors are preferably operated at different wave
lengths, for example by using different filters in their respective
optical trains, then it becomes clear that not only is the quantity
of information gathered voluminous but that information is made up
of many different kinds.
The movement of the rotor is continuous while the movement of the
turntable is preferably intermittent, that is, indexed. The
apparatus is programmed in such case, by suitable electronic
circuitry, to make the measurements of absorbance while the
cuvettes are not moving but are in a dwell period. This is more
easily accomplished than attempting to have the turntable moving at
a continuous slow speed and programming the photometers to do their
scanning for short periods of time while the cuvettes are aligned
with the respective photometer trains during rotation. The
invention, however, includes a structure of this latter type.
Where the materials comprising the samples to be measured by the
apparatus comprise sources of radiation in and of themselves, being
luminescent, fluorescent or radioactive, the light source is not
required. The source in such case may be turned off or blocked.
The amount of radiation transmitted by each specimen or aliquot
carried in the cuvettes is detected on each scan and is converted
into a digital value proportional to absorbance by means of an
electrical circuit which includes an A/D converter. The A/D
converter of each photodetector is carried by the rotor itself
adjacent to the photodetector thereby economizing in connections
and rendering transmission from the moving rotor to the fixed
portion of the apparatus relatively simple. The digital value is
transmitted from the photometer rotor by suitable means coupling
the rotating part with the fixed part of the apparatus. One
embodiment includes a light emitting diode and another has slipring
means. The signals are transmitted to a receiver which is
stationary and thence to suitable storage or processing means. For
example, the signals may pass first to a console where they receive
routing information from a master control unit that governs the
programming and operation of the entire apparatus.
The apparatus is arranged to provide end point information as well
as information on kinetic reactions.
The invention has an important advantage in that the relationship
between the light source and photodetector in every case is
geometrically fixed so that there can be no variation during
rotation of the rotor. Since the turntable of cuvettes is mounted
on the same axis any slight eccentricity which exists by reason of
construction or develops during use has no practical effect on
measurements made.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective somewhat diagrammatic view of one
embodiment of the complete apparatus of the invention;
FIG. 2 is a fragmentary perspective view of the cuvette turntable
and the photometer rotor illustrating one embodiment of the
photometer means, portions being shown in section and other
portions being broken away;
FIG. 3 is a median fragmentary sectional view through the data
generating components of the apparatus further detailing the
embodiment of FIG. 2;
FIG. 4 is a view similar to that of FIG. 3, but detailing a second
embodiment of the photometer means and a second embodiment of the
data transmission arrangement;
FIG. 4a is a fragmentary view of a portion of FIG. 4 but
illustrating a modified form of the invention utilizing a split
beam arrangement; and
FIG. 5 is an electrical block diagram primarily of the portions of
the apparatus concerned with the generation and transmission of
digitized absorbance data.
DESCRIPTION OF THE PREFERRED EMBODIMENT
With reference to FIGS. 1 and 5 which are somewhat diagrammatic,
the subject apparatus can be composed of a control console 10 and a
chemistry processing portion 12. Input information, concerning each
sample and the different chemical tests to be performed on aliquots
of each specific sample, can be supplied by way of a keyboard 14
and/or data cards fed into a receiver 16 of suitable data input
means 18. The input information then is applied to a master control
unit 20, which has many functions, only some of which will be
mentioned hereinafter, but those skilled in the art will appreciate
the more complete control ambit of this unit. A first function of
the master control unit 20 can be to feed the input information to
a readout unit 22, which can include a visual display 24 and a
printer of a tape 26, from which the operator can verify that the
input information has been entered accurately.
The master control unit 20 can store a list of commands pertinent
to each of the chemistry tests that the apparatus is capable of
performing. Thus, when the input information associates a specific
sample with a specific set of tests, and assuming the apparatus has
needed diluent and reagents, all that remains to be accomplished by
the human operator is to have placed the sample into an appropriate
one of the sample holders 28 in a sample disc 30. Thereupon, the
master control unit 20 can control the transferring of sample
aliquots into cuvettes 32 mounted in an annular array in a
turntable which is part of the data generating portion 34. An
aliquot and diluent transfer mechanism 36, forms of which are
known, can accomplish the transferring, with each required
chemistry test being associated with an identified cuvette 32 for
that specific sample. As the several aliquots are being dispensed,
the cuvette array will be indexed forward one step for each cuvette
and its associated aliquot. As used herein, "step" and "indexed"
include but are not limited to discrete movements, since the
cuvette array could be continuously moving slowly.
A reagent supply area 38 has separate reagent containers 40 in a
reagent disc 42. First and second reagent dispensers 44 and 46 will
add appropriate reagents to specific cuvettes as those cuvettes
advance around the path of movement of the annular array. The
dispensing point of the first reagent dispenser relative to the
cuvette path is spaced several steps prior to that of the second
dispenser 46 so that in this space interval, which corresponds to a
known time interval, the first reagent can have reacted with an
aliquot prior to the introduction of the second reagent. Some
chemical tests may require the addition of reagent from only one of
the dispensers.
The aliquot and diluent transfer mechanism 36 as well as the
reagent dispensers 44 and 46 can be of the type and operate as
disclosed with reference to FIGS. 13c and 16 of U.S. Pat. No.
