U.S. patent application number 10/274381 was filed with the patent office on 2003-05-08 for automated system and method for processing specimens to extract samples for both liquid-based and slide-based testing.
This patent application is currently assigned to MONOGEN INC.. Invention is credited to Mayer, William J., Pressman, Norman J..
Application Number | 20030087443 10/274381 |
Document ID | / |
Family ID | 27406711 |
Filed Date | 2003-05-08 |
United States Patent
Application |
20030087443 |
Kind Code |
A1 |
Pressman, Norman J. ; et
al. |
May 8, 2003 |
Automated system and method for processing specimens to extract
samples for both liquid-based and slide-based testing
Abstract
Apparatus and method for processing specimens, e.g., biological
specimens, to extract samples for both liquid (i.e., extracellular)
and slide-based (i.e., intracellular) testing. Both types of
samples can be obtained from a single fluid specimen. A fluid
sampling station removes fluid from a specimen container and places
it in a sample receptacle. A specimen acquisition station removes
fluid from the container, separates particulate matter (e.g.,
cells) from the removed fluid, and forms a sample layer of
particulate matter, which is transferred to a slide. The two
sampling operations can be carried out in any order. The fluid
sample receptacle may have a special one-way valve arrangement. The
apparatus can be automated so as to process multiple fluid
specimens in their respective containers. The machine according to
this invention is a "platform instrument" that can produce all
required liquid samples and slide-based samples for essentially all
cytopathology tests.
Inventors: |
Pressman, Norman J.;
(Glencoe, IL) ; Mayer, William J.; (South
Barrington, IL) |
Correspondence
Address: |
FOLEY AND LARDNER
SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
MONOGEN INC.
|
Family ID: |
27406711 |
Appl. No.: |
10/274381 |
Filed: |
October 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60330092 |
Oct 19, 2001 |
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60372080 |
Apr 15, 2002 |
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60373658 |
Apr 19, 2002 |
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Current U.S.
Class: |
436/46 ; 422/400;
422/63; 435/287.2 |
Current CPC
Class: |
B01F 35/60 20220101;
B01L 2300/044 20130101; B01L 9/52 20130101; G01N 2035/00089
20130101; G01N 35/1016 20130101; G01N 2035/0405 20130101; Y10T
436/255 20150115; Y10T 436/12 20150115; G01N 2035/00138 20130101;
B01L 3/508 20130101; G01N 1/2813 20130101; G01N 35/00029 20130101;
G01N 27/22 20130101; G01N 2035/0441 20130101; G01N 2035/0462
20130101; Y10T 29/53039 20150115; Y10T 436/25375 20150115; B01L
2300/0681 20130101; B01L 2300/0851 20130101; B01D 2321/10 20130101;
B01D 2321/2008 20130101; B01D 2321/2016 20130101; G01N 35/0099
20130101; B01D 61/22 20130101; B01D 2321/02 20130101; G01N
2035/0427 20130101; B01D 2321/16 20130101; G01N 2035/0443 20130101;
Y10T 436/11 20150115; B01F 35/605 20220101; G01N 35/00 20130101;
B01L 2300/0822 20130101; B65B 7/161 20130101; B01D 63/08 20130101;
B01L 2200/025 20130101; G01N 2001/2826 20130101; G01N 2035/0458
20130101; B01D 61/18 20130101; Y10T 29/49822 20150115; B01D 65/08
20130101; G01N 35/04 20130101; B01F 33/5011 20220101; B01L 3/50825
20130101; B65B 69/00 20130101; G01N 2001/1025 20130101; B01F 27/88
20220101; B01L 2300/042 20130101; B01L 2300/046 20130101; B01D
2321/2066 20130101; Y10T 436/112499 20150115; B01F 27/13 20220101;
G01N 1/4077 20130101; Y10T 436/113332 20150115; B01L 3/502
20130101; G01N 35/021 20130101; B01L 9/06 20130101 |
Class at
Publication: |
436/46 ;
435/287.2; 422/102; 422/63 |
International
Class: |
G01N 035/00; C12M
001/34; G01N 021/00; B01L 003/00 |
Claims
1. An automated method for individually processing multiple fluid
specimens of in respective containers, the method comprising:
transporting the containers seriatim along a processing path to
present them to a preprocessing head, and subsequently to other
processing heads comprising a fluid sampling draw head and a
specimen acquisition head, in either order, the preprocessing head
adapted to perform a preprocessing operation on the specimen in
each container presented to it, the fluid sampling draw head
adapted to remove preprocessed fluid from any container presented
to it and place the removed fluid sample in a respective sample
receptacle, the specimen acquisition head adapted to aspirate
preprocessed fluid from any container presented to it, pass the
aspirated fluid through a filter so as to collect a particulate
matter sample on the surface of the filter, and press the filter
against a respective slide positioned in proximity to the
processing path to transfer the particulate matter sample to the
slide; actuating the preprocessing head in response to presentation
of a container thereto so as to carry out the preprocessing
operation independently; actuating the fluid sampling draw head in
response to presentation of a container thereto so as to carry out
the fluid removal operation independently; and actuating the
specimen acquisition head in response to presentation of a
container thereto so as to carry out the aspirating/sample
transfer-to-slide operation independently.
2. An automated method according to claim 1, comprising
transporting sample receptacles seriatim to the fluid sampling draw
head along a receptacle path that intersects the processing
path.
