U.S. patent application number 10/274360 was filed with the patent office on 2003-05-15 for article dispensing apparatus and method.
This patent application is currently assigned to MONOGEN, INC.. Invention is credited to Mayer, William J., Wroblewski, Lucien J..
Application Number | 20030089731 10/274360 |
Document ID | / |
Family ID | 27406711 |
Filed Date | 2003-05-15 |
United States Patent
Application |
20030089731 |
Kind Code |
A1 |
Mayer, William J. ; et
al. |
May 15, 2003 |
Article dispensing apparatus and method
Abstract
Method and apparatus for storing and dispensing articles, one at
a time, from the bottom of a stack of like articles. The articles
are yieldably supported in at least one upright stack above an
outlet, e.g., a resilient choke, sized to pass the articles if
forced therethrough. Articles are dispensed by pressing downwardly
on the stack with sufficient force and for sufficient duration to
overcome the yieldable supporting force and move the lowest article
through the outlet. Sensors may be provided for sensing when an
article is dispensed, when the tube is empty, and the type of
article in the holder. The method and apparatus are especially
useful in a vial-based automated system for processing multiple
specimens of biological fluid, wherein a filter assembly must be
dispensed into a filtration chamber associated with each specimen
vial.
Inventors: |
Mayer, William J.; (South
Barrington, IL) ; Wroblewski, Lucien J.; (Downers
Grove, IL) |
Correspondence
Address: |
FOLEY AND LARDNER
SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
MONOGEN, INC.
|
Family ID: |
27406711 |
Appl. No.: |
10/274360 |
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: |
221/279 |
Current CPC
Class: |
B01D 65/08 20130101;
B01L 2300/0681 20130101; Y10T 29/53039 20150115; G01N 1/4077
20130101; G01N 35/00029 20130101; G01N 2035/0427 20130101; B01L
9/06 20130101; B01L 2200/025 20130101; B01D 61/22 20130101; G01N
35/0099 20130101; B01L 3/50825 20130101; B01L 2300/0851 20130101;
G01N 2035/0443 20130101; Y10T 436/25375 20150115; B01L 2300/0822
20130101; B01D 2321/02 20130101; B01D 2321/10 20130101; B01L
2300/046 20130101; G01N 35/021 20130101; G01N 2035/00089 20130101;
B65B 7/161 20130101; G01N 35/1016 20130101; G01N 2035/0462
20130101; B01D 2321/16 20130101; B01D 2321/2008 20130101; B01F
35/605 20220101; B01L 3/502 20130101; B01L 3/508 20130101; Y10T
436/11 20150115; B01F 27/13 20220101; G01N 2035/0405 20130101; B65B
69/00 20130101; B01D 2321/2066 20130101; B01D 63/08 20130101; Y10T
436/12 20150115; B01L 2300/042 20130101; G01N 35/00 20130101; G01N
2035/0441 20130101; Y10T 436/255 20150115; G01N 2001/1025 20130101;
Y10T 29/49822 20150115; B01D 2321/2016 20130101; G01N 35/04
20130101; G01N 1/2813 20130101; Y10T 436/112499 20150115; B01F
27/88 20220101; B01L 9/52 20130101; G01N 27/22 20130101; G01N
2035/00138 20130101; B01D 61/18 20130101; G01N 2001/2826 20130101;
Y10T 436/113332 20150115; B01L 2300/044 20130101; G01N 2035/0458
20130101; B01F 33/5011 20220101; B01F 35/60 20220101 |
Class at
Publication: |
221/279 |
International
Class: |
B65H 001/08 |
Claims
1. An apparatus for dispensing articles one at a time from the
bottom of a stack of like articles, comprising: a holder adapted to
house a plurality of like articles in an upright stack, the holder
having a bottom dispensing outlet with a resilient choke configured
to support and retain the stack of articles under their own weight
and deflect to permit articles to pass through the outlet when the
stack is pressed downwardly; a pusher mechanism having a pusher
member mounted for vertical movement to press down on the stack of
articles; and a controller responsive to an input signal to advance
the pusher member sufficiently to force the lowest article in the
stack past the choke and through the outlet.
2. An apparatus according to claim 1, wherein the holder comprises
a tube.
3. An apparatus according to claim 2, wherein the tube has a
longitudinal slot, and the pusher member comprises an arm that
extends laterally into the tube through the slot.
4. An apparatus according to claim 3, wherein the slot extends the
full length of the tube.
5. An apparatus according to claim 4, wherein the choke comprises
fingers formed by a plurality of slits at the bottom of the
tube.
6. An apparatus according to claim 5, wherein the pusher mechanism
comprises a lead screw driven by a stepper motor for effecting
movement of the aim.
7. An apparatus according to claim 2, wherein the choke comprises
fingers formed by a plurality of slits at the bottom of the
tube.
8. An apparatus according to claim 1, comprising a sensor connected
to the controller for sensing the passage of one article through
the outlet, the controller being responsive to said passage to
arrest the pusher member.
9. An apparatus according to claim 1, comprising a sensor connected
to the controller for sensing when the holder is empty.
10. An apparatus for dispensing articles one at a time from the
bottom of a selected stack of like articles, comprising: a turret
mounted for rotation about a vertical axis; an actuator for
rotating the turret; a plurality of upright holders supported on
the turret at the same radial distance from the axis, each holder
adapted to house a plurality of like articles in an upright stack
and having a bottom dispensing outlet with a resilient choke
configured to support and retain the stack of articles under their
own weight and deflect to permit articles to pass through the
outlet when the stack is pressed downwardly; a pusher mechanism
having a pusher member mounted for vertical movement to press down
on the selected stack of articles; and a controller coordinating
rotation of the turret and operation of the pusher mechanism to
position the selected stack of articles at a dispensing position
beneath the pusher member and advance the pusher member
sufficiently to force the lowest article in the selected stack past
the choke and through the outlet.
11. An apparatus according to claim 10, wherein each holder
comprises a tube.
12. An apparatus according to claim 11, wherein each tube has a
longitudinal slot, and the pusher member comprises an arm that
extends laterally into the tube of the selected stack through the
slot.
13. An apparatus according to claim 12, wherein the slot extends
the full length of the tube.
14. An apparatus according to claim 13, wherein each choke
comprises fingers formed by a plurality of slits at the bottom of
the tube.
15. An apparatus according to claim 14, wherein the pusher
mechanism comprises a lead screw driven by a stepper motor for
effecting movement of the arm.
16. An apparatus according to claim 11, wherein each choke
comprises fingers formed by a plurality of slits at the bottom of
the tube.
17. An apparatus according to claim 10, comprising a sensor
connected to the controller for sensing the passage of one article
through the outlet, the controller being responsive to said passage
to arrest the pusher member.
18. An apparatus according to claim 10, comprising a sensor
connected to the controller for sensing when the holder in the
dispensing position is empty.
19. An apparatus according to claim 18, comprising a sensor
connected to the controller for detecting the type of article in
the holder in the dispensing position.
20. An apparatus according to claim 10, comprising a sensor
connected to the controller for detecting the type of article in
the holder in the dispensing position.
21. An apparatus according to claim 10, comprising eight holders
symmetrically supported on the turret.
22. A method of storing and dispensing articles one at a time from
the bottom of a stack of like articles, comprising: yieldably
supporting the articles in an upright stack above an outlet sized
to pass the articles if forced therethrough; and pressing
downwardly on the stack of articles with sufficient force and for
sufficient duration to overcome the yieldable supporting force and
move the lowest article through the outlet.
23. A method of storing and dispensing articles one at a time from
the bottom of a selected stack of like articles, comprising:
yieldably supporting the articles in a plurality of upright stacks,
each stack consisting of like articles held above an outlet sized
to pass the articles if forced therethrough; moving the selected
stack of articles into a dispensing position; and pressing
downwardly on the selected stack of articles with sufficient force
and for sufficient duration to overcome the yieldable supporting
force and move the lowest article through the outlet.
24. A method according to claim 23, comprising sensing the type of
article in the stack in the dispensing position, and moving a
different stack of articles to the dispensing position if the
sensed article is not of a selected type.
25. A method according to claim 23, wherein the stacks of articles
are supported on a rotary member, and the step of moving the
selected stack of articles into the dispensing position comprises
moving all of the stacks simultaneously.
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 commonly owned U.S. non-provisional
application Ser. No. 10/122,151, filed Apr. 15, 2002, which is also
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present disclosure is directed to apparatus and methods
for collecting and processing specimens of particulate
matter-containing liquid, e.g., biological fluid, including
collecting and depositing onto a microscope slide or other surface
a uniform layer of particulates therefrom (e.g., cells) suitable
for examination (e.g., use in cytology protocols).
BACKGROUND ART
[0003] Diagnostic cytology, particularly in the area of clinical
pathology, bases cytological interpretations and diagnoses on
examination of cells and other microscopic objects. The accuracy of
the screening process and diagnosis, and the preparation of
optimally interpretable samples from specimens typically depends
upon adequate specimen and sample preparation. In this regard the
ideal sample would consist of a monolayer of substantially evenly
spaced cells, which enables cytotechnologists, cytopathologists,
other medical professionals, and automated screening and diagnostic
equipment to view or image the cells more clearly so that
abnormalities can be identified more readily, more accurately and
more reproducibly. Newer methodologies such as immunocytochemistry
and cytometric image analysis require preparation apparatus and
methods that are safe, effective, accurate, precise, reproducible,
inexpensive, efficient, fast and convenient.