3,883,305 entitled Automatic Chemical Analysis Apparatus and
assigned to the assignee of the present invention. Such transfer
dispensers would swing arcuately between the source of fluid 28 or
40 and a cuvette 32. Both when receiving and dispensing fluid the
probe of the dispensers can move down into the vessels 28, 32 and
40, but would be elevated to be able to swing free thereof in an
arcuate path.
Between the time and position that the aliquot is dispensed and the
first reagent is dispensed there is a distance along the path of
the cuvettes during which measurement of the transmittance of the
aliquot with its diluent and the cuvette walls can be accomplished.
Just prior to the point that each cuvette is again being positioned
beneath the aliquot dispenser mechanism 36 there is a laundry
station 48 having probes and mechanisms for removing the reactants,
if any, from the cuvette, washing the cuvette and making it usable
for receipt of a new aliquot. The laundry station can be similar to
that disclosed with reference to FIG. 16 of U.S. Pat. No.
3,883,305.
The data-generating means 34 are characterized by the presence of a
plurality of photodetectors radially arranged around a rotor 56 and
comprising a source of radiation such as a lamp 50 and individual
radiation detectors 52 which can be photoelectric cells,
photomultipliers or the like. Each detectors 52 may have its own
light source 50 as shown in the embodiments of FIGS. 2 and 3 or
there may be a single light source such as the lamp 50 in the
embodiment of FIG. 4. (The same reference numerals are applied to
the same or equivalent components in the two embodiments).
In the first embodiment the individual lamps 50 are located
outboard of the path followed by the circular array of cuvettes,
while in the second embodiment the single lamp 50 is located at the
axis of the rotor 56.
In both embodiments the photodetector means are wholly carried by
the rotor 56 insofar as the source and detector 52 are concerned.
The radiation paths 54 in all events are substantially shorter than
that of the Greaves et al patent above-mentioned because each path
of FIGS. 2, 3 and 4 is direct and has no bends produced either by
mirrors, prisms or fiber-optic elements. Such path will always be
at most about the radius of the rotor 56 and usually, as for
example in the embodiment of FIGS. 2 and 3, a fraction of the rotor
radius. Thus, the path is a few centimeters long and has the barest
minimum of optical elements in the train. No matter how well
constructed optical elements are, their slight inaccuracies,
aberrations, light refractions and scattering are cumulative so
that long trains like those of Greaves et al lose and absorb
radiant energy during passage decreasing the available signal to
noise ratio in making photometric measurements.
The advantages of the invention are principally derived where there
is a plurality of photometers mounted on the rotor 56 but some of
the advantages of the invention are available if only one
photometer is utilized; hence reference to "photometer means" is
intended to encompass both concepts. It is clear that in a single
photometer as compared with a rotor having eight photometers the
rate at which data can be gathered would be less for the single
photometer than for the multiple photometer device, assuming that
the number of cuvettes in the turntable and the speed of rotation
of the rotor are the same in both cases. A single photometer
apparatus can have its rate of data generation increased by
increasing its speed of rotation. The capacity of data handling,
storage and so on of the data processing means will be dependent
upon the amount of data being generated. Likewise the complexity of
the data processing means will be related to the variety of data
generated. All of these factors and more come into play in the
choice of the number of photometers, the speed of the rotor, the
wavelengths at which measurements are made, and the chemical
reactions which can be handled by the apparatus.
For comparison purposes it is pointed out that the scale of the
drawings in FIGS. 2 to 4 is such that the diameter of the rotor 56
measured below the location of the lamps 50 in FIG. 3 is
approximately 30 centimeters so that the total optical path from
lamp 50 to the photoresponsive device is less than about 2
centimeters in the embodiments of FIGS. 2 and 3 and less than about
8 centimeters in the embodiment of FIG. 4.
The circle of cuvettes 32 carried on the disc or turntable 74
rotates on the axis 58 which is also the axis of rotation of the
rotor 56. Thus, the cuvette array and the photometers are
concentric. The mounting and driving means for the rotor 56 and the
turntable 74 will be detailed with reference to FIGS. 2 to 4;
however operational, timing and position relationships can be
considered with reference to FIG. 1. As mentioned above, the rotor
56 in FIGS. 2 to 4 may be considered to have a diameter of about 30
centimeters which indicates a scale of roughly half-size in those
Figures. FIG. 1 is illustrated at about one-fifth full size. In
neither case is this intended to be limiting since the invention
has broad application to many different forms and sizes of
apparatus.
It will be apparent from the foregoing that during its complete
circuit of movement for a single revolution of the turntable 74 any
given cuvette 32 will have had its aliquot subjected to fluid
processing, chemical reaction and measurement, and as well will be
prepared to receive a new aliquot for the repetition of the cycle.
The path of the cuvettes is a circle in the apparatus which has
been illustrated and will be described as such, but modified forms
of the invention may vary this.
The turntable 74 will be indexed at a relatively slow rate, making
a total of about five to twenty revolutions per hour, with the
periods of dwell somewhat longer than the periods of movement. This
speed is said to be relatively slow in contrast to the speed of the
rotor 56 with its photometers which will be normally rotating at a
speed of as much as several hundred revolutions per minute. Thus,
for each dwell period, at which time the measurements are
preferably programmed to be taken, there can be many rotations of
the rotor taking place with the corresponding number of
measurements being made by all photometers of all cuvettes.