3. An automated method according to claim 2, comprising
transporting sample receptacles with fluid samples therein seriatim
from the fluid sampling draw head along a receptacle path that
intersects the processing path.
4. An automated method according to claim 3, wherein the transport
of sample receptacles to and from the fluid sampling draw head is
synchronized with the transport of containers along the processing
path.
5. An automated method according to claim 1, wherein each container
has therein a processing assembly with an aspiration tube, and the
fluid sampling draw head removes fluid from the container through
the aspiration tube.
6. An automated method according to claim 5, wherein the processing
assembly has an upper particulate matter separation chamber adapted
to receive a filter, and the aspiration tube depends from and
communicates with the separation chamber.
7. An automated method according to claim 5 or claim 6, wherein
each sample receptacle has an inlet, the fluid sampling draw head
places the inlet of a sample receptacle into sealing engagement
with the processing assembly aspiration tube, and fluid is drawn
directly into the sample receptacle.
8. An automated method according to claim 7, wherein the inlet of
the sample receptacle comprises a one-way valve that allows fluid
flow into but not out of the sample receptacle, the fluid sampling
draw head places the one-way valve into sealing engagement with the
processing assembly aspiration tube, and fluid is drawn directly
into the sample receptacle through the one-way valve.
9. An automated method according to claim 8, wherein the fluid
sampling draw head moves the sample receptacle downwardly to engage
the one-way valve with the processing assembly aspiration tube
before fluid is drawn into the sample receptacle, and upwardly to
disengage the one-way valve from the aspiration tube after fluid
draw.
10. An automated method according to claim 9, comprising
transporting sample receptacles seriatim to the fluid sampling draw
head along a receptacle path that intersects the processing
path.
11. An automated method according to claim 10, comprising
transporting sample receptacles with fluid samples therein seriatim
from the fluid sampling draw head along a receptacle path that
intersects the processing path.
12. An automated method according to claim 11, wherein the
transport of sample receptacles to and from the fluid sampling draw
head is synchronized with the transport of containers along the
processing path.
13. An automated method according to claim 12, wherein the fluid
sampling draw head draws a predetermined quantity of fluid into the
sample receptacle.
14. An automated method according to claim 1, wherein the fluid
sampling draw head draws a predetermined quantity of fluid into the
sample receptacle.
15. An automated apparatus for individually processing multiple
fluid specimens of in respective containers, the apparatus
comprising: a container transport for supporting and advancing
containers seriatim along a processing path; a preprocessing head
along the processing path adapted to perform a preprocessing
operation on the specimen in each container presented thereto by
the container transport; a fluid sampling draw head along the
processing path downstream of the preprocessing head adapted to
remove preprocessed fluid from the containers and place the removed
fluid samples in respective sample receptacles; a specimen
acquisition head along the processing path downstream of the
preprocessing head adapted to aspirate preprocessed fluid from the
container presented thereto by the container transport and pass the
fluid through a filter so as to collect a particulate matter sample
on the surface of the filter, and press the filter against a
respective slide positioned in proximity to processing path to
transfer the particulate matter sample to the slide; and a
controller governing operation of the preprocessing head, operation
of the fluid sampling draw head, operation of the specimen
acquisition head and movement of the container transport, the
controller responding to presentation of a container to the
preprocessing head to cause the preprocessing head independently to
preprocess the specimen in the container presented thereto, the
controller responding to presentation of a container to the fluid
sampling draw head to cause the fluid sampling draw head
independently to remove preprocessed fluid therefrom, and the
controller responding to presentation of a container to the
specimen acquisition head to cause the specimen acquisition head
independently to aspirate preprocessed fluid therefrom and transfer
the particulate matter sample from the filter to the slide.
16. An automated apparatus according to claim 15, comprising a
receptacle transport that transports sample receptacles seriatim to
the fluid sampling draw head along a receptacle path that
intersects the processing path.
17. An automated apparatus according to claim 16, wherein the
receptacle transport transports sample receptacles with fluid
samples therein seriatim from the fluid sampling draw head along a
receptacle path that intersects the processing path.
18. An automated apparatus according to claim 17, wherein the
receptacle transport transports sample receptacles to the fluid
sampling draw head on one side of the processing path, and
transports sample receptacles with fluid samples therein away from
the fluid sampling draw head on the other side of the processing
path.
19. An automated apparatus according to claim 18, wherein the
receptacle transport and the container transport are
synchronized.
20. An automated apparatus according to claim 15, wherein each
container has therein a processing assembly with an aspiration
tube, and the fluid sampling draw head is adapted to draw fluid
from the container through the aspiration tube.
21. An automated apparatus according to claim 20, wherein the
processing assembly has an upper particulate matter separation
chamber adapted to receive a filter, and the aspiration tube
depends from and communicates with the separation chamber.
22. An automated apparatus according to claim 20 or claim 21,
wherein each sample receptacle has an inlet, and the fluid sampling
draw head has an actuator that moves a sample receptacle toward the
container to place the inlet of the sample receptacle into sealing
engagement with the processing assembly aspiration tube, whereby
fluid is drawn directly into the sample receptacle.
23. An automated apparatus according to claim 22, wherein the inlet
of the sample receptacle comprises a one-way valve that allows
fluid flow into but not out of the sample receptacle, and the
actuator of the fluid sampling draw head moves the sample
receptacle to place the one-way valve into sealing engagement with
the processing assembly aspiration tube, whereby fluid is drawn
directly into the sample receptacle through the one-way valve.