[0004] Cytological examination of a sample begins with obtaining
specimens including a sample of cells from the patient, which can
typically be done by scraping, swabbing or brushing an area, as in
the case of cervical specimens, or by collecting body fluids, such
as those obtained from the chest cavity, bladder, or spinal column,
or by fine needle aspiration or fine needle biopsy. In a
conventional manual cytological preparation, the cells in the fluid
are then transferred directly or by centrifugation-based processing
steps onto a glass microscope slide for viewing. In a typical
automated cytological preparation, a filter assembly is placed in
the liquid suspension and the filter assembly both disperses the
cells and captures the cells on the filter. The filter is then
removed and placed in contact with a microscope slide. In all of
these endeavors, a limiting factor in the sample preparation
protocol is adequately separating solid matter from its fluid
carrier, and in easily and efficiently collecting and concentrating
the solid matter in a form readily accessible to examination under
a microscope.
[0005] Currently, biological specimens are collected for
cytological examinations using special containers. These containers
usually contain a preservative and transport solution for
preserving the cytology specimen during shipment from the
collection site to the diagnostic cytology laboratory. Further,
cytology specimens collected from the body cavities using a swab,
spatula or brush are also preserved in special containers with
fixatives (e.g., alcohol or acetone fixatives) prior to
transferring cells onto the slide or membrane for staining or
examination. Specimen containers are known that allow a
liquid-based biological specimen to be processed directly in the
container so as to obtain a substantially uniform layer of cells on
a collection site (in a filter housing defining a particulate
matter separation chamber) that is associated with the container
itself. See, for example, U.S. Pat. Nos. 5,301,685; 5,471,994;
6,296,764; and 6,309,362, of Raouf A. Guirguis, all of which are
incorporated herein by reference.
[0006] The filtration techniques taught in these patents in
practice have yielded fairly good results in terms of obtaining
close to a monolayer of cells on slides, but there is room for
improvement. Further, the types of specimen containers disclosed in
these patents require specially configured apertured covers and
adapters therefor that are designed to mate with the filter
housing, and with suction equipment (e.g., a syringe or a
mechanized vacuum source) used to aspirate liquid from the
container and draw it through the filter. In addition, extraction
of the filter so that it can be pressed against a microscope slide
to transfer collected cells to the slide requires disassembly of
the cooperating parts of the cover and/or adapters associated
therewith. If the processing is done by automated equipment,
special handling devices are required to carry out such
disassembly. All of this complexity adds time, and material and
labor cost to the processing required prior to the actual cytology
examination.
[0007] In general, automated equipment thus far developed for
processing liquid-based specimens have not performed with
sufficient consistency, reliability, speed and automation to
satisfy current and projected needs in cancer screening and other
cytology-based medical, analytical, screening and diagnostic
procedures. The vial-based automated processing system disclosed
herein provides a safe, elegant and effective solution to these
problems.
SUMMARY DISCLOSURE OF THE INVENTION
[0008] The specimen vial disclosed herein houses a complete
processing assembly, typically one for mixing the liquid-based
specimen therein and for holding a filter on which a uniform layer
of cells can be collected from the specimen. It is expected that
the specimen vial would be prepackaged with a liquid preservative
solution, as is commonplace, and sent to the point-of-care site for
specimen collection.
[0009] The processing assembly is coupled to a simple cover for the
vial by means of a simple and inexpensive releasable coupling. When
the cover is removed at the point-of-care site (physician's office,
clinic, hospital, etc.), the processing assembly remains with the
cover to allow medical personnel easy access to the container
interior for insertion of a biological specimen into the vial. The
cover, along with the attached processing assembly, is then
replaced to seal the vial. The vial may then be sent to a
laboratory for processing.
[0010] When the vial is manipulated in a simple way while still
closed, the processing assembly detaches from the cover and remains
in the vial for access by automated or manual laboratory equipment
when the cover is subsequently removed. In a preferred embodiment,
a downward force on the center of the cover is all that is required
to detach the processing assembly from the cover. In contrast with
the prior art specimen vials discussed above, the vial of the
present invention requires no further interaction with the cover,
which can be removed by a simple uncapping device and is discarded
to avoid contamination. Ribs inside the vial support the processing
assembly in the proper position for access during processing. This
self-contained vial and processing assembly arrangement minimizes
human operator exposure to biohazards, such as tuberculosis or
other pathogens in sputum or in other specimens types, such as
urine, spinal tap fluid, gastric washings, fine-needle aspirates,
and gynecological samples.
[0011] The automated specimen processing apparatus disclosed herein
is referred to as the "LBP" device (for liquid-based preparation),
and is designed to produce slides of high quality and consistency.
The LBP device also can be interfaced with a device for detecting
and/or quantifying multiple morphologic, cytochemical, and/or
molecular changes at the cellular level.
[0012] During the past two years or so, a review of the literature
and reanalysis of existing data have led to the identification of a
panel of molecular diagnostic reagents that are capable of
detecting and characterizing lung cancer, which is the most common
cancer, with high sensitivity and specificity. See, for instance,
commonly owned U.S. patent application Ser. No. 10/095,297 and Ser.
No. 10/095,298, both filed Mar. 12, 2002, and Ser. No. 10/241,753,
filed Sep. 12, 2002. Here, the cells can be reacted with antibodies
and or nucleic-acid "probes" that identify a pattern of changes
that is consistent with a diagnosis of cancer. The molecular system
can utilize algorithms fine tuned for that tumor heterogeneity.
[0013] Identifying molecular changes at the cellular level is one
of the ways cancer can be detected early and at a more curable
stage. Such molecular diagnostic devices can be used for early
detection and diagnosis with the necessary sensitivity and
specificity to justify their use as population-based screens for
individuals who are at-risk for developing cancer. Such a molecular
diagnostic device also can be used to characterize the tumor,
thereby permitting the oncologist to stratify his/her patients, to
customize therapy, and to monitor patients in order to assess
therapeutic efficacy and disease regression, progression or
recurrence. The availability of such tests will also foster the
development of new and more effective therapeutic approaches for
the treatment of early stage disease.
[0014] Such molecular diagnostics are designed to balance cost and
test performance. While screening tests must exhibit high
sensitivity and specificity, cost is always a critical factor, as
the tests are typically directed to performing on a large number of
individuals who, while at-risk, do not typically have symptomatic
evidence of the disease. In this respect, the present LBP device
can be interfaced with a molecular diagnostic device to develop a
system for automatically diagnosing cancer, with a minimum or no
human intervention. Alternatively, the present LBP device can be
interfaced with a pathology work station, where medical
professionals can observe individual slides prepared by the LBP
device. The resulting diagnosing system, regardless whether an
automated device or a manual observation device is interfaced, can
be interfaced with an integrated data management system based on
specialized software and a computer operating system to manage data
entry and exchange of information, and network with the laboratory
and hospital information systems.
[0015] The present LBP device transports multiple specimen vials of
the novel type mentioned above sequentially through various
processing stations and produces fixed specimens on slides, each
slide being bar-coded and linked through a data management system
to the vial and the patient from which it came. Fresh slides are
automatically removed one at a time from a cassette, and each is
returned to the same cassette after a specimen is fixed thereon.
Multiple slide cassettes can be loaded into the LBP device, and the
device will automatically draw fresh slides from the next cassette
after all of the slides of the preceding one have been used. The
slide cassettes preferably are configured for liquid immersion and
interfacing with automated staining equipment that will stain the
specimens without having to remove the slides from the cassette. In
this regard the cassettes preferably have slots that allow for
liquid drainage, and slots or other means that cooperate with the
hooks normally used in the staining equipment to suspend other
types of slide holders. The same slide cassettes are also
configured to interface with automated diagnostic equipment and
other devices that are part of an integrated system.
[0016] While specimen vials can be loaded into the transport
manually, the full benefits of automation can be realized by using
an optional vial handling system that automatically loads specimen
vials for processing, and removes each one after its processing is
complete. In one example of such a handling system the vials
initially are loaded manually into special space-saving trays that
hold up to forty-one vials each. Up to eight trays can be loaded
into the LBP device, and the device will process all of them
sequentially, removing one at a time from a tray and returning
processed (and resealed) vials to a tray. The trays also can be
used for storing and retrieving processed vials.
[0017] Each vial is transported through the LBP device on a
computer-controlled conveyor, in its own receptacle. (In the
example disclosed the conveyor has thirty receptacles.) The vials
and the receptacles are keyed so that the vials proceed along the
processing path in the proper orientation, and cannot rotate
independently of its respective receptacle. They first pass a bar
code reader (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
including a cap disposal operation; a primary mixing or dispersal
station; a filter loading station; a specimen acquisition and
filter disposal station; a cell deposition station; and a
re-capping station. There is also a slide presentation station, at
which a fresh microscope slide is presented to the specimen
acquisition station for transfer of the specimen to the slide. Each
of the stations operates independently on the vial presented to it
by the conveyor, but the conveyor will not advance until all of the
operating stations have completed their respective tasks.
[0018] The vial uncapping station has a rotary gripper that
unscrews the cover from the vial, and discards it. Before doing so,
however, the uncapping head presses on the center of the cover to
detach the internal processing assembly from the cover. The primary
mixing station 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 dispenses a specimen-specific
filter type into a particulate matter separation chamber (manifold)
at the top of the processing assembly. The specimen acquisition
station 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 monolayer of cells on the bottom surface of the
filter. Thereafter the monolayer specimen is transferred to a fresh
slide, and the vial moves to the re-capping station, where a foil
seal is applied to the vial.
[0019] An improved filter system ensures that the highest quality
monolayer specimens are produced. Specimen liquid flows through the
filter as well as substantially across the front surface of the
filter. Specifically, the specimen liquid is made to have a
secondary flow component across the filter surface. The secondary
flow is designed to flow radially outwardly or have a substantial
radial component, which creates a shearing action that flushes or
washes clusters of relatively weakly adhering particulates so that
a more uniformly distributed and thinner layer can be formed on the
front surface of the filter. In this respect, the present system
includes a peripheral outlet through which specimen liquid can flow
from the area adjacent the front surface of the filter.