Preferably there should be a minimum of one revolution of rotor 56
per dwell period.
In this way, many time spaced photometric measurements of the
reaction in any specific cuvette can be made, recorded and/or
stored for data processing in a single circuit of the cuvette path,
that is, during one revolution of the turntable 74. The described
mode of processing and endpoint determination can readily be
effected in this period of time, not only for the aliquot in the
single cuvette 32 but for a continuous number of aliquots being
added to and removed from the cuvettes 32 of the turntable 74.
If there are 120 cuvettes 32 mounted on the turntable 74 and the
turntable is indexed once every six seconds, one full circuit is
achieved as a single revolution of the turntable 74 relative to the
housing carrying the data generating components 34 every twelve
minutes. If the rotor 56 and its eight photometers rotate around
the axis 58 at a speed of one revolution every six seconds, this is
a relatively slow speed of ten revolutions per minute or 120
revolutions of the rotor 56 for each revolution of the turntable
74. If we assume that measurements are being made at all times,
each cuvette 32 of the array on the turntable 74 will be scanned
photometrically 960 times in a complete circuit relative to the
housing carrying the data generating components, for example,
relative to the point where the aliquot has been inserted. If the
speed of the rotor 56 is doubled the number of measurements will
increase to 1920 times, but it should be appreciated that since
this is for only one cuvette and its aliquot, the total number of
measurements made in a single revolution of the turntable 74 is of
the order of 18,000 for the slower speed of the rotor 56 and 36,000
for the double speed mentioned.
Since some of the positions where cuvettes 32 will be located will
be employed for laundering the cuvettes, some will be employed for
injecting the aliquot and carrying the same to the reagent
insertion location and some may even be employed for agitation, the
total number of cuvette positions around the circular path where
the measurement or monitoring is taking place may be less than the
total number of cuvettes. Thus the total number of measurements
mentioned above may be less than stated by an amount which takes
into account the locations needed for the above-mentioned
functions. It might be mentioned that monitoring may be continued
at every position, if desired, leaving the data processing control
means to discard readings which have no significance. Readings made
during periods where laundering is taking place could be equated to
blank measurements and even some information can be acquired from
the aliquot in non-reactive condition before the introduction of
reagents. For the purposes of the discussion which follows, it will
be assumed that 800 separate photometric measurements, can be made
on each aliquot where the rotor is rotating at ten revolutions per
minute, there are 120 cuvettes, the indexing is taking place at a
rate of one revolution of the turntable 74 in twelve minutes, each
step of the indexing occurs every 6 seconds and there are several
stations along the path of the cuvette array which are occupied by
functions that are not concerned with photometric monitoring.
Since 800 measurement points of a reaction, each measurement being
three-fourths of a second apart during ten minutes, may not be
required and since certain chemical tests can be monitored better
at a specific wavelength, each of the photometers can be provided
with a specific filter 60 so that each photometer can produce
radiation and make measurements at its own wavelength. Assuming
that each of the filters 60 is different and information from a
specific aliquot in a specific cuvette most valuably can be
obtained from only one of the eight photometers, then there can be
obtained from such one photometer one hundred measurements of the
reaction of that one aliquot during the ten minute cycle because
there is one measurement every six seconds. Certainly, if it is
desired that a reaction be monitored more often than once every six
seconds, more than one of the photometers can be constructed to
operate at the same wavelength.
It is pointed out that the photometers which are illustrated in the
drawings are equally spaced around the rotor 56, but other
arrangements where the photometers are grouped or spaced unequally
are encompassed by the scope of the invention. Bichromatic
determinations may be desirable in pairs of photometers very
closely spaced.
As known, with the proper choice of reagents, several different
reactions can be monitored at the same wavelength; hence, with a
capability of several different wavelengths and suitable reagent
selection, numerous different tests can be processed by the
apparatus. Since all of the cuvettes are being scanned by each of
the photometers, the availability of different photometers
monitoring at different wavelengths permits aliquot alone as well
as a reaction in a cuvette to be monitored by more than one
photometer and therefore at more than one wavelength, with the
separation of time between monitoring at different wavelengths
being three-fourths of a second in the illustrated embodiment. It
will of course vary pursuant to construction and requirements. Each
aliquot need not be monitored at all wavelengths, nor does each
sample have to provide aliquots for all tests capable of being
achieved by use of the apparatus. The data into the input means 18
and the master control unit 20 can be controlled and programmed in
such a manner as to command the execution of only those tests
requested for each sample and will employ cuvettes only as needed,
thereby reducing the total amount required of sample and reagent
volumes and maximize the utilization of the cuvette positions and
the photometer means to maximize sample throughput of the
apparatus.
The apparatus does not require a fixed set of several tests for
each sample even if different ones of the set of tests would not be
requested for certain of the samples nor, as is also well known in
the prior art, does the apparatus cause empty cuvettes representing
"skipped" tests to occupy space in the rotating array on the
turntable 74. The just mentioned and other sample processing
control functions by the master control unit are carried on a
function control bus 62, shown in FIG. 5.