24. An automated apparatus according to claim 23, wherein the
actuator of the fluid sampling draw head moves the sample
receptacle downwardly to engage the one-way valve with the
processing assembly aspiration tube before fluid is drawn into the
sample receptacle, and upwardly to disengage the one-way valve from
the aspiration tube after fluid draw.
25. An automated apparatus according to claim 24, comprising a
receptacle transport that transports sample receptacles seriatim to
the fluid sampling draw head along a receptacle path that
intersects the processing path.
26. An automated apparatus according to claim 25, wherein the
receptacle transport transports sample receptacles with fluid
samples therein seriatim from the fluid sampling draw head along a
receptacle path that intersects the processing path.
27. An automated apparatus according to claim 26, wherein the
receptacle transport transports sample receptacles to the fluid
sampling draw head on one side of the processing path, and
transports sample receptacles with fluid samples therein away from
the fluid sampling draw head on the other side of the processing
path.
28. An automated apparatus according to claim 27, wherein the
receptacle transport and the container transport are
synchronized.
29. An automated apparatus according to claim 28, wherein the fluid
sampling draw head draws a predetermined quantity of fluid into the
sample receptacle.
30. An automated apparatus according to claim 15, wherein the fluid
sampling draw head draws a predetermined quantity of fluid into the
sample receptacle.
31. An automated apparatus according to claim 15, wherein each
sample receptacle comprises a test tube having an open end and a
one-way valve at the other end that allows fluid flow into but not
out of the test tube, and the fluid sampling draw head comprises a
vacuum fitting adapted to releasably engage the open end of a test
tube and apply suction thereto.
32. An automated apparatus according to claim 31, wherein each
container has therein a processing assembly with an aspiration
tube, and the fluid sampling draw head comprises an actuator that
moves the test tube to place the one-way valve into sealing
engagement with the processing assembly aspiration tube, whereby
fluid is drawn directly into the test tube through the one-way
valve.
33. An automated method for individually processing multiple fluid
specimens in respective containers, the method comprising:
transporting the containers seriatim along a processing path to
present them to a fluid sampling station and a specimen acquisition
station, in either order; the fluid sampling station adapted to
remove fluid from any container presented to it and place the
removed fluid sample in a sample receptacle, the specimen
acquisition station adapted to remove fluid from any container
presented to it, separate particulate matter from the removed fluid
and form a sample layer of particulate matter; actuating the fluid
sampling station in response to presentation of a container thereto
so as to carry out the fluid removal operation independently; and
actuating the specimen acquisition station in response to
presentation of a container thereto so as to carry out the fluid
removal, particulate matter separation and sample formation
operation independently.
34. An automated method according to claim 33, comprising
transporting sample receptacles seriatim to and from the fluid
sampling station along a receptacle path.
35. An automated method according to claim 34, wherein the
transport of sample receptacles to and from the fluid sampling
station is synchronized with the transport of containers along the
processing path.
36. An automated method according to claim 35, wherein the
receptacle path is that intersects the processing path.
37. An automated method according to claim 36, wherein the specimen
acquisition station is adapted to collect a layer of particulate
matter on a surface of a filter, and press the filter against a
slide positioned in proximity to the processing path to transfer
the particulate matter sample to the slide.
38. An automated method according to claim 33, wherein the specimen
acquisition station is adapted to collect a layer of particulate
matter on a surface of a filter, and press the filter against a
slide positioned in proximity to the processing path to transfer
the particulate matter sample to the slide.
39. An automated apparatus for individually processing multiple
fluid specimens in respective containers, the apparatus comprising:
a container transport for supporting and advancing containers
seriatim along a processing path; a fluid sampling head along the
processing path adapted to remove fluid from any container
presented to it and place the removed fluid sample in a sample
receptacle; a specimen acquisition head along the processing path
adapted to remove fluid from any container presented to it,
separate particulate matter from the removed fluid, and form a
sample layer of particulate matter; and a controller governing
operation of the fluid sampling head, operation of the specimen
acquisition head and movement of the container transport, the
controller responding to presentation of a container to the fluid
sampling head to cause the fluid sampling head independently to
remove fluid therefrom, and the controller responding to
presentation of a container to the specimen acquisition head to
cause the specimen acquisition head independently to remove fluid
therefrom, separate particulate matter from the removed fluid, and
form a sample layer of particulate matter.
40. An automated apparatus according to claim 39, comprising a
receptacle transport that transports sample receptacles seriatim to
and from the fluid sampling station along a receptacle path.
41. An automated apparatus according to claim 40, wherein the
receptacle transport and the container transport are
synchronized.
42. An automated apparatus according to claim 41, wherein the
receptacle path is that intersects the processing path.
43. An automated apparatus according to claim 42, wherein the
specimen acquisition station is adapted to collect a layer of
particulate matter on a surface of a filter, and press the filter
against a slide positioned in proximity to the processing path to
transfer the particulate matter sample to the slide.
44. A receptacle for collecting a fluid sample, comprising: a
hollow body for receiving and holding fluid; a one-way valve
carried by the body and having a fluid flow passage between the
exterior and the interior of the body, the valve being
pressure-actuated to permit fluid flow into the body interior when
the exterior pressure exceeds the interior pressure, and preventing
outflow of fluid from the body under the influence of any other
relative pressure conditions; and a vent in the body remote from
the valve.