[0020] The filter assembly preferably has a holder, a frit seated
in the holder, and a membrane filter positioned over and in contact
with the outer surface of the frit. The frit can extend beyond the
end of the holder. The membrane filter can be attached to the
holder. The sidewall portion extending beyond the holder forms an
area through which the specimen liquid can flow, creating a
secondary flow. The holder can be configured so that the frit is
slightly bowed outwardly at the center so that when pressure is
applied to a slide during the specimen transferring step, the
central portion of the frit flattens to more evenly contact the
membrane filter to the slide for more effective transfer.
[0021] The manifold at the upper end of the processing assembly
seats the filter assembly with the membrane filter side facing
down. The manifold preferably has a substantially conically
configured bottom wall that rises from the central inlet (which
communicates with the depending suction tube portion of the
processing assembly). The filter assembly and the conically
configured bottom wall form a manifold chamber that has a slight
gap at its periphery, forming a peripheral outlet, by virtue of
raised members or standoffs that act as spacers. The standoffs can
have channels between them through which the specimen liquid can
flow out of the manifold chamber.
[0022] Various preferred materials and possible alternatives are
specified herein for several components of the system. It is to be
understood that material choices are not limited to the specific
materials mentioned, and that the choice of an alternate material
is governed by many factors, among them functionality, molding
accuracy, durability, chemical resistance, shelf life, cost,
availability, and/or optical clarity (e.g., to address user
requirements or marketing issues).
[0023] In its most basic aspect the invention claimed herein is
directed to a method of storing and dispensing articles one at a
time from the bottom of a stack of like articles. The articles are
yieldably supported in an upright stack above an outlet sized to
pass the articles if forced therethrough. Dispensing is
accomplished by pressing downwardly on the stack of articles with
sufficient force and for sufficient duration to overcome the
yieldable supporting force and move the lowest article through the
outlet. Articles can also be stored in a plurality stacks, each
stack consisting of like articles. In that case the method involves
the initial step of moving a selected stack into a dispensing
position.
[0024] Another aspect of the claimed invention involves apparatus
for carrying out the above methods. The articles to be dispensed
are stored in a holder having a bottom dispensing outlet with a
resilient choke configured to support and retain the stack of
articles under their own weight. The choke deflects to permit
articles to pass through the outlet when the stack is pressed
downwardly. A pusher mechanism has a pusher member mounted for
vertical movement to press down on the stack of articles. A
controller responsive to an input signal advances the pusher member
sufficiently to force the lowest article in the stack past the
choke and through the outlet.
[0025] The holder may take the form of a tube having a longitudinal
slot through which an arm of the pusher member extends laterally
into the tube. The choke may have fingers formed by a plurality of
slits at the bottom of the tube. A sensor connected to the
controller senses the passage of one article through the outlet to
arrest further movement of the pusher member. Other sensors may be
provided for sensing when the tube is empty, and for sensing the
type of article in the tube. These latter sensors are especially
useful in apparatus having a plurality of holders mounted, for
example, on a rotatable turret, whereby the proper stack of
articles is moved into the dispensing position for engagement by
the pusher member.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0026] Preferred embodiments of the disclosed system and the
invention, 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, in which:
[0027] FIG. 1 is a vertical sectional view through a specimen vial
for use with the LBP device, showing the processing assembly
(stirrer) in the vial coupled to the cover;
[0028] FIG. 2a is a front elevational view of the container portion
of the vial;
[0029] FIG. 2b is a top plan view of the container, shown with the
stirrer removed;
[0030] FIG. 3 is a top plan view of the stirrer;
[0031] FIG. 4 is a bottom plan view of the liner that fits within
the cover;
[0032] FIG. 5 is an exploded vertical sectional view of the stirrer
and a filter assembly adapted for use in the stirrer;
[0033] FIG. 6 is a vertical sectional view of the upper portion of
the stirrer, showing the filter assembly in place in the
particulate matter separation chamber;
[0034] FIG. 7a is a partial schematic view of the arrangement
depicted in FIG. 6, showing the flow of liquid and particulate
matter separated therefrom;
[0035] FIG. 7b is a view similar to FIG. 7a, showing liquid flow in
a prior art filter system;
[0036] FIG. 8 is an exploded, cross-sectional view of the filter
assembly;
[0037] FIG. 9 is a schematic illustration of the dimensional
configuration of the flow manifold;
[0038] FIG. 10 is a vertical sectional view of the specimen vial
similar to FIG. 1, but showing the stirrer detached from the
cover;
[0039] FIG. 10a is a partial vertical sectional view similar to
FIG. 10, showing a modification of the stirrer;
[0040] FIG. 11 is a top plan view of the LBP device;
[0041] FIG. 11a is a schematic diagram of the operating sequence of
the LBP device;
[0042] FIG. 12 is a front perspective view of the LBP device, with
certain parts removed for clarity;
[0043] FIG. 13 is a rear perspective view of a portion of the LBP
device, showing the auto loader/unloader mechanism;
[0044] FIG. 14 is a top plan view of the auto loader/unloader
mechanism;
[0045] FIG. 15 is a front elevational view of the auto
loader/unloader mechanism;
[0046] FIG. 15a is a detail sectional view taken along line 15a-15a
in FIG. 14;
[0047] FIG. 16 is an elevational view of an alternative embodiment
of a gripper for the auto loader/unloader mechanism;
[0048] FIG. 17 is a perspective view of a specimen vial tray used
in the auto loader/unloader mechanism;
[0049] FIG. 18 is an enlarged detail view taken at encircling line
18 in FIG. 17;
[0050] FIG. 19 is a bottom perspective view of the specimen vial
tray of FIG. 17;
[0051] FIG. 20 is a perspective view of three stacked specimen vial
trays;
[0052] FIG. 21 is a block diagram showing specimen vial handling
and data flow;
[0053] FIG. 21a is a pictorial diagram showing an overall
laboratory system incorporating the LBP device;
[0054] FIG. 21b is a relational database table;
[0055] FIG. 22 is a block diagram showing a computer or work
station;
[0056] FIG. 23 is a facsimile of a computer screen;
[0057] FIG. 24 is a facsimile of another computer screen;
[0058] FIG. 25 is a facsimile of two computer screens;
[0059] FIG. 26 is a vertical sectional view of a specimen vial
being uncapped;
[0060] FIG. 27 is a front elevational view, partly in section, of a
specimen vial engaged by the uncapping head of the LBP device;
[0061] FIG. 28 is a top plan view of the uncapping head, taken
along line 28-28 in FIG. 27;
[0062] FIG. 29 is a side elevational view of the uncapping station
of the LBP device;
[0063] FIG. 30 is a sectional view taken along line 30-30 in FIG.
29;
[0064] FIG. 31 is a top plan view of the uncapping station of FIG.
29;
[0065] FIG. 32 is a vertical sectional view of a specimen container
showing engagement by the primary stirring head;
[0066] FIG. 33 is a side elevational view of the primary stirring
station of the LBP device;
[0067] FIG. 34 is a front elevational view of the primary stirring
station;
[0068] FIG. 35 is a top plan view of the primary stirring
station;
[0069] FIG. 36 is a vertical sectional view of a specimen container
during filter loading;
[0070] FIG. 37 is a side elevational view of the magazine portion
of the filter loading station of the LBP device;
[0071] FIG. 38 is a front elevational view of the pusher portion of
the filter loading station;
[0072] FIG. 39 is a top plan view of the pusher portion of the
filter loading station;
[0073] FIG. 40 is a top plan view of the magazine portion of the
filter loading station;
[0074] FIG. 41 is a vertical sectional view of a specimen container
during specimen acquisition;
[0075] FIG. 42 is a vertical sectional view of a specimen container
during specimen transfer to a slide;
[0076] FIG. 43 is a side elevational view of the specimen
acquisition station of the LBP device;
[0077] FIG. 44 is a front elevational view of the lower portion of
the specimen acquisition station;
[0078] FIG. 45 is a top plan view of the specimen acquisition
station, partly in section, taken along line 45-45 in FIG. 43;
[0079] FIG. 46 is a top plan view of the specimen acquisition
station;
[0080] FIG. 47 is a schematic of a bubble flow meter used in the
specimen acquisition station;
[0081] FIG. 47a is a schematic of a modification of the flow meter
of FIG. 47;
[0082] FIG. 48 is a schematic of a vacuum system used in the
specimen acquisition station;
[0083] FIG. 49 is an operation chart for the vacuum system of FIG.
48;
[0084] FIG. 50 is a front perspective view of the re-capping
station of the LBP device;
[0085] FIG. 51 is a side elevational view of the re-capping
station;
[0086] FIG. 52 is a front perspective view of a slide cassette used
in the LBP device;
[0087] FIG. 53 is a detail perspective view of the slide cassette
taken from FIG. 52;
[0088] FIG. 54 is a rear perspective view of the slide
cassette;
[0089] FIG. 55 is a side elevational view of the slide
cassette;
[0090] FIG. 56 is a top plan view of the slide presentation system
of the LBP device; and
[0091] FIG. 57 is a side elevational view of the slide presentation
system.
DETAILED DESCRIPTION OF BEST MODE
[0092] A full description of this vial-based specimen handling and
processing system must begin with the vial itself, which consists
of a container, a cover and a processing assembly (stirrer) in the
vial.
Specimen Vial
[0093] Referring to FIGS. 1, 2a and 2b, the vial 10 comprises a
container 20, a cover 30 and a processing assembly 40. Processing
assembly 40 is designed to carry out several functions, among them
mixing, and for this preferred rotary embodiment will be referred
to as a stirrer for the sake of convenience. Container 20
preferably is molded of a translucent plastic, preferably
polypropylene, and has a substantially cylindrical wall 21,
surrounding its longitudinal axis, joined to a conical bottom wall
22. Possible alternative plastics include ABS and
polycyclohexylenedimethylene terephthalate, glycol (commercially
available from Eastman Kodak Co. under the name EASTAR.RTM. DN004).