It will be mentioned at this point by way of recapitulation and
emphasis that the apparatus of the invention has great flexibility
in being applicable to many choices of testing but without
sacrificing economy or throughput. As mentioned above, each aliquot
need not be monitored on all wave lengths. In addition to this,
each sample does not have to provide aliquots for all tests capable
of being accomplished by the apparatus. Test selection is here
achieved without loss of analytical capacity, without wasting any
of the aliquots or reagents, without carrying out any unnecessary
tests whose data are useless and without skipping any cuvettes .On
this account it can be appreciated that the throughout of the
apparatus is also not affected by the great versatility of the
device.
It may be said of this apparatus that it has true test selectivity
without the equivocation of prior automatic chemistry devices in
that if a test is not performed in a given cuvette that same
cuvette is available for another test.
Next, with reference to FIGS. 2 and 3, the details of one
embodiment of the data generating component assembly 34 will be
discussed, with some reference also to FIG. 4. As shown, each
radiation source 50 and its associated detector 52 are relatively
close together and on a line and securely mounted to the rotor 56
and thereby define therebetween the short radiation path 54 of
fixed length which lies on a radius from the axis 58. The rotor 56
is arranged to rotate on the axis 58 and is provided with a
depending rotary sleeve 64 which is journaled on bearings 66
mounted to the housing base members 68 and 70. Suitable drive means
72 can be coupled to the sleeve 64 to apply the rotational movement
to the rotor 56 and its photometers, two of which are illustrated
in FIG. 3. The photometer components and the short radiation paths
54 therebetween are thus held in fixed orientation with respect to
each other and their radial orientation with respect to the axis
58. The journalled mounting of the support 56 provides a precision
orientation of the radiation path 54 with respect to its distance
from the axis 58, such distance remaining substantially constant as
the rotor 56 is rotated.
The bearings 66 can be of any suitable conventional design and
construction. The criteria for such bearings are accuracy,
smoothness, reliability, in addition to providing the thrust
support needed in view of the weight of the rotor 56 and its
components. Radial support requirements in view of the weight and
forces generated during rotation of the rotor 56 must also be taken
into consideration in choosing the bearings 66.
The construction described together with a judicious choice of high
quality bearings 66 will result in accurate tracking of the
photometers during rotation of the rotor 56 thereby enable accurate
and repetitively identical photometric measurements to be taken
during operation of the apparatus. Notwithstanding precautions
taken to assure accurate tracking and elimination of any
eccentricity during rotation, the nature of the invention is such
that some eccentricity during this rotation will not adversely
affect accuracy as it would in the case of the type of apparatus
disclosed in Greaves et al, above-mentioned.
The annular array of cuvettes 32 is mounted on the turntable 74 as
explained. These may be removable cuvettes or the turntable may be
molded or otherwise formed with the cuvettes 32 permanently
attached thereto. The turntable 74 is journalled for rotation on
the same axis 58 as that of the rotor 56 and the disposition of the
turntable is above the rotor 56 so that access may be had to the
entrances to the cuvettes 32 from above, as will be explained. The
array of cuvettes extend downwardly from the body of the turntable
74 which is somewhat disc-like or planar in character, defining an
annular ring path through which all of the cuvettes travel during
rotation of the turntable 74. This ring intersects all of the
radiation paths 54 of the photometers mounted on the rotor 56.
These paths 54 are radially arranged about the rotor 56 and in the
case of the very short paths 54 of the embodiments of FIGS. 2 and 3
the spaces between the filters 60 and the lamps 50 also define a
similar ring that coincides with that formed by the path of
cuvettes 32.
The photometers 50-52 can be mounted on the upper surface of the
rotor 56 in any suitable manner by clamps or brackets or the like
or could be mounted on the interior of a thickened disc forming the
rotor which could be accurately molded to receive the same. In such
case, a groove or trough or annular configuration could be formed
in the upper surface of the rotor 56 in annular configuration to
receive and clear the depending array of cuvettes during their
rotation. The radiation paths could then be arranged to pass
through the groove in a radial direction which will enable them to
pass unobstructed through the walls of the cuvette where the
aliquot being measured is located. The cuvettes are obviously made
out of some transparent or translucent material and should have
properly oriented walls that do not refract or scatter the beam of
radiation passing through the same.
The cuvette turntable 74 has a hub with depending collar 76, is
centered on the axis 58 and is journalled for rotation by means of
bearings 78 that are mounted between the collor 76 and the sleeve
64, thus permitting the cuvette turntable to be rotated
independently of the rotation of the photometer rotor 56. Rotation
of the turntable 74 in an indexing mode can be effected by
conventional means not shown in FIG. 3, but illustrated in FIG. 4
and discussed with respect thereto. Since the turntable 74 and the
photometer rotor 56 are coaxial on the same axis 58, and the collar
76 of the turntable 74 rotates within the sleeve 64 of the rotor
56, the path of the cuvettes and the area swept by the photometers
are concentric and the cuvettes are caused to intercept the short
radiation path 54 of each photometer with highly reproducible
positional accuracy thereby promoting accurate photometric
measurements without need for complex light guiding arrangements
employed in the prior art.