45. A receptacle according to claim 44, wherein the valve comprises
an inlet portion opening to the exterior of the body, and an outlet
portion opening to the body interior, the flow passage extending
between the inlet portion and the outlet portion, at least a
portion of the flow passage being resiliently biased to a closed
position when the interior and exterior pressures are substantially
equal, and expandable to allow fluid flow into the body in response
to a positive pressure differential across the valve from the inlet
portion to the outlet portion.
46. A receptacle according to claim 45, wherein the portion of the
flow passage in the outlet portion tapers toward the resiliently
biased portion.
47. A receptacle according to claim 46, wherein the outlet portion
has a tapered tip that is exposed to the body interior, and the
resiliently biased portion of the flow passage extends through the
tapered tip.
48. A receptacle according to any one of claims 45-47, wherein the
portion of the valve in which the resilient flow passage is formed
is made of resilient material.
49. A receptacle according to claim 48, wherein said resilient
material is an elastomer.
50. A receptacle according to claim 48, wherein the entire valve is
made of resilient material, the inlet portion adapted to form a
seal with the source of the fluid to be collected.
51. A receptacle according to claim 50, wherein said resilient
material is an elastomer.
52. A receptacle according to any one of claims 45-47, wherein the
inlet portion is made of a resilient material adapted to form a
seal with the source of the fluid to be collected.
53. A receptacle according to claim 52, wherein said resilient
material is an elastomer.
54. A receptacle according to any one of claims 44-47, wherein the
vent comprises a port through which gases leave the body interior
as the body fills with fluid.
55. A receptacle according to claim 54, wherein the body is
generally tubular with the valve at one end of the tube and the
vent comprising the open other end of the tube.
56. A receptacle according to claim 55, wherein the vent is adapted
to be sealed with a closure after the fluid sample is obtained.
57. An apparatus for obtaining different types of samples from a
fluid specimen in a container, comprising: a support for the
container; a fluid sampling head adapted to remove fluid from the
container and place the removed fluid in a sample receptacle; and a
specimen acquisition head adapted to remove fluid from the
container, separate particulate matter from the removed fluid, and
form a sample layer of particulate matter.
58. An apparatus according to claim 57, wherein the receptacle has
an inlet, and the fluid sampling head is adapted to aspirate fluid
from the container and through the inlet directly into the
receptacle by applying suction to the receptacle.
59. An apparatus according to claim 58, wherein the specimen
acquisition head is adapted to aspirate fluid from the container
and through a filter to collect the sample layer on the filter.
60. An apparatus according to claim 59, wherein the specimen
acquisition head is adapted to transfer the sample layer of
particulate material to a slide.
61. A method for obtaining different types of samples from a fluid
specimen in a container using a single apparatus, comprising:
supporting the container in the apparatus; placing the specimen in
fluid communication with a fluid sampling station of the apparatus,
whereby fluid is removed from the container and placed in a sample
receptacle; and placing the specimen in fluid communication with a
specimen acquisition station of the apparatus, whereby fluid is
removed from the container, particulate matter is separated from
the removed fluid, and a sample layer of particulate matter is
formed.
62. A method according to claim 61, wherein the apparatus places
the sample layer of particulate matter on a slide.
63. A method according to claim 60, claim 61 or claim 62, wherein
the specimen is a biological specimen.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of commonly owned U.S.
provisional application No. 60/330,092, filed Oct. 19, 2001, No.
60/372,080, filed Apr. 15, 2002, and No. 60/373,658, filed Apr. 19,
2002, all of which are incorporated herein by reference. This
application also is related to the commonly owned non-provisional
application filed concurrently herewith, entitled "Automated System
and Method for Processing Multiple Liquid-Based Specimens" and
naming Norman J. Pressman and William J. Mayer as inventors, which
is also incorporated herein by reference.
TECHNICAL FIELD
[0002] The invention relates to processing fluid specimens, e.g.,
biological fluid specimens, to extract samples for testing.
BACKGROUND
[0003] In the medical community it is commonly hypothesized and
accepted that patient outcomes are improved by early disease
detection, diagnosis, and therapeutic monitoring and intervention.
Scientific advances in cell biology, cytogenetics, and molecular
pathology are leading to new screening and diagnostic methods with
increased sensitivity and specificity. These improved means for
early detection and diagnosis, as well as these improved means for
therapeutic monitoring, are being implemented, for example, in
reference laboratories, medical clinics, and hospital-based
clinical testing laboratories.
[0004] Many classes of diseases are either cell-based (e.g., (a)
cancers such as lung, colorectal, bladder, prostate, cervical and
breast cancer, and (b) neurological and muscular degenerative
diseases such as Alzheimer's and Parkinson's diseases) or based
upon the cellular environment and products within the patient or
host organism (e.g., (a) immune diseases such as HIV/AIDS and
autoimmune diseases, and (b) other infectious diseases such as
sexually transmitted diseases (STDs) of the gynecological tract
caused by viral, bacterial, fungal, parasitic or other infectious
agents). Advanced screening and diagnostic methods are often based
on the detection of molecules, molecular events, or foreign
organisms both within (i.e., intracellular) and external to (i.e.,
extracellular) suspicious, a typical, infected, and/or cancer
cells.