A small portion 24 of wall 21 preferably is flat, the outer surface
of the flat portion adapted to receive indicia, e.g., a bar code
label, containing information concerning the specimen placed in the
vial. Although only one flat portion is shown, the container could
be configured without a flat portion, or with two or more flat
portions, each adapted to receive indicia. Alternatively, the
indicia could be located on a curved portion of wall 21. The bottom
end of flat portion 24 has an arcuate notch 25 which acts to keep
the container in a proper orientation when handled by the LBP
device, which as noted is designed to cradle the container and move
it through various processing stations. A differently shaped notch
(e.g., V-shaped) can be used as long as the notch properly mates
with the LBP device. Other suitable mating structures can be used
instead.
[0094] Four longitudinal ribs 26 project inwardly from wall 21. The
upper ends 27 of ribs 26 form rests for the stirrer 40 when it is
detached from cover 30 (see FIG. 10). The top of container 20 has
an opening 28 and a standard right-hand helical thread 29 that
preferably extends for one and one half turns and mates with a
similar thread on cover 30. Other types of cover-to-container
coupling may be used, such as a bayonet coupling, snap-fit
arrangement, etc.
[0095] Cover 30 comprises a commercially available simple molded
plastic threaded cap 31, and a novel liner 32 retained in the cap.
Cap 30 preferably is molded of polypropylene, but ABS and
EASTAR.RTM. DN004, among others, are alternative plastic material
choices. Cap 31 has a flat solid top, and an externally knurled
depending flange with an internal helical thread 33 that mates with
thread 29 on container 20. Referring to FIG. 4, liner 32 is molded
of plastic material, preferably polyethylene, and has a
substantially flat base 34 sized to fit snugly within cap 31,
behind thread 33, so that the liner is not readily separated from
the cap. As seen in FIG. 1, liner base 34 serves as a gasket-type
seal between the cap 31 and the rim of the container wall 21.
[0096] Liner base 34 has a coupler in the form of an annular
projection 35 that preferably is slightly conical in shape,
preferably forming an angle of about 5.degree. to its central axis.
In other words, the inner diameter of annular coupler 35 is greater
at its proximal end, where it joins liner base 34, than at its
distal end. Liner base 34 also has a central annular boss 36 that
projects further from base 34 than annular coupler 35 so as to
interact with stirrer 40, as described below. While the use of a
separate liner mated to a standard cap is preferred, the cover
could be integrally molded in one piece to include the annular
coupler 35 and the central annular boss 36. Such a one-piece cover
(or even the two-piece cover described above) could instead be
configured to act as a plug-type seal by projecting into and
sealing against the inside of the rim of container wall 21.
[0097] Referring to FIGS. 1, 3 and 5, stirrer 40 is molded of
plastic, preferably polypropylene, and has a circular base or
bottom wall 41, sloped at its center, with a central inlet port 42;
a central depending suction tube 43 with two diametrically opposed
suction ports 44 near the bottom of the tube; and a dispersing
(mixing) element in the form of laterally extending vanes 45. The
upper portion of the stirrer 40 has a cup-shaped particulate matter
separation chamber or manifold 46 defined by base 41 and an
upstanding annular wall 47. The upper edges of wall 47 are beveled,
the inner edge 48 preferably being beveled to a greater degree to
facilitate placement of a filter assembly F in manifold 46, as
described below. Possible alternative plastic material for the
stirrer include ABS and EASTAR.RTM. DN004.
[0098] Annular wall 47 serves as a coupler for releasably coupling
the stirrer 40 to cap liner 32, and is therefore dimensioned to fit
snugly within annular coupler 35 (see FIG. 1). Specifically, there
is a friction or press fit between couplers 35 and 47 such that
normal handling of the closed vial, and normal handling of cover 30
when removed from container 20 (e.g., to place a biological
specimen in the container) will not cause separation of the stirrer
from the cover. Coupler 47 is dimensioned relative to coupler 35 so
that there is a very slight initial diametrical interference,
preferably about 0.31 mm. Coupler 47 is stiffer than coupler 35, so
assembly of the stirrer to the cover involves slight deformation
principally of coupler 35, resulting in a frictional force that
keeps the stirrer and the cover engaged. Application of an external
force to the vial that overcomes this frictional retention force
will cause stirrer 40 to detach from cover 30 and drop by gravity
further into container 20 (see FIG. 10).
[0099] The external separation force preferably is applied to the
central portion of cover 30 (see the arrow in FIG. 10), which
deflects cap 31 and liner 32 inwardly. As illustrated in FIG. 1,
central boss 36 on liner 32 is dimensioned such that its distal end
just contacts or lies very close to base 41 of the stirrer. Thus,
when the central portion of the cover is depressed, central boss 36
will deflect further than annular coupler 35 on liner 32 and push
stirrer 40 out of engagement with coupler 35. Inward deflection of
liner 32 also causes coupler 35 to spread outwardly, thereby
lessening the retention force and facilitating detachment of the
stirrer. The separation force applied to cover 30 and required to
detach the stirrer should be in the range of 5 to 30 lbs.,
preferably about 12 lbs.
[0100] Once detached from the cover 30, stirrer 40 comes to rest on
the upper ends 27 of ribs 26. See FIG. 10. The particulate matter
separation chamber (manifold) 46 thus is stably supported near the
container opening and easily accessed by the LBP processing heads,
which will manipulate the stirrer so as to process the specimen
directly in the container. At least three ribs 26 are required to
form a stable support for the stirrer, but four are preferred
because that number seems to promote more thorough dispersion of
the particulate matter in the liquid during stirring. Should the
stirrer inadvertently become detached from the cover at the
point-of-care site, the physician or an assistant simply places the
stirrer loosely in the vial so that it descends into the specimen
and then screws the cover on as usual. This is not difficult
because the ribs in the vial allow insertion of the stirrer in only
one direction. Once the vial is closed with the specimen inside,
the stirrer remains in the vial throughout processing and is sealed
therein when the vial is recapped.
[0101] A small percentage of patient specimens, as may be found in
gynecological Pap test and other specimen types, contain large
clusters of cells, artifacts, and/or cellular or noncellular
debris. Some of these large objects, if collected and deposited on
a slide, can obscure the visualization of diagnostic cells and,
consequently, result in a less accurate interpretation or diagnosis
of the slide sample. Since most of these features are not of
diagnostic relevance, their elimination from the sample is, in
general, desirable. To achieve this result, the side suction ports
44 in the stirrer suction tube 43 preferably are eliminated (see
FIG. 10a) in favor of close control of the interface between the
bottom of the suction tube 43 and the small projection 23 at the
center of bottom wall 22 of the container 20. This interface
effectively forms a metering valve whose geometry (orifice) 23a is
created when the stirrer 40 rests on the ribs 26 of the container
20 (see FIG. 10). Proper sizing of the annular flow orifice 23a
prevents large objects from entering the suction tube 43, while
allowing the passage of smaller objects that may be diagnostically
useful. While the orifice 23a has a thin passage section and a
small metering area, clogging is not an issue due to its large
diameter. The annular orifice 23a preferably has an outside
diameter on the order of 0.105 in. and an inside diameter on the
order of 0.071 in., yielding a passage width on the order of 0.017
in. This orifice size is optimized for gynecological specimens.
Filter System
[0102] FIGS. 6 and 8 illustrate one embodiment of a filter assembly
F according to the present invention. FIGS. 3 and 6 illustrate one
embodiment of a manifold 46 (in stirrer 40) according to the
present invention. The filter system includes the filter assembly F
and the manifold 46.
[0103] Referring to FIGS. 6 and 8, the filter assembly F comprises
a filter housing or holder 200, a porous frit 202, and a porous
membrane filter 205. FIG. 8 shows these components more clearly in
an exploded view. The holder 200 can be cup- or container-shaped,
having a recess or cavity 206 for seating the frit 202 and a
chamber 207 between the frit 202 and the holder 200. The frit 202
and the membrane filter 205 can be made of the materials disclosed
in the Guirguis patents identified above, namely U.S. Pat. Nos.
5,301,685 and 5,471,994, the disclosures of which are incorporated
herein by reference.
[0104] In the present filter assembly F the membrane filter 205,
the frit 202, and the holder 200 are assembled together as a unit.
The frit 202, which has a cylindrical shape, is first seated in the
holder 200. Then the membrane filter 205 is permanently affixed,
adhered, joined, or fused to the holder 200. In the illustrated
embodiment, the outer perimeter or edge of the membrane filter 205
is fused to the holder 200. In this regard, the holder 200 has a
bevel or chamfer 208 formed around an outer circumferential corner
209. The chamfer 208 provides an angled surface to which the
membrane filter 205 can be attached using a conventional bonding
technique, such as ultrasonic welding. The holder 200 and the
membrane filter 205 should be made of materials that will fuse
together. Preferably both are made of polycarbonate, although an
ABS holder will work with a polycarbonate membrane filter.
Thermoplastic polyester could be used for the holder if the
membrane filter is made of the same material. The frit 202
preferably is made of polyethylene.
[0105] Referring to FIG. 8, the holder 200 preferably is
cylindrical and comprises a substantially cup-shaped body having a
bottom wall or base 210 and a substantially upright cylindrical
sidewall 211 extending therefrom and terminating in a rim 211a. The
sidewall 211 has an annular shoulder 212 extending radially
inwardly, toward the center. The shoulder 212 acts as a seat that
accurately positions the frit 202. Frit 202 preferably is
dimensioned so that the frit's outer or front face 213 is proud of
(extends beyond) the rim 211a when the peripheral portion of the
frit's rear face abuts the shoulder 212.