To enhance the continuously smooth rotary motion of the photometer
rotor 56 it can be designed with weighted circumferential volume to
operate with a flywheel effect. In contrast the cuvette turntable
74 should be relatively lightweight if the indexing thereof is to
be accomplished in steps with dwell periods between steps.
FIG. 4 illustrates primarily a slightly modified arrangement of the
photometer means 50-52. Such modification and other differences
between FIGS. 3 and 4 will be presented after the discussion of
FIG. 5, which includes explanation of most of the operation of the
structure shown in both FIGS. 3 and 4.
As shown in FIGS. 3-5, the electrical output from the radiation
detectors 52 is coupled to electrical components for analog to
digital conversion and transmission from the data generating
component assembly 34 to the control console 10 (FIG. 1).
Preferably, the electrical components would be secured to portions
of the rotor 56 and its sleeve 64, by way of circuit components,
circuit boards and connectors such as 80 and 82, so that the
electrical components can move along with their associated
photometers, during their rotation around the axis 58, without the
need for slip rings, commutators or the like at the sensitive
points of the circuit or more complex wiring arrangements. The
transmission of a large quantity of discrete electrical
measurements in the form of analog values from a plurality of
radiation detectors 52 that is continuously moving presents
problems, both mechanical and electrical, which will be recognized
by those skilled in the art. It is believed that the need for
greater throughput of precise data from many photometers,
concerning numerous chemical tests being carried out on a high
number of aliquots, is not practically satisfied by the prior
technology. The arrangement in FIG. 5 provides an efficient,
flexible, yet simple and precise mode of data transmission.
Commencing with the top left of FIG. 5, there is shown one of the
assemblies mounted on the rotor 56 which will be termed a
photometer module 84 with its radiation source 50 directing its
radiation to pass through the walls of one of the cuvettes 32 and
strike the sensitive surface of the detector 52, after passing
through the filter 60. The detector could be a silicon diode, a
photomultiplier, vacuum photodiode or other photoresponsive device.
A few milliseconds of scanning time by one of the photometers
moving past an effectively stationary cuvette will be sufficient to
obtain the required analog measurement of the radiation incident on
the detector 52 to enable eventual calculation of absorption and
absorbance. The detector 52 responds to the amount of radiation
transmitted through the aliquot in the cuvette and the cuvette
walls by generating an electric signal proportional to such amount
of radiation. An integrator 86 is connected to the detector and
converts the generated signal to an output voltage signal which is
proportional to the transmittance of the aliquot. A logarithmic
analog to digital converter 88 is coupled to the output of the
integrator and generates as its output on a line 90 a digital
signal which is a function of the absorbance of the aliquot. One
example of a log A/D converter usable herein is set forth in Dorman
et al U.S. Pat. No. 3,566,133. For ease of illustration, only one
of the eight photometer modules 84 is illustrated, but all eight of
the photometer output lines 90 are shown.
Since at one instantaneous position of the continuously moving
photometer rotor 56 all eight of the detectors 52 could be
respectively receiving radiation which has traversed the samples in
eight different cuvettes, a digital multiplexer 92 is connected to
all of the photometer output lines 90. The multiplexer operates in
typical switching manner under the control of a data control unit
94, by way of a control line 96, discretely to transfer the data
from each of the log A/D converters 88 to the data control unit on
a data line 98. Such data can be handled in the form of binary
bits, with one binary word representing the absorbance reading from
one cuvette. The correlation of each specific absorbance data word
with its aliquot or cuvette identification can be accomplished by
the data control unit. The means for such identification and
coupling same to data control unit are not illustrated and are
within the skill of the art. After the data word has been
transferred to the data control unit 94, that unit will generate a
reset command on a line 100 to the appropriate log A/D converter 88
to enable that converter to receive the next analog signal derived
from the next cuvette to be scanned by that one photometer 84.
Each integrator 86 will be reset by its A/D converter when its
digital word is fed into the multiplexer. A reset line 102 carries
that command, usually prior to the resetting of the A/D converter
by the data control unit 94. To ensure that the radiation through
one cuvette does not include radiation from an adjacent cuvette as
seen by its integrator 86 the integrator can be enabled by a start
integrate command line 104 which can be triggered in response to
one of various conditions, such as: a timing relationship with the
rotor drive means 72, or a positioning of the cuvette relative to
the radiation path 54, or the shape of the output signal waveform
from the detector 52.
Depending upon the sophistication of the data control unit 94 and
the size of its memory, if any, the manner of data input-output
handling can be variable. For example, by employing a simple data
control unit, each instance that a digital word is fed into the
data control unit it can be transmitted to the master control unit
20 and be processed therein for receipt by the readout unit 22. The
master control unit can have a data storage and correlation
capacity as well as the earlier mentioned function control,
instruction and command information. On the other hand, if the data
control unit has sufficient storage capacity, at least all data
words such as the 960 mentioned which are obtained during one or
more rotations of the rotor 56 can be stored therein.
Assuming that each of the photometers 52 is operating at a
different wavelength and that a specific cuvette 32 is to be
monitored by only the one photometer 52 operating at that
wavelength which optimizes the measurement of the specific reaction
occurring in that cuvette, then of the 960 data words received by
the multiplexer 92 during one cycle or revolution of the photometer
rotor 56, only one hundred twenty of those words (for the example
described) normally would be needed by the master control unit 20.