[0005] Specimens from patients are collected when patients undergo
screening, diagnostic or therapeutic monitoring examinations.
Examples of screening examinations during which such specimens are
collected include examinations for lung cancer as evidenced by
sputum analyses, colorectal cancer, cervical cancer as evidenced by
PAP smears and pelvic gynecological examinations, bladder cancer as
evidenced by voided urine analyses, and skin cancer examinations.
These specimens need to be processed before expert medical
professionals and analytical instruments (e.g., cytotechnologists,
pathologists, hematologists, blood chemistry analyzers, flow
cytometers, spectrometers) can evaluate, interpret and
classify/diagnose samples from these specimens. Specimen processing
may involve many diverse steps including, but not limited to
specimen collection, cell dispersal, disaggregation of mucous,
fixation, aliquoting, homogenization, cell-deposition, staining,
cellular molecular labeling, and glass microscope-slide
coverslipping techniques.
[0006] The outcome or byproducts of specimen processing protocols
are patient samples that are ready for subsequent human or machine
assessment. Typically, two types of cytopathology samples are
prepared depending upon whether the clinical material will be
subjected to intracellular or extracellular analyses. Samples
prepared for intracellular cytopathology analyses are either
microscope slide-based (for expert human review or machine
assessment) or liquid-based for assessment by flow cytometers, PCR
analyzers and/or other analytical instruments. Samples prepared for
extracellular cytopathology analyses are predominantly liquid
samples collected or subsequently placed into test tubes, vials or
other sample containers for biomedical liquid samples.
[0007] Slide-based preparations can be produced by several
techniques, such as conventional cervical-vaginal Papanicolaou
(PAP) smears or by improved means such as LBP (liquid-based
preparation) technologies that result in thin-layer or monolayers
of cells deposited onto glass microscope slides for improved
visualization and/or machine analysis. The MonoGen MONOPREP.TM. LBP
instrument, which is disclosed in the aforementioned provisional
application No. 60/372,080 and in the aforementioned
non-provisional application filed concurrently herewith, is an
example of such a slide and sample preparation device. These types
of sample preparations (i.e., LBP slides) are used for
intracellular analyses with numerous testing methods such as the
direct visualization employed by conventional PAP tests performed
by expert cytotechnologists and pathologists, and peripheral blood
leukocyte differential whole blood counts performed by
hematologists. Other intracellular analyses include molecular
diagnostic tests that determine the presence, absence,
overexpression or underexpression of proteins (e.g.,
immunocytochemistry techniques) or other molecules found within
cells or organelles (e.g., nuclear, nucleolar, mitochondrial,
cytoplasmic) including the detection of cytogenetic molecular
changes in DNA structure (e.g., sequencing) and content (e.g., in
situ hybridization techniques).
[0008] Liquid samples are often produced for machine analyses of
extracellular content. These samples include test tubes of
heparinized blood for blood chemistry tests (e.g., SGOT, NA, K, CA,
Alkaline Phosphatase, PSA, BUN/creatinine ratio, hemoglobin,
hematocrit, blood gluocose, and HDL and LDL cholesterol content).
Technologies used for extracellular analyses from liquid samples
include, but are not limited to, PCR (i.e., Polymerase Chain
Reaction), NASBA (Nucleic Acid Strand-Based Amplification),
microarray genetyping, hybrid capture, direct hybridization,
sequencing, spectrometers, liquid chromatography, fluorescent
antibody detection, antigen detection, immunochemistry, enzyme
chemistry, DNA analysis, nuclear probe detection, viral and RNA
quantification, flow microfluorometric cytometers, and cell
sorters. Tests on these liquid samples include, but are not limited
to tests for chlamydia, cytomegalovirus (CMV) including detection
of CMV antigens by EIA, trachomatis detection by direct and
amplified probes, hepatitis (B and C) core IgG and IgM and surface
antibodies and antigens, pneumonia including by direct probe
techniques, HIV-1 detection by detection and quanitification by
direct and amplified probes, and mycobacteria turberculosis DNA and
RNA quantitation and detection via direct and amplified probes.
[0009] Some tests (e.g., detection of presence of non-host
infectious organisms) can be based upon either intracellular assays
(e.g., slide-based samples) or extracellular assays (e.g., liquid
samples). Examples include tests for the detection of STDs
including gonorrhea, trachomatis, and chlamydia (GTC).
[0010] Machines already exist to take specimens collected at the
point-of-care (POC) site and produce LBP microscope slide-based
samples (e.g., the MonoGen MONOPREP.TM. LBP system referenced
above, and the Cytyc THINPREP.RTM. 2000 and 3000 LBP machines).
Other machines already exist to take POC specimens and produce
liquid samples (e.g., blood chemistry analyzers from Olympus
America, Inc.) and perform a variety of extracellular tests. No
single instrument exists that can produce samples from clinical
cytology specimens that are suitable for both types of
analyses.
SUMMARY DISCLOSURE OF THE INVENTION
[0011] The invention is a system and method for processing
specimens to extract samples for both liquid (i.e., extracellular)
and slide-based (i.e., intracellular) testing. It is an improvement
on the LBP device, system and method disclosed in the
aforementioned provisional application No. 60/372,080 and in the
aforementioned non-provisional application filed concurrently
herewith; and, like that LBP device and system, is compatible with
post-processing machines, and can be interfaced with other devices
as well as a central hospital or laboratory information system.