[0106] The inner diameter of the sidewall 211 can be dimensioned to
frictionally engage and hold the frit 202 in place. In this
respect, the frit's outer diameter can substantially correspond to
the inner diameter of the sidewall 211 to mechanically, i.e.,
frictionally, hold the frit 202 in place. However, since the
membrane filter 205 covers the frit 202, the frit need not be
frictionally held to the holder. That is, the frit 202 can be
loosely seated in the holder. Frictionally seating the frit 202 in
the holder 200, however, maintains the frit 202 in place so that
attachment of the member filter 205 can be done at a remote site.
It also simplifies and reduces the cost of mass production of
filter assemblies because the holder 200 and the frit 202 can be
joined to make a secure subassembly and stored for later attachment
of the membrane filter 205.
[0107] After the frit 202 is seated in the holder 200, the membrane
filter 205 is draped over the frit's outer face 213 and the exposed
portion 214 of the frit's side wall 215 that extends beyond the
holder 200, and is attached to the chamfer 208, as is better seen
in FIG. 6. The frit's exposed outer sidewall portion 214 provides
an annular surface area through which the specimen liquid can flow
to provide a dual flow path, as schematically illustrated in FIG.
7a.
[0108] The filter assemblies F can be coded to denote different
pore size and pore density (number of pores per unit
cross-sectional area) as may be required for specific processing
protocols. Color coding of filter assemblies is preferred, although
any form of machine-detectable coding can be used, including
distinguishing projections, such as small nipples, for
tactile-based sensor recognition. The LBP device is provided with a
sensor that can discriminate between these colors or other codes to
ensure proper filter selection. The filter assemblies also can be
provided in paper carriers for easy insertion into the LBP
device.
[0109] Referring back to FIG. 8, the holder's bottom wall 210 has a
central opening 204 through which vacuum can be applied to draw
specimen liquid therethrough. The holder 200 further includes a
central projection or protrusion 216 extending into the holder from
the bottom wall 210. The central protrusion 216 is aligned with the
opening 204 and positioned in the chamber 207, which is defined by
the frit's inner face 218, the inner face 219 of the bottom wall
210 and the inner side 220 of the sidewall 211. The protrusion 216
is substantially hollow and has a plurality of side openings 221
that distribute vacuum to the chamber 207 and provide a
substantially symmetrical flow through the chamber. The specimen
liquid drawn through the membrane filter 205 and the frit 202 fills
the chamber 207 and exits the chamber 207 through the side openings
221 and the central opening 204.
[0110] The protrusion 216 has an abutting surface 217 that faces
and extends toward the holder's open face. The abutting surface 217
is configured to abut against the frit's rear face 218. In
particular, the abutting surface 217 is slightly proud of the
annular shoulder 212. That is, the abutting surface 217 lies
slightly above or beyond the level of the annular shoulder 212 so
that the frit's outer face 213 bows slightly outwardly when the
frit is installed in the holder. For example, the abutting surface
217 can extend beyond the height of the annular shoulder 212 by
about 0.002 inch. The resulting slight bow created by the
protrusion pushing out the central portion of the frit 202 ensures
that the central part of the membrane filter 205 contacts the
slide. The pressure applied to the slide during imprinting flattens
the frit's front surface 213, ensuring full contact of the membrane
filter 205 with the slide to more effectively transfer the
collected particulates to the slide and minimizing any deposition
artifacts. If this slightly bowed configuration is desired, the
frit 202 preferably is securely seated in the holder 200, such as
by friction as previously explained.
[0111] Due to the bowed frit configuration, the membrane filter 205
need not be taut. This simplifies the manufacturing process,
reduces cost, and reduces the rejected part rate. Anything short of
a major wrinkle can work effectively. As noted, the frit 202
preferably is slightly deformable, its compliance allowing it to
flex and flatten against a glass slide post aspiration to transfer
cells and other objects of interest from the filter to the slide.
To accomplish this the frit should have an elasticity that allows
it to be crushed flat by application of a force of 8 lbs. through a
displacement of 0.0016 in. Good frit materials include sintered
polyethylene and sintered polyester. The frit 202 may be a porous
material, with spatially random pores, typically with pore sizes in
the range of about 50-micrometer to 70-micrometer. A significant
attribute of this material is that it is of low fluidic impedance
relative to the material of the thin membrane filter 205 (which
typically has pore sizes of about 5-micrometer to 8-micrometer). In
other words, the pressure drop across the frit 202 is much less
than the pressure drop across the membrane filter 205. Thus, fluid
that passes through the filter flows freely through the frit.
Alternatively, instead of having randomly positioned pores, the
frit 202 may be made of a material or structure that has many
parallel channels of small (e.g., 50-micrometer to 70-micrometer)
inner diameters through which aspirated fluid and particulates may
flow. Such a parallel-channel arrangement would behave as an inner
fluid-pervious medium with an apparent low fluidic impedance. In
fact, any material or device with the proper low fluidic impedance
and deformability/resilience characteristics may be used in the
specimen acquisition station, whether it has pores or not.
[0112] It has been found that flowing the specimen liquid
substantially or mostly in an axial direction, i.e., perpendicular
to the membrane filter, can accumulate layers or clusters of
particulates, as schematically illustrated in FIG. 7b, particularly
if the vacuum is applied through the membrane filter for a longer
period than necessary. This can happen even with the Guirguis dual
flow design, which provides some secondary flow components that are
radially directed. See, for example, FIGS. 4 and 12 of Guirguis'
U.S. Pat. Nos. 5,471,994 and 5,301,685. It seems that the secondary
flow generated by that configuration is insufficient to create an
effective flushing, or shearing action across the membrane filter.
An earlier Guirguis patent, namely U.S. Pat. No. 5,137,031,
discloses a funnel- or cone-shaped manifold. In that arrangement,
however, there is no secondary radial outflow at its periphery. As
there is no flow other than directly through the filter itself,
there is no substantial radial flow component. Accordingly, the
specimen liquid only flows substantially perpendicularly to the
membrane filter.
[0113] Referring to FIG. 6, the inner diameter of the upright wall
47 of the manifold 46 at the top of stirrer 40 is dimensioned to be
slightly larger than the outer diameter of the filter assembly F,
namely the holder's sidewall 211, so that the manifold 46 can
receive and seat the filter assembly F, with the membrane filter
205 facing down, as illustrated. The filter assembly F can be
loosely seated in the manifold 46. When the filter assembly F is
seated in the manifold 46, the outer peripheral edge of the
membrane filter 205 rests on the bottom wall 41. The bottom wall 41
is configured to have a well or recess that forms a manifold
chamber M when the filter assembly F is seated in the manifold 46.
The chamber M is thus bounded by the outer surface of the membrane
filter 205 and the upper surface 41S of the bottom wall 41.
[0114] The present dual flow arrangement solves the problem of
particulate build-up or accumulation on the face of the membrane
filter. This arrangement causes a shearing force or action across
the front face of the membrane filter that is sufficient to flush
the particulates aside and keep them from building up or layering.
Built-up or layered particulates have a weaker bond to the layer
underneath them as they build up, because the suction power
decreases as the pores of the membrane filter 205 become covered
with particulates. A shearing force is created by imparting a
tangential or substantially radial flow component to the specimen
liquid across the front face of the membrane filter 205. This flow
component is substantially parallel to the front face of the
membrane filter, i.e., it is perpendicular to the built-up
direction of the layers, and flushes the particulates radially
outwardly, away from the front face of the membrane filter.
[0115] To provide a secondary or radial flow path, the manifold 46
is configured to provide a small spacing or gap G (see FIG. 6) at
the periphery of the manifold chamber M, between the front face of
the membrane filter 205 and the upper surface 41S of the bottom
wall 41, to allow flushed particulates to exit the manifold chamber
M, away from the front face of the membrane filter. The gap G must
be large enough to prevent the particulates from clogging it. That
is, if the gap G is made too small for the particulates being
filtered, the gap G can get clogged, cutting off the secondary
flow. The minimum size of the gap ultimately depends on the
particulate size, the viscosity of the specimen liquid, and the
temperature of the specimen liquid. It has been determined that the
gap G should be at least 0.004 in. to prevent clogging by cellular
particulates.
[0116] Referring to FIGS. 3 and 6, to create the gap G, which forms
an outflow nozzle, the bottom wall 41 of manifold 46 includes a
plurality of spaced standoffs or raised ribs 48a around the
periphery of the manifold 46. The spaces 49 between the ribs 48a
provide a passage for specimen liquid to exit the chamber M. In the
illustrated preferred embodiment, the manifold 46 has an inner
diameter of 23.4 mm, and has thirty-six ribs 48a, evenly spaced at
10.degree.. The ribs are 0.150 mm high and arcuately blend into the
surrounding shoulder with a radius R of 0.63 mm, as illustrated. Of
course, the present invention contemplates other configurations of
spaced ribs or standoffs, which are intended to precisely space the
filter assembly from the bottom wall 41 so that a precise outflow
area is created. Depending on the number and thickness of ribs or
standoffs, the total outflow area can be reduced as much as 50% as
compared to the inlet area.
[0117] It has been observed in the Guirguis type filter arrangement
referred to above that specimen liquid traveling radially outwardly
loses velocity. The present dual flow filter system compensates for
the velocity slowdown by providing a shallow, substantially conical
surface across which the specimen liquid flows. This surface forms
a substantially conical distribution manifold chamber M confronting
the membrane filter 205. The chamber M according to the present
invention has an annular radial outlet O, through spaces 49, having
an area that is about equal to or smaller than the maximum area of
the central inlet I. Referring to FIG. 9, the "face" area of the
radially directed annular flow passage is cylindrical and is
defined (bounded) at any given radius R.sub.1, R.sub.x, R.sub.y, .
. . , R.sub.2 by the front surface of the membrane filter 205 and
the conical surface 41S of the manifold. As the specimen liquid
travels outwardly, the radius increases while the manifold height
decreases. The manifold chamber M can be configured so that the
height H.sub.1, H.sub.x, H.sub.y, . . . , H.sub.2 decreases at a
rate which maintains the face area of the annular passage
substantially uniform from the inlet I to the outer perimeter
outlet O of the manifold, yielding a substantially linear radial
flow velocity across the face of the membrane filter 205.