The determination of which data words are to be employed for data
processing is developed from the input information which associates
specific samples with specific tests. The master control unit 20
then assigns each specific cuvette to a sample and a test and
thereby a specific photometer; whereupon, the data word required
from that cuvette for each revolution of the rotor 56 can be
identified and related to the data words from the same cuvette 32
obtained from each of the next following rotor revolutions, which
in the preferred embodiment totals one hundred twenty revolutions
of the photometer rotor 56.
Depending upon the desirable extent of communications between the
data control unit 94 and the master control unit 20, the sizes of
their memories, the speed of operation of the apparatus, etc., all
of which involve cost, throughput and other factors which influence
engineering design, the engineering design can cause all ninety six
thousand words to be transmitted to the master control unit for its
selection of the needed twelve thousand data words; or, the two
control units 20 and 94 can communicate such that only the desired
twelve thousand words are transmitted from the data control unit to
the master control unit.
The engineering design is influenced by the timing of the
transmission of the data words from the data control unit to the
master control unit. There may be a finite amount of unused time
between the scanning of each cuvette, while the rotor 56 is moving
into alignment with the next set of eight cuvettes, and also at the
end of each revolution, when the cuvette array is indexed one step.
Since the apparatus can operate in the continuous mode, as earlier
described, one revolution can be followed by the next without any
significant disruption, as contrasted to the batch mode of
operation. Hence, data also can be transmitted in a continuous mode
and not stored until some later time and then dumped into a
processing unit. This continuous transmission of data from the data
generating component assembly 34 to the control console 10 may be
with some control by the data control unit 94, rather than
exclusively by the master control unit 20, as abovementioned.
In referring to unused time above, that is, time between the
scanning of cuvettes or at the end of a revolution, no limitations
on the invention are intended. Thus, it is feasible to measure dark
current between cuvette scannings to set the photometer scales. The
readings can readily be identified by the control unit and
processed as desired and programmed.
Although a continuous operation mode has well known advantages over
batch operation, there can be conditions which warrant batch
handling. The apparatus of this invention can be used in batch
processing. For example, the entire cuvette turntable 74 could be
in the form of a removable disc to be replaced by one or more
similar discs having the cuvettes already filled with aliquots and
possibly even reagents, each replacement disc being a batch. If the
batch would consist of only a few aliquots, the cuvette disc could
be constructed in segments and then only a segment or portion of
the disc be replaced with a prepared segment of cuvettes. Likewise,
a stat or urgently needed test could be "inserted" into the
apparatus.
Such a structure would have a turntable like that shown at 74 with
a thin plastic disc, perhaps formed by vacuum molding a synthetic
resin sheet with the depressions forming the cuvettes, capable of
being clamped or snapped onto the upper surface of the turntable.
The operation of the apparatus would not be too much different,
being required only to enable proper orientation of the replaceable
disc to provide sample identification and with some modification
which starts and stops the apparatus so that the attendant may
remove the used disc and replace it with a new one.
In normal operation such a disc or turntable would not be required
to rotate and its cuvettes would be scanned by the plurality of
photometers during rotation of the rotor 56. Stepping of the disc
or turntable 74 would be useful where the apparatus could be
alternated between continuous and batch modes. The removability of
the disc on the turntable 74 could be of advantage where stat
testing is to be done and it is not desired to integrate such tests
in with the routine ones being processed. Stepping could also be of
advantage along with removability in a batch mode where the steps
carry different sets of filters into the radiation paths.
In a batch method device where the rotor carries a plurality of
photometers, such photometers could employ individual lamps 50 for
each photodetector 62 or a single central source of radiation
serving all photometers.
One variation of the invention could comprise a fixed or indexing
turntable with cuvettes and a rotor having a single photometer, but
differing from the structure of DeMendez et al patent mentioned
above in that the rotor also carries a filter wheel arranged
vertically and intercepting the beam of radiation from the
photometer before it passes through the cuvettes. The rotor in such
case is arranged to stop momentarily at each cuvette and
automatically rotate the filter wheel to provide several
measurements at different wavelengths that are identified by
suitable synchronizing means to be sent to the proper address of
the storage or recording device through data control means. In this
way, the effect of plural photometers is achieved without the need
for any duplication of photometers.
It is pointed out that the reference to the rotation or revolutions
of the rotor 56 is not to be considered limited to movement in one
direction since it is feasible for the rotor 56 to oscillate by
rotating substantially one revolution and then reversing itself to
rotate a revolution in the opposite direction, etc.
Next, with reference to FIG. 5, there will be disclosed both types
of data flow and control; first, that which requires two-way
communications between the control units 20 and 94; and second,
one-way communications. The latter, although simpler than the
former, would require more sophistication and also more storage
capacity by the master control unit.
Two-way communications between the master control unit and the data
control unit can be accomplished with the aid of a pair of
communications logic units 106 and 108, a pair of transmitters 110
and 112, and a pair of receivers 114 and 116. The elements 106, 110
and 114 would be housed in the rotating portion of the data
generating component assembly 34. The corresponding elements 108,
112 and 116 would be located in the control console 10 and/or a
stationary portion of the assembly 34. A control bus 118 and a data
bus 120 link the data control unit 94 with its communications logic
unit 106.