[0012] The machine according to this invention is a "platform
instrument" that can produce all required liquid samples and
slide-based samples for essentially all cytopathology tests,
whether performed by visual examination by expert humans or
analytical instruments, and/or whether performed based upon
cytomorphological, cytogenetic, molecular diagnostic,
microbiological, virological or other technologies and techniques.
This is accomplished in a safe, fast, automated and efficient
manner. The integration of the need for both types of samples from
a single specimen minimizes the risk of introducing clerical errors
associated with mislabeling and mishandling of patient specimens,
samples, and associated data. This integration also minimizes the
risk of producing disparate results from a variety of types of
assays that are each based upon non-representative samples from the
specimens of a single patient.
[0013] One aspect of the invention relates to a method and
apparatus for obtaining different types of samples from a fluid
specimen in a container. The container is supported in the
apparatus, and the specimen is placed in fluid communication with a
fluid sampling station of the apparatus, which removes fluid from
the container and places in a sample receptacle. The specimen is
also placed in fluid communication with a specimen acquisition
station of the apparatus, which removes fluid from the container,
separates particulate matter from the removed fluid, and forms a
sample layer of particulate matter. The two sampling operations can
be carried out in any order.
[0014] The method and apparatus may be automated for processing
multiple specimens in respective containers. For example, the
specimen containers may be transported seriatim along a processing
path, and may first be subjected to an optional preprocessing
operation. Here, too, the two sampling operations can be carried
out in any order. Sample receptacles used to collect fluid samples
can be fed to the fluid sampling station automatically along a path
that intersects the container processing path. Movement of
containers and receptacles along their respective paths can be
synchronized. The sample layer formed at the specimen acquisition
station may be transferred to a slide. As used herein, the term
"slide" encompasses glass microscope slides as well as any other
substrate on which a sample may be placed for subsequent testing or
analysis.
[0015] Another aspect of the invention relates to a receptacle for
collecting a fluid sample, e.g., for use at the fluid sampling
station. The receptacle has a hollow body for receiving and holding
fluid. A one-way valve is carried by the body and has a fluid flow
passage between the exterior and the interior of the body. The
valve is pressure-actuated to permit fluid flow into the body
interior when the exterior pressure exceeds the interior pressure,
and prevents outflow of fluid from the body under the influence of
any other relative pressure conditions. There is also a vent in the
body remote from the valve.
[0016] The valve has an inlet portion opening to the exterior of
the body, and an outlet portion opening to the body interior. The
flow passage extends between the inlet portion and the outlet
portion. At least a portion of the flow passage is resiliently
biased to a closed position when the interior and exterior
pressures are substantially equal, and is expandable to allow fluid
flow into the body in response to a positive pressure differential
across the valve from the inlet portion to the outlet portion. The
valve preferably is made of resilient material, e.g., an elastomer,
and preferably is configured so that it can be coupled directly to
the fluid source to be sampled.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0017] Preferred embodiments of the disclosed apparatus and method,
including the best mode for carrying out the invention, are
described in detail below, purely by way of example, with reference
to the accompanying drawing figures, in which:
[0018] FIG. 1a is a top plan view of the LBP device disclosed in
the aforementioned provisional application No. 60/372,080 and in
the aforementioned non-provisional application filed concurrently
herewith, showing a modification according to this invention;
[0019] FIG. 1b is a schematic diagram of the operating sequence of
the LBP device, adapted in accordance with this invention;
[0020] FIG. 2 is a schematic illustration of the fluid sampling
draw station according to this invention;
[0021] FIG. 3 is a schematic detail view of the fluid sampling draw
station of FIG. 2;
[0022] FIG. 4 is a schematic detail plan view showing how the fluid
sampling draw station of this invention interfaces with the LBP
device; and
[0023] FIG. 5 is a schematic view showing sample fluid extraction
for testing.
DETAILED DESCRIPTION OF BEST MODE
[0024] FIG. 1a shows the overall arrangement of the aforementioned
LBP device, which transports multiple specimen containers
sequentially through various processing stations and produces fixed
specimens on slides, each slide being bar-coded and linked through
a data management system (DMS) to the vial and the patient from
which it came. In the preferred arrangement, each container has a
special internal processing assembly detachably coupled to its
cover, and is transported through the LBP device on a
computer-controlled transport (conveyor) 240, in its own receptacle
246. (In the example shown the conveyor has thirty receptacles.)
The containers and the receptacles are keyed so that the containers
proceed along the processing path in the proper orientation, and
cannot rotate independently of their respective receptacles.
[0025] The containers first pass a bar code reader 230 (at a data
acquisition station), where the vial bar code is read, and then
proceed stepwise through the following processing stations of the
LBP device: an uncapping station 400 including a cap disposal
operation; a preprocessing station 500; a filter loading station
600; a specimen acquisition and filter disposal station 700; and a
re-capping station 800. These six stations are structured for
parallel processing, meaning that all of these stations can operate
simultaneously on different specimens in their respective
containers, and independently of the other. The conveyor will not
advance until all of these operating stations have completed their
respective tasks.