[0118] In this regard, still referring to FIG. 9, the maximum
theoretical radial flow area of a round manifold inlet I can be
defined as the circumference (2.pi.R.sub.1) multiplied by the
height of the manifold chamber H.sub.1. In this instance,
2.pi.R.sub.1H.sub.1 defines the total circumferential area of the
manifold inlet I. The maximum circumferential flow area of a round
manifold outlet O can be defined as 2.pi.R.sub.2H.sub.2. If the
outlet flow area is to equal the inlet flow area, then the inlet
and outlet areas can be expressed as:
2.pi.R.sub.1H.sub.1=2.pi.R.sub.2H.sub.2
R.sub.1H.sub.1=R.sub.2H.sub.2
[0119] Using this expression, the heights, e.g., H.sub.x, H.sub.y,
can be defined at their given radii, e.g., R.sub.x, R.sub.y from
the inlet I to the outlet O. If the heights H.sub.1, . . . ,
H.sub.x, . . . , H.sub.y, . . . H.sub.2 from the inlet to the
outlet are plotted, the resulting surface 41S would be curved, not
linear. However, it has been observed that a significantly curved
lower manifold surface does not work as effectively as a linear
surface 41S. Accordingly, the present preferred embodiment
contemplates a linear or substantially or nearly linear surface 41S
(which can be slightly curved) extending from the inlet to the
outlet. Also, there is a minimum height H.sub.2 of about 0.006 inch
clearance for the specimen liquid to effectively flow. Based on
this requirement, the minimum R.sub.1 can be defined as
0.006R.sub.2/H.sub.1 inches. With this configuration, as the
specimen liquid is drawn through the filter, the specimen liquid
traverses the front face of the membrane filter 205 in a direction
that is substantially parallel to or approaching nearly parallel to
the front face of the membrane filter, creating the desired
shearing action.
[0120] Empirical study has revealed that for a linear conical
surface 41S, the area of the outlet O preferably should be less
than or equal to the maximum area of the inlet I. That is,
R.sub.1H.sub.1 R.sub.2H.sub.2. For example, the exemplary manifold
can have the following dimensions (all units here in mm):
R.sub.1=1.24, H.sub.1=1.32, R.sub.2=10.00, H.sub.2=G=0.15. The
maximum inlet area would thus be 3.27.pi. mm.sup.2 and the outlet
area 3.007.pi. mm.sup.2, which is slightly less than the maximum
inlet area, but greater than the average inlet area, which can be
defined as 50% of the maximum inlet area (1.64.pi. mm.sup.2). Thus,
the outlet area can fall between the maximum inlet area and the
average inlet area. Another example can have the following
dimensions (all units here in inches): R.sub.1=0.040,
H.sub.1=0.060, R.sub.2=0.400, H.sub.2=0.006. The maximum inlet area
would thus be 0.0048.pi. in.sup.2, which is equal to the outlet
area.
[0121] In summary, the manifold chamber M that confronts the
substantially flat membrane filter should have a shallow,
funnel-shaped configuration and a peripheral outlet so as to create
a substantial radial flow across the outer surface of the membrane
filter. The radial flow creates a shearing action that washes or
flushes away any particulates that are relatively weakly attached
so as to leave a very thin layer of particulates--a monolayer--on
the surface of the membrane filter.
LBP Device and Method
[0122] FIGS. 11-57 illustrate a preferred embodiment of an LBP
device according to the present invention. The LBP device is an
automated machine for preparing slides for viewing, imaging or
optical analysis. The LBP device can use the above-described dual
flow filtering system (FIGS. 6, 7a, 9) to collect monolayers or
thin layers of cells and transfer them onto slides.
[0123] Referring to FIG. 11, the illustrated embodiment of the LBP
device can be compartmentalized into at least six discrete
processing stations: data acquisition station (bar code reader)
230; uncapping station 400; primary stirring station 500; filter
placement station 600; specimen acquisition station 700; and
re-capping station 800. These six stations are structured for
parallel processing, meaning that all these stations can operate
simultaneously and independently of the other. The LBP device also
includes a separate data reading station, a slide presentation
station, a slide handling station, and a cassette handling station,
all of which can be incorporated as an integrated system 900. The
LBP device further includes a transport mechanism 240 for moving
the specimen containers to the various operating stations. It can
further incorporate an auto loading mechanism 300 that
automatically loads and unloads specimen vials onto and from the
transport mechanism. All stations are computer-controlled. FIG. 11a
shows the operating sequence of the LBP device. This is the
top-level table from which the operating software is
structured.
[0124] FIG. 12 shows the basic structural elements of the LBP
device, namely a frame 260 preferably made of extruded aluminum,
preferably on casters (not shown) for mobility, and a machined
aluminum base plate 262 supported by the frame and on which the
main operating mechanisms are mounted. Beneath the base plate is a
compressor 264 for supplying compressed air for powering some of
the components; a vacuum pump (not shown) which provides a vacuum
source for various components; stainless steel shelves for holding
the vial trays used in the auto loading mechanism 300; and
electrical components, including power supplies and controllers,
and miscellaneous equipment. A compressor would not be required if
electrically-powered actuators were used instead of air-powered
actuators. A user interface, e.g. a touch-sensitive LCD display
(not shown), is mounted to the left of the transport mechanism 240
and gives the technician control over machine operation beyond the
normal automated processing protocols. See FIG. 25, which shows
examples of a log-in screen (top) and a navigation screen (bottom)
as they might appear on the user interface. Of course, other
screens would be presented to the user as he/she interacts with the
user interface.
[0125] An "economy" version of the LBP device can take the form of
a counter-top model for processing a more limited number of
specimens at a time. In such a model certain components can be
eliminated, such as frame 260 and auto loading mechanism 300, while
other components can be scaled back, such as the capacity of filter
placement station 600. External sources of vacuum and compressed
air could be used to power such a device, while other components
(power supplies, controllers, etc.) could be repositioned to one or
more modules adjacent to or on a modified machine base plate.
Various ways of implementing these modifications will be readily
apparent to those skilled in the art.
[0126] Transport Mechanism
[0127] Referring to FIG. 11, the transport mechanism 240 comprises
an endless link-belt conveyor 242 driven by a stepper motor (not
shown) around precision sprockets 242, 244. The conveyor has a
plurality of receptacles or carriers 246, linked by pins 248, for
receiving a corresponding number of specimen vials. The illustrated
embodiment in FIG. 11 has 30 receptacles, numbered 1 through 30.
Depending on the sample vial size and the length of the conveyor,
the LBP device can use fewer than or greater than 30 receptacles,
as desired or feasible, sufficiently long to permit all processing
to be completed in a single line.
[0128] The receptacles 246 of the link-belt conveyor are guided
between the sprockets by pairs of guide rails 250 forming tracks,
and has a conventional position correction system (not shown) to
accurately position the receptacles. The LBP device can track the
position of each receptacle and step-drive or index them in a
conventional manner. For instance, the LBP device can include
linear position sensors, such as optical sensors or a
photo-interrupter on each link, that can feed the position to a
controller for registering carrier position and precisely indexing
each carrier at each of the processing stations along the
processing path. The manner of driving the conveyor for precise
alignment and positioning is conventional and thus will not be
described further.
[0129] The guide rails 250 that form tracks in Z and Y axes engage
slots machined in the sides of the receptacles. See, for example,
FIGS. 29, 33, 37 and 43. The mechanical tracks and drive sprockets
can be constructed of a self-lubricating plastic for operation
without the need to add an external lubricant. The receptacles 246
each can have a window 247 (see FIG. 12) for allowing access to
laser or optical scanning of the bar code on the specimen
containers. The conveyor can be hard-coated aluminum,
.RTM.-impregnated with PTFE7 for easy cleaning. The link pins 248
can be precision ground and hardened. The link pins can be axially
fixed in location in the non-rotating link bore. Rotating link
bores can be fitted with a suitable bearing material capable of
operation without additional lubricant. For operator safety, the
conveyor operation can be interlocked with the cover of the machine
(not shown).
[0130] The receptacles 246 are also configured so that they receive
or seat the specimen vials in a particular orientation. That is,
the specimen vials and the receptacles are complementarily
configured or keyed so that the vials can only be seated in the
receptacles in a particular orientation. For example, the vials can
be "D" shaped, namely having a flat side (see FIGS. 2a, 2b), and
the receptacles can be "D" shaped so that the flat sides align with
each other. In this way the vials do not rotate relative to the
receptacles, while allowing unrestricted vertical movement relative
to the receptacles. In addition to the D shape, each vial can have
a bottom notch 25 (see FIG. 2a), and the receptacles can have a
mating peg or stud (not shown) that keys into the notch 25. While
the illustrated notch and peg are arcuate, they can take on other
mating shapes (e.g., V-shaped).
[0131] Vial Loading/Unloading Mechanism
[0132] FIGS. 12, 13 and 14 show the automated vial loading and
unloading mechanism 300. A pivoted pick-and-place arm 304 is
mounted on an elevator carriage 306 driven by a vertical (Y-axis)
lead screw motor 308 atop a vertical standard 310. Arm 304 has a
conventional electrically- or pneumatically-operated jaw-type
gripper 312 adapted to grasp and move specimen vials 10 in three
degrees of freedom. Arm motion in horizontal planes is afforded by
lateral lead screw motor 314, which is pivotally mounted in a
clevis-type bracket 316 to elevator carriage 306. Instead of a
jaw-type gripper as shown, the pick-and-place arm can be equipped
with a conventional pneumatically operated suction-head type
gripper as shown in FIG. 15. Such a gripper has a silicone rubber
bellows 318 which seals against the cover 30 of a vial when placed
against the cover and subject to suction through a suction line
320. Whether mechanical or pneumatic, actuation of the gripper is
accomplished through the programmed operation of the machine as is
understood by those skilled in the art.