In like manner, control and data buses 122 and 124 link the master
control unit 20 with the communications logic unit 108. Typical of
the bidirectional control information on the buses 118 and 122
would be the availability of one or more data words to be written
into or read from one or the other or both of the memories in the
units 20 and 94 and the availability of the associated logic unit
106 and 108 to receive or transmit such data.
Since in the now being described embodiment of the electronics
there is to be two-way communications between the data control unit
in the reaction table and the master control unit in the control
console, the control and data buses 118-124 will be bidirectional
as indicated by the arrowheads in FIG. 5. Also, the communications
logic units 106 and 108 will possess two-way capabilities. A
commercial form of such communications unit is the IM 6402
Universal Asynchronous Receiver--Transmitter of Intersil
Corporation, Cupertino, California. Such unit can be used in the
other communications embodiment to be disclosed subsequently.
The bidirectional data buses 120 and 124 will carry each data word
serially in parallel bit order, but the inputs from the receivers
114 and 116 and the outputs to the transmitters 110 and 112 will be
serially by bit. The preferred embodiments of the transmitters and
receivers, as illustrated in FIGS. 3 and 5, respectively are
photoemissive and photosensitive. FIG. 4 employs a slip ring
assembly 110-116; however, other forms of transmission and
reception are possible, such as of the radio frequency type and are
encompassed within the general terms and are not to be considered
limited by the illustration of the preferred embodiments.
Phototransmission, as by a photodiode, is both simple and well
suited to the handling of binary serial bit data and is well known
to those skilled in the art. Moreover, photoemission and reception
are less subject to interference than radio transmission,
especially when the elements 110-116 can be closely spaced.
As shown in FIG. 3 the transmitter 110 and receiver 114 can be
housed within the sleeve 64 and rotate therewith close to the axis
58. The associated elements 116 and 112 could be stationary and lie
close to the projection of the axis 58 and be wired into the logic
unit 108 in the control console 10. Mounted in such a manner close
to axis 58, the fact that the transmitter 110 and receiver 114 are
rotating will not cause errors in the binary bit data transmission.
On the other hand, if the magnitude of a signal, rather than
presence or absence thereof, were the measure of the test data and
the control commands, then relative movement of the transmitters
and receivers could produce transmission errors.
From the foregoing it will be appreciated that for economical use
of storage capacity in the master control unit 20 only the desired
data words should be transmitted from the data control unit 94. To
effect such economy the input information from the data input means
18 will enable the master control unit to establish a listing of
the aliquots or their cuvettes from which data is desired. As new
samples are added to the sample disc 30, associated input
information fed into the master control unit and old samples
complete their testing the "desired" listing will be updated
continuously. As each data word is received by the data control
unit 94 from the multiplexer 92 it will, by two-way communications,
be checked with the desired data list and only be transmitted to
the master control unit after an affirmative comparison. This
communication will require the data control unit and its logic unit
to have interchanges on the buses 118 and 120 regarding: the fact
that a data word has been received from the multiplexer,
identification of that word and that the logic units 106 and 108
are ready to communicate that identification information to the
master control unit.
In like manner, the master control unit and its buses 122 and 124
with its logic unit 108 will: acknowledge availability to
communicate, receive the identification data, provide a comparison
reply and then either cause the data word to be discarded by the
data control unit or cause it to be transmitted for storage by the
master control unit. Each communication will require transmission
and receipt by one or the other pair of components 110 and 116, or
112 and 114.
In the other embodied form of data communications, all data words
are transmitted from the data control unit 94 to the master control
unit 20 and the latter then itself will decide which data words to
continue to store for ultimate readout purposes. Because of this
simpler form of communications the data buses 120 and 124 need only
feed in the direction toward the master control unit, the
communications logic unit 106 will operate only as a sending unit,
the communications logic unit 108 will operate only as a receiving
unit and the transmitter-receiver pair of elements 112 and 114 will
not be required. The bidirectional control buses 118 and 122
between the control units and their respective communications logic
units are required for the purposes above-mentioned.
The differences between the embodiments of FIGS. 3 and 4 will now
be described. First, concerning the photometer means, the radiation
source 50 of FIG. 4 is located at the axis 58 and comprises a
single element such as a General Electric type 58 tungsten lamp
rather than a plurality of lamps positioned around the periphery of
the photometer rotor 56 as in FIG. 3. The source 50 in FIG. 4 is
connected to the rotor 56 for rotation therewith.
A plurality of lens-containing optical tubes 126 are mounted to the
photometer rotor 56 of FIG. 4 such that one end of each tube is
proximate to the radiation source 50 and the other end of each tube
is close to the annular path or pattern traversed by the cuvettes
and is aligned with a specific one of the radiation or photometric
detectors 52. The photometric detectors 52 are also mounted on the
rotor 56 substantially as in the FIG. 3 embodiment. The paths or
patterns swept by the beams of radiation reaching each detector is
in effect the same as in FIG. 3.