[0026] The preprocessing station is the location at which
preprocessing operations, such as specimen dispersal within its
container, are performed prior to the container and its specimen
moving on for further handling. The preprocessing station typically
performs a dispersal operation. In the preferred embodiment, the
dispersal operation is performed by a mechanical mixer, which
rotates at a fixed speed and for a fixed duration within the
specimen container. In this example, the mixer serves to disperse
large particulates and microscopic particulates, such as human
cells, within the liquid-based specimen by homogenizing the
specimen. Alternatively, the specimen may contain subcellular sized
objects such as molecules in crystalline or other conformational
forms. In that case, a chemical agent may be introduced to the
specimen at the preprocessing station to, for example, dissolve
certain crystalline structures and allow the molecules to be
dispersed throughout the liquid-based specimen through chemical
diffusion processes without the need for mechanical agitation. Such
a chemical preprocessing station introduces its dispersing agent
through the preprocessing head.
[0027] There is also an integrated system 900 that includes
additional bar code readers, slide cassettes, handling mechanisms
for slide cassettes and individual slides, and a slide presentation
station 702 at which the specimen acquisition station transfers a
representative sample from a specimen to a fresh microscope slide.
An optional auto loading mechanism 300 automatically loads and
unloads specimen vials onto and from the transport mechanism. All
stations and mechanisms are computer-controlled. FIG. 1b shows the
operating sequence of the LBP device. This is the top-level table
from which the operating software is structured.
[0028] In the preferred embodiment of the LBP device disclosed in
the aforementioned applications, the vial uncapping station 400 has
a rotary gripper that unscrews the cover from the vial, and
discards it into a biosafety disposable waste handling bag. Before
doing so, however, the uncapping head presses on the center of the
cover to detach the internal processing assembly from the cover.
The preprocessing (mixing) station 500 has an expanding collet that
grips the processing assembly, lifts it slightly and moves (e.g.,
spins) it in accordance with a specimen-specific stirring protocol
(speed and duration). The filter loading station 600 dispenses a
specimen-specific filter type into a particulate matter separation
chamber (manifold) at the top of the processing assembly. The
specimen acquisition station 700 has a suction head that seals to
the filter at the top of the processing assembly and first moves
the processing assembly slowly to re-suspend particulate matter in
the liquid-based specimen. Then the suction head draws a vacuum on
the filter to aspirate the liquid-based specimen from the vial and
past the filter, leaving a thin layer of cells on the bottom
surface of the filter. Thereafter the thin layer specimen is
transferred to a fresh slide, and the container moves to the
re-capping station, where a foil-type seal is applied.
[0029] In accordance with a preferred embodiment of the present
invention, the LBP device shown in FIG. 1a also is equipped with a
fluid sampling draw station 100, which is adapted to engage the
processing assembly (stirrer) present in any of the specimen
containers processed by the LBP device. As illustrated in this
figure, the fluid sampling draw station 100 is located just after
(downstream of) the mixing station 500 of the LBP device. However,
the fluid sampling draw station instead could be located downstream
of the specimen acquisition station 700.
[0030] Referring to FIGS. 2 and 3, sample receptacles in the form
of special molded plastic test tubes 102 are used to collect
specimen fluid at the fluid sampling draw station 100, to be
processed by other preprocessing devices, or external PCR or other
test protocols, devices, or systems. Test tube 102 preferably is
transparent to a sensor, and is designed to collect about 5 ml of
specimen fluid, although smaller or larger test tubes or other
types of sample receptacles could be employed. Each test tube 102
preferably is laser-etched with a unique machine-readable bar code
number 103. The test tubes themselves and/or their closure caps 105
may be color-coded to distinguish specimen types (e.g., blood,
urine, sputum, gastrointestinal, cervical, prostate). Specimen
types may also be distinguished by employing receptacles (test
tubes) of different size or height.
[0031] Test tube 102 is fitted with a thermoplastic elastomer
one-way valve 104, e.g., a flap valve, on one end. The resilient
nature of the valve material normally keeps the small flow passage
therein squeezed tightly shut without the potential of sample
leakage. This valve has an exposed frontal surface 112, the purpose
of which is to act as a gasket when it is coupled to the element
from which it is to draw fluid. In the preferred arrangement, that
element is the suction tube 43 of the processing assembly (stirrer)
40 already in the specimen container 20, which is on the conveyor
of the LBP device. The exposed tip of the valve, adjacent the inlet
port 108, preferably is tapered so as to enter and positively seal
against the upper end of the stirrer suction tube 43. The normally
closed very small flow passage through outlet port 110 is formed in
a tapered tip that is exposed to the test tube interior. The
opposite end of the test tube is open, but can be sealed after
filling by a cap 105 (e.g., sealed with an elastomer stopper).
[0032] One-way valve 104 is actuated by elevating the pressure on
its inlet port 108 relative to the pressure on its outlet port 110.
In this embodiment, a vacuum applied to the open end of the test
tube also is applied to outlet port 110 of the valve, causing fluid
to be drawn through the normally closed valve flow passage therein
in only one direction inwardly. Alternatively, pressurization of
specimen container 20 would force fluid through stirrer tube 43 and
one-way valve 104, into test tube 102.
[0033] After filling and capping, neither a positive pressure
within test tube 102 nor rough handling of the test tube can force
fluid back out through one-way valve 104. This eliminates a source
of potential biohazard and cross-sample contamination. However, the
resilient material of valve 104 can be coaxed mechanically to allow
outflow of fluid. FIG. 5 shows one example of how a sample of the
collected fluid can be extracted from a test tube 102. A syringe
103 may be used to access fluid through the one-way valve 104. The
action of the one-way valve allows a blunt-faced cannula to enter
the test tube 102 without damaging the self-sealing characteristics
of the valve. Either a hand-held syringe or a mechanically actuated
cannula (connected to a vacuum source) can be used for this
purpose.