[0133] Referring to FIGS. 17-20, specimen vials 10 are stored in
special injection molded plastic vial trays 330 that slide into the
machine on shelves 320 (see FIG. 12). To avoid confusion, it should
be pointed out that FIGS. 13-15 show a different form of tray (made
of stamped steel), but the operation of the mechanism that rotates
the trays, regardless of their construction, is the same. The
plastic vial trays 330 are the preferred form, and are preferably
made of polypropylene. The term "tray" as used herein is not
limited to the embodiments shown, and should be construed to cover
any type of carrier, rimmed or rimless, that can support and move a
generally planar array of discrete articles generally in the manner
described herein.
[0134] Each tray 330 has forty-one circular recesses 332 sized and
configured to receive specimen vials 10 only in one orientation.
The upper edge of each recess 332 preferably has a beveled edge
333, which facilitates smooth insertion of vials. The recesses are
arranged in a close-pack array of four concentric rows, preferably
as follows. The outermost row has sixteen recesses; the next row in
has eight recesses; the third row in has nine recesses; and the
innermost row has eight recesses. The receptacles of adjacent rows
are offset for closer spacing. The receptacles of the second row
are radially aligned with the receptacles of the fourth (innermost)
row. The receptacles of the outermost row are spaced at 18.degree.
on center. The receptacles of each of the other rows are spaced at
36.degree. on center. Of course, other receptacle arrays could be
used as long as they permit access of all vials by the
pick-and-place arm 304. Each receptacle has a unique and
addressable location, so that any vial can be accessed at will and
in any sequence.
[0135] As noted above, orientation of specimen vials during the
processing is critical, so the proper orientation of the stored
vials in these trays ensures that the pick-and-place arm 304 will
properly position each vial in a conveyor receptacle 246.
Accordingly, each recess 332 has at its bottom (see FIG. 19) a
fixed indexing peg 334 that is sized to fit into notch 25 in the
vial. The pegs 334 are installed, e.g., by adhesive, in grooves 335
that are molded into the tray adjacent the bottoms of the recesses
332. Some of the pegs have been omitted from FIG. 19 for
illustrative purposes.
[0136] The pegs 334 are arranged at specific angles with respect to
the median plane of the tray 330 such that each vial removed from
the tray is delivered to a transport receptacle with its notch
aligned with the mating peg in that receptacle, and vice versa.
Each of these angles is dictated by the rotational position of the
tray 330 when a vial in a specific recess 332 is to be accessed by
the pick-and-place arm 304, and the angular rotation of the
pick-and-place arm from the point of vial pick-up to the point of
vial placement in the conveyor receptacle 246. The determination of
these angles is considered to be within the abilities of one of
ordinary skill in the art.
[0137] The tray 330 also has three upstanding guide posts 336, each
with a spring-loaded ball 338 at its tip, which cooperate with
guides (not shown) above each shelf 302 and serve to guide the tray
into the machine as it is inserted and ensure its proper
orientation. The guide posts 336 also serve as stacking posts when
the trays are stacked for storage (see FIG. 20), the balls 338
engaging dimples 339 (see FIG. 19) in the bottom of the superior
tray.
[0138] The tray 330 also has a large flared notch 340 which is
oriented toward the machine when the tray is inserted on a shelf
302. The innermost portion of the notch 340 has opposed keyways 342
which are adapted for engagement by floating keys, as described
below. The keyways preferably are formed in a milled brass hub
insert 343 that is recessed flush with the top of the tray and
secured thereto by screws.
[0139] Referring to FIGS. 14, 15 and 15a, a rotary outer spindle
350 is journaled at its top and its bottom in bearings 352, 354,
respectively. Outer spindle 350 engages and rotates only one tray
at a time so that the pick-and-place arm 304 can access vials
therefrom by moving downwardly through an opening 266 in base plate
262 and past any idle trays via their homed notches 340. FIG. 14
shows the home positions of the trays in dashed lines, with their
notches 340 aligned and embracing outer spindle 350. Spindle 350 is
rotated in a precision manner from the bottom by a
computer-controlled rotation stepper motor 356 and a timing belt
358 engaging timing gears 360, 362. A downwardly facing optical
rotary position sensor 363 located over the aligned tray notches
detects when and how far a tray is rotated from its home position
and provides control feedback for rotation of stepper motor
356.
[0140] Within outer spindle 350 is an inner spindle 364 carrying
eight pairs of opposed keys 365, one pair for each tray. The keys
365 project from outer spindle 350 through opposed slots 366 in the
outer spindle (see FIG. 15a, which is a sectional view through the
spindles and the center portions of the bottom two trays). The
inner spindle 364 is moved vertically within the outer spindle 350
by an internal lead screw 372. Lead screw 372 is rotated by lead
screw stepper motor 374 through a timing belt 376 and timing gears
378, 380. A key "home" sensor 382 (see FIG. 15) is located at the
top of inner spindle 364 to provide a reference point, i.e., when
the machine is turned on, it will "home" the inner spindle to the
key home sensor 382 and then reference its movements from
there.
[0141] The even vertical spacing of the pairs of keys can be seen
in FIG. 15. This spacing, or pitch, differs from the pitch of the
keyways 342 in a full complement of installed trays 330.
Accordingly, which keyways are engaged by the keys depends on the
vertical position of inner spindle, and only one pair of keyways
(tray) can be engaged at any time. The enlarged view of FIG. 15a
shows that the keyways 342 of bottom tray 330-1 are engaged by keys
365, while the keyways of the tray above it, 330-2, are not engaged
by any keys. Movement of inner spindle 364 by one-eighth the pitch
difference disengages one tray and engages the immediately adjacent
tray. The operation of the loading and unloading mechanism is
unaffected by the absence of one or more trays from the tray slots,
which are defined by shelves 302.
[0142] When a selected tray is to be accessed by the pick-and-place
arm 304 (as determined by the computer controller), the lead screw
motor 374 moves the inner spindle the appropriate distance so that
the appropriate keys engage the keyways of the selected tray. The
rotation motor 356 then rotates the keyed tray to the proper
angular position so the arm 304 can access a particular recess 332.
The superposed arrangement of the trays, the way in which a
selected tray is accessed by the gripper 312 through the flared
notches 340 of superior trays, and the close-pack spacing of the
recesses 332 in each tray make for an extremely compact, high
capacity and efficient vial handling system that is readily
incorporated into the compact base of the LBP device.
[0143] In the embodiment shown, the LBP device can accommodate up
to eight trays holding forty-one specimen vials each. One of the
forty-one recesses can be reserved for a cleaning vial, which would
contain a cleaning solution and be run through the LBP device to
clean the various parts of the device that normally come into
contact with specimen fluid. Alternatively, the forty-first vial
could contain a typical control specimen for calibration purposes.
Thus the LBP device can accommodate up to at least 320 vials
containing specimens to be processed. The device is therefore
capable of operating continuously unattended for a long
duration--at least eight hours--so that specimen processing can be
carried out even when laboratory personnel are not normally
present, such as at night.
[0144] When the trays 330 are bar-coded or otherwise labeled with
machine-readable identifying data, they can be used in an automated
storage device that can access a particular tray on command. The
tray-identifying data can be input into the integrated data
management system so that the location of any specimen vial in tray
storage can be readily ascertained.
[0145] A cost reduction in tray-based storage of specimen vials can
be achieved by using a liner-type system in conjunction with trays
330. For example, vials can be supported and stored in thin
sheet-like liners (not shown) that conform to trays 330 and slip
readily into recesses 332. The liners are stiff enough to be
self-supporting when fully loaded, can be stacked, and can be
housed in wheeled carts for ease of mobility.
[0146] Data Accessioning and Specimen Management
[0147] It is, of course, important to keep track of each specimen
vial and the specimen slides produced from each vial. Accordingly,
the LBP device typically communicates with the integrated data
management system (DMS) 104 through an accessioning station 102 or
other computer. FIG. 21 schematically illustrates specimen vial
handling and the flow of data that is integrated into to operation
of the LBP device. The communication link between the LBP device
and the DMS can be made via ethernet or other protocol using a
direct peer-to-peer connection, or through a server-based
network.
[0148] The specimen processing operation begins with collecting or
transferring data from the labeled specimen vial, e.g. via a bar
code reader on a data entry terminal or accessioning station, to
the DMS via either a direct connection or over a network. Specimen
tracking data can include, for example, the patient's name, test
identification (ID) number, patient data, and any special
processing instructions. For example, the bar-coded specimen vial
can be linked to the patient information initially by a paper
requisition form and subsequently by an assigned, unique numerical
ID in the database. In a preferred embodiment, the patient and test
information including the vial bar code can be entered into the
networked DMS database at the point-of-care site (e.g., physician's
office), thereby eliminating entirely the need for a paper
requisition form. U.S. Pat. No. 5,963,368 (incorporated herein by
reference), which is assigned to AccuMed International, Inc. (now
Molecular Diagnostics, Inc., or MDI) discloses a similar concept as
applied to a computer-controlled instrument for analyzing
biological specimens (a microscope) and storing data from each
analysis. The '368 patent is exclusively licensed to MonoGen, Inc.
(the owner of this application) in the field of liquid-based
cytology in combination with or for use with non-fluorescence based
image analysis devices, processes, systems and/or instruments.
MonoGen's commercially available pathology work station and data
management system implement the concept disclosed in the '368
patent.
[0149] Each specimen vial includes an identification (ID) symbol or
label (e.g., bar code) and/or a stored information label or symbol
such as a hologram or a memory chip or device. The present
embodiment contemplates reading an ID label using an optical
reader, such as a bar code reader, which provides the information
to a DMS for sharing information between different work stations or
instruments at the same or different locations, such as
laboratories, doctors' offices, hospitals, or other patient care
providers. FIG. 21a depicts an overall laboratory system wherein
the DMS is expanded to link specimen/patient data through a server
to a variety of specimen processing devices and/or computerized
work stations for fully integrated specimen management.