One advantage of employing a single source 50 is that it is easier
to dissipate the heat generated thereby and thus easier to regulate
the temperature of the cuvettes 32. Note that in the embodiment
shown in FIG. 3 the individual lamps are located quite close to the
annular ring defined by the cuvette path so that the heat of these
lamps could be radiated or transmitted to the materials carried by
the cuvettes. The nature of many of the reactions whose
characteristics are being measured is such that temperature changes
are critical. As a matter of fact, means will often be provided for
incubation of the cuvettes during their scanning and the
arrangement of FIG. 4 enables such structure to be easier achieved
and more effective in operation because of the absence of heat
sources.
Another advantage of a single source such as in FIG. 4 is that
there is no problem with different intensities, colors or
wavelengths which can be expected in a plurality of different
lamps, even where matched. Whatever happens to the single source
lamp 50 happens to all readings made so that the effect is not felt
where relative measurements are made. The lamp 50 can be cooled
very easily by air circulated in its vicinity in a manner which
will not cool, for example, the cuvettes. The power supply for a
single source 50 is simpler and more economical.
In the views described thus far shown there is a single beam 54
which passes through the cuvette 32 and thence impinges upon the
photodetector 52 after passing through a filter 60 which is usually
in close proximity if not incorporated into the photodetector. In
the structure of FIG. 4 it is feasible to focus the light beam into
a very fine pencil for passage through the lower portion of the
cuvettes 32 but in addition it is feasible to incorporate beam
splitting means into the focussing tube or outside thereof to
provide two beams which may be directed in parallel paths through
different levels of the cuvettes for investigating different strata
of the analyte. Such as a structure is shown in FIG. 4a to be
described in detail below.
In FIG. 4a components equivalent to those of FIG. 4 carry the same
reference numerals primed. The rotor 56' has a focussing tube 126'
which directs a beam 54' derived from a source such as 50 (not
shown in FIG. 4a) to a semisilvered or dichroic mirror 150 arranged
at 45.degree. in front of the tube 126'. A part of the beam passes
through the mirror 150 and becomes a bottom beam 54'b and another
is reflected at 90.degree. upward and thence reflected from the
45.degree. angled mirror 152 to become the upper beam 54'u. These
beams pass through different levels of the liquid 154 carried in
the cuvette 32' mounted in the turntable 74' which is disposed to
move in a path which carries it and its companion cuvettes through
the groove 156 provided in the rotor 56.
There are two photodetectors at 52' and 52" mounted on the rotor 56
in suitable cavities aligned with the mirrors 150 and 152,
respectively, and thus aligned to receive the beams 54'b and 54'u
against their sensitive surfaces. Each is provided with a filter
60' and 60", respectively. Openings 158 and 60 respectively enable
the beams to pass.
It will be obvious that the beam 54' emerging from the focussing
tube 126' splits, part going through a lower stratum of the liquid
154 and part going through an upper stratum of the same liquid. The
photodetectors 52' and 52" are independent, each providing a
different signal which can be transmitted through suitable
connections to data processing equipment to provide additional
information concerning the reaction which may be going on in the
cuvette 32'.
FIG. 4 shows the drive means for the cuvette turntable 74, which
was not illustrated in FIG. 3, because of drawing space
limitations. A motor 128 has its drive shaft 130 coupled by a
pinion gear 132 to a suitably mating configuration 134 on the
periphery of the turntable 74. If the indexing of the cuvettes is
to be in steps, the motor 128 could be a stepping motor, or there
could be provided linkage, clutch means, etc., for providing
appropriately timed stepping from a continuously driven motor.
As earlier mentioned briefly, a slip ring assembly 110-116 can
provide the receiver and transmitter needs of the apparatus and
couple data and other communications from and to the reaction table
34 and the master control unit 20. Such slip ring units are
available commercially.
From the above, it now should be understood how the entire
apparatus operates with its moving photometer means and preferably
in a continuous mode to place into the master control unit 20 the
digitized values of the readings related to absorbance from the
data generating components assembly 34. Since reaction can be
monitored at frequent intervals during a prolonged period of time
rather than a small portion thereof, both rate and end point data
are obtainable. Once into the master control unit, the raw data can
be associated with each test and supplied to the readout unit 22
without any data reduction, conversion or analysis, such being left
to the skill of a technician in interpreting the same. In a
preferred mode of operation the master control unit would have the
capability of associating the data for each test, obtaining
mathematic rate and/or end point determination, then converting
that information into a reading of the chemistry value in the
desired concentration units for the test, thereafter feeding the
results into the readout unit.
Although some variations in structure and operation of this
chemical reaction monitoring apparatus have been disclosed
hereinabove, other variations are capable of being made by those
skilled in the art without departing from the spirit or scope of
the invention as defined in the appended claims. For example, the
preferred embodiments teach continuous movement of the photometer
rotor; however, a stepping device movement can be employed. Also,
the photometer means are spaced around the circumference of their
support, since such positioning enables a uniform weight
distribution around the support; however, the photometer means
could be mounted with variable spacing especially if the path of
motion is other than circular. It may be desired to employ
disposable cuvettes. If so, the laundry station 48 would be
replaced by means for removing used cuvettes and for inserting
clean cuvettes into the cuvette turntable 74. At least in such
situation, the cuvettes need not move around a closed path.
Reagents need not be liquid but may dispensed dry. Cuvettes may be
used in a disposable mode with the reagent already in place,
requiring only the addition of the aliquot and a diluent.
* * * * *