[0034] In operation, as part of the LBP device, the fluid sampling
draw station 100 moves the test tube 102 downwardly to force-couple
the one-way valve 104 to the stirrer 40 in a specimen container 20
presented to the station. A vacuum cap 120 fitted with a gasket is
coupled to the distal (uncapped) end of the test tube to draw fluid
up through the hollow stirrer tube 43 and through the one-way valve
104. The vacuum cap 120 is connected to the LBP system vacuum
source and is controlled by a solenoid valve. The same pneumatic
actuator (not shown) that forces the one-way valve 104 into
engagement with the stirrer 40 also presses the vacuum cap 120
against the test tube to make the vacuum seal. A conventional
fluid-level control system includes liquid-level sensors 106 that
monitor the aspiration process and signal operation cut-off to a
controller when the proper level is reached. A bar code reader 109
(see FIG. 4) reads the bar code on the test tube, links the test
tube bar code number to the bar code number of the specimen
container (e.g., vial), and the acquired data is entered into the
data management system (DMS). Thereafter, a cap 105 is applied to
the distal end of the test tube at a capping station 107.
[0035] Actuation of the fluid sampling draw station 100 preferably
is governed by the particular processing protocol for each
specimen. Accordingly, there may be specimen containers 20 from
which no fluid sample is drawn, in which case the fluid sampling
draw station will remain idle while such a container dwells there.
It is also possible for the fluid sampling draw station to draw a
variable fluid volume, again dependent on the particular processing
protocol for each specimen. To accomplish that, a plurality of
vertically spaced fluid level sensors 106 would monitor the
changing level of fluid in the test tube 102, and liquid draw would
be terminated when the specified fluid volume is acquired.
[0036] FIG. 4 shows details of how the fluid sampling draw station
100 interfaces with the LBP device. In one embodiment, empty test
tubes 102 are loaded in a vibratory bin feeder 114, which orients
the test tubes valve-end-down and dispenses them via a
gravity-operated track into a transport feed mechanism, such as a
bandolier carrier or ribbon feeder 116. This transport mechanism
indexes the test tubes laterally of the container transport
conveyor 240 of the LBP device (top to bottom as seen in FIG. 4,
left to right as seen in FIG. 2). This may be accomplished, e.g.,
by means of a walking beam escapement operated by two air cylinders
(not shown). One cylinder delivers linear motion, while the other
supplies the engage/disengage function. The bandolier carrier 116
also allows the vertical motion of a test tube required to clamp
the valve tip seal 112 to the stirrer tube 43 during
aspiration.
[0037] Test tube capping takes place at a capping station 107, as
mentioned above. Here, a molded elastomer stopper 105 is
escapement-fed from a supply bowl (not shown) and pressed into the
open top of the test tube to form a seal. For this operation,
stoppers 105 are supplied to the unit in pre-loaded tubes and
escaped from the tube into a pressing chamber (not shown), where an
air-operated actuator forces the stopper onto the test tube neck.
An air blow/vacuum system 130 cleans any residual fluid from the
tip of the one-way valve 104. Filled test tubes are then ejected
from the carrier 116 at an ejection station, where they are
delivered to a collection bin 118.
[0038] It is to be understood that the invention is not limited in
its application to the details of construction and the arrangement
of components and methods of the preferred embodiments described
above and illustrated in the drawing figures. Variations will be
apparent to those skilled in the art without departing from the
scope of the invention, which is defined by the appended claims. As
one example, the one-way valve could be made of any suitable
resilient material, or could be made of a harder material that is
coated or otherwise joined to a resilient material in those areas
that require flexibility for sealing. As another example, sample
receptacles (e.g., test tubes) may be fed to (and removed from) the
fluid sampling draw station using any suitable mechanism(s), such
as direct feed by a vibratory bowl feeder, or individual placement
and removal by a pick-and-place mechanism.
[0039] Further, it should be noted that the invention in its
broadest aspects does not require specimen premixing, or any type
of specimen preprocessing. Nor does it require the use of specimen
vials that come prepackaged with the special internal processing
assembly 40 shown in FIG. 2 and disclosed in the aforementioned
provisional application No. 60/372,080 and the aforementioned
non-provisional application filed concurrently herewith. Nor does
it require a conveyor to feed specimens to the operating
stations/heads automatically. And it does not require use of the
specific type of specimen acquisition/slide-making station 700
disclosed in those applications and described above. Thus, for
example, other commercially available LBP processes and machines,
such as the Cytyc THINPREP.RTM. 2000 and 3000 LBP devices, could be
used to make the slide-based samples in accordance with this novel
method for processing fluid specimens to obtain both liquid samples
and slide-based samples. In such embodiments, the specimen
container, microscope slide, filter, and liquid sample receptacle
can be placed manually into the device by a machine operator.
INDUSTRIAL APPLICABILITY
[0040] The above disclosure presents a safe, effective, accurate,
precise, reproducible, inexpensive, efficient, fast and convenient
system and method for handling and processing liquid-based
specimens, e.g., cellular specimens, to obtain both liquid samples
and slide-based samples for subsequent testing and/or analysis.
* * * * *