[0150] A separate bar code reader 230 (see FIG. 11) is mounted on
the LBP machine itself, and scans all specimen vials prior to
processing through a slit in each transport receptacle 246. Each of
the transport receptacles 246 is tracked using this symbol or code,
such as a bar code that can be read with a conventional optical
reading device. The bar code readers used in the LBP device can be
any commercially available type, such as Keyence BL-600, with a
minimum BCR target code capability of Interleaved 2 of 5, Code
128c, or EAN-128. The bar code readers preferably are sealed in
liquid-tight enclosures for operator protection. After reading,
specimen vial/transport receptacle ID data are transmitted to the
DMS of the host database or work station. The host database or
local work station can then transmit back to the LBP device the
specific processing protocol to be performed on that individual
specimen.
[0151] Some of the most important functions of the data management
system (DMS) include:
[0152] Obtaining data on the patient and the specimen during
accessioning, and making this available to each instrument as
required to set processing parameters and to provide medical data
to the slide reviewer;
[0153] Maintaining chain of custody of specimens and slides to
ensure data integrity;
[0154] Compiling data and printing required forms for regulatory,
compliance, and laboratory management reports;
[0155] Generating medical reports and ensuring integrity using
safeguarded digital electronic signatures;
[0156] Managing billing for instruments on "per use" charges;
[0157] Storing optimal processing protocols for each process and
supplying to the instrument in accordance with the specimen type
and/or user requirements; and
[0158] Facilitating remote diagnostics and repair, and providing
user manuals and troubleshooting guides.
[0159] FIG. 21b shows an example of a relational database table
that can be used to accomplish these tasks.
[0160] The DMS can provide paper-free data flow among the different
stages of the cytology process, saving a significant amount of
personnel time and cost, reducing transcription errors, improving
accuracy, and eliminating the space required to store paper
records. By automating and managing data acquisition, storage and
retrieval, each operation becomes more efficient, significantly
reducing the turn-around time for specimens. Specimen quality is
enhanced by automated calibration and cross-checking routines that
identify potential problems early. Flexible foreign language
support for worldwide sales assists laboratories in multicultural
environments.
[0161] The DMS provides a common user interface that provides
detailed information on the operation of each connected laboratory
device and work station, and together with online user manuals and
training aids eases use and minimizes training. The DMS handles the
exchange of all relevant patient and specimen data with the users'
own LIS (or other data management systems) through a provided
software interface. Moreover, remote instrument diagnostic
capabilities ensure maximum interruption-free operation. The
reduction in paperwork, ready cross-compatibility with other
instruments and existing computer networks, and integration with
the central hospital or laboratory information system provides
significant user benefits.
[0162] In typical operation, the laboratory: (1) receives a
requisition from the healthcare provider along with the
pre-bar-coded specimen vial, (2) assigns a unique ID number
(accession number) to the specimen, and (3) based on information on
the requisition, enters a specific LBP test ID to specify the
process to be used. FIG. 23 shows an example of the accessioning
(data entry) screen that is presented to the technician, into which
the vial bar code, accession number and LBP process code are
entered. When the specimen vial is loaded into the LBP device for
processing, the LBP device automatically reads the bar code on the
specimen vial and transmits the bar code number (106) to the DMS,
which sends back the processing parameters for the selected test,
and the number of slides to be produced. The LBP device returns an
acknowledgment (108) and processes the specimen, making one or more
slides as instructed via the DMS. Immediately before the LBP device
imprints a specimen slide with material filtered from a specimen
vial, the LBP device reads the bar code from the pre-bar-coded
slide that is to receive the specimen sample. The LBP device sends
each slide bar code (110) and its associated vial bar code to the
DMS which updates the patient database with the slide bar code
number, cross-references it to the correct vial number, and signals
(112) the LBP device to proceed. The LBP device then imprints a
cytological sample from the specimen onto one or more slides and
readies the onboard data log for the next specimen to be processed.
FIG. 24 shows an example of a DMS menu screen showing data items
that are now linked in the DMS database, including the vial number,
slide number(s) and patient data. The DMS can produce a printable
report listing slide ID numbers and associated vial ID numbers,
patient data and processing protocols.
[0163] At a minimum the protocol variables include specimen mixing
parameters (stirring speed and time) and filter selection.
Typically, primary stirring speed can be varied from 500 rpm to
3,000 rpm selectable in 50 rpm steps. The stirring interval can be
varied from 5 to 120 seconds, selectable in 5 second increments.
Choice of filter type is based on average pore size diameter:
either 5 micron (red housing), e.g. for non-gynecological
specimens, such as sputum specimens, or 8 micron (white housing),
e.g. for gynecological specimens, depending on the test protocol
selected.
[0164] The LBP device is capable of processing mixed sample-runs
(i.e., runs that may include vials containing various types of
specimens) interchangeably and without the need for batch
processing of same-type specimens. Specimen processing can include
at least 100 different processing protocols resident within the DMS
and accessible to users. Predefined procedure codes (test ID's)
such as the following can be used to simplify operator input and
specify which processing protocol is used:
1 1 breast cyst, L 2 breast cyst, R 3 bronchial brushing 4
bronchial washing 5 bronchoalveolar lavage 6 cerebrospinal fluid 7
colonic brushing/wash 8 esophageal brushing/wash 9 gastric
brushing/wash 10 gingival (buccal) scrape 11 gyn PAP test 12
intestinal brushing/wash 13 nipple discharge, L 14 nipple
discharge, R 15 ovarian cyst, L 16 ovarian cyst, R 17 pericardial
effusion 18 peritoneal effusion 19 pleural effusion 20 rectal
brushing/wash 21 sputum, induced 22 sputum, spontaneous 23 urine,
catheterized 24 urine, voided
[0165] Each specimen is processed with a new filter to prevent the
possibility of cross contamination. In the present embodiment,
either of two or more different filter types can be specified for
versatility in test selection (the device's eight filter tubes
allow for up to eight different filter types). Processing
parameters for each type of specimen preparation can be determined
remotely and in advance, and communicated to the processing device
using a bi-directional communication link utilizing the specimen
vial bar code as the key identifier. The LBP device can utilize
default (pre-loaded into the DMS) process protocols as well as
laboratory-generated process protocols that users can add to the
DMS.
[0166] An overfilled-vial sensor (not shown) can be positioned at
or just downstream of the bar code reader 230 to detect whether an
excessive amount of fluid is present in each translucent vial.
Opening and processing an overfilled vial can result in hazardous
spillage or ejection of biological fluid. Accordingly, if an
overfilled vial is detected, the DMS will be so notified and the
complete LBP processing protocol for that vial will be canceled,
allowing the overfilled vial to proceed through the processing path
unopened. Alternatively, an overfilled condition can be sensed at
the conveyor holder 246 into which vials are loaded by the vial
loading mechanism 300. If an overfilled vial is detected there, the
DMS will be so notified and the loading mechanism will be
instructed immediately to return the overfilled vial to its tray
330.
[0167] A similar approach can be used to deal with other anomalies
detected as each vial is loaded into the conveyor. For example, a
sensor (not shown) can be used to detect an unreadable bar code on
the vial, or detect when a vial is improperly position in the
holder 246. When any such condition is detected, the DMS will be so
notified and the loading mechanism will be instructed immediately
to return the overfilled vial to its tray 330.
[0168] FIG. 22 is a block diagram showing the components of a
general purpose computer system or work station 270, which can be
used to run the DMS. The computer system 270 typically includes a
central processing unit (CPU) 272 and a system memory 274. The
system memory 274 typically contains an operating system 276, a
BIOS driver 278, and application programs 271, such as a DMS. In
addition, the computer system 270 can include input devices 273,
such as mouse, keyboard, microphone, joystick, optical or bar code
reader, etc., and output devices, such as a printer 275P, and a
display monitor 275M.
[0169] The computer system or work station can be connected to an
electronic network 280, such as a computer network. The computer
network 280 can be a public network, such as the Internet or
Metropolitan Area Network (MAN), or other private network, such as
a corporate Local Area Network (LAN) or Wide Area Network (WAN), or
a virtual private network. In this respect, the computer system 270
can include a communications interface 277, such as ethernet, USB,
or Firewire, which can be used to communicate with the electronic
network 280. Other computer systems 279, such as a remote host
database, other types of work stations including automated
analyzers, and computers or databases (e.g., LIS) of a hospital,
laboratory, or other medical establishment, can also be linked to
the electronic network 280. Other LBP devices, as well as other
types of specimen processing instruments (e.g., automated slide
stainers and coverslippers) 279a can also be connected to each
other and the DMS via the network.
[0170] One skilled in the art would recognize that the
above-described system includes typical components of a general
purpose computer system connected to an electronic network. Many
other similar configurations can be used to control the LBP device
and its processes. Further, it should be recognized that the
computer system and network disclosed herein can be programmed and
configured by one skilled in the art to implement the methods,
system, and software discussed herein, as well as provide requisite
computer data and electronic signals to implement the present
invention.
[0171] In addition, one skilled in the art would recognize that the
"computer" implemented invention described further herein may
include components that are not computers per se, but include
devices such as Internet appliances and Programmable Logic
Controllers (PLCs) that may be used to provide one or more of the
functionalities discussed herein. Furthermore, while "electronic"
networks are generically used to refer to the communications
network connecting the processing sites of the present invention,
one skilled in the art would recognize that such networks could be
implemented using optical or other equivalent technologies. One
skilled in the art would recognize that other system configurations
and data structures can be provided to implement the functionality
of the present invention. All such configurations and data
structures are considered to be within the scope of the present
invention. In this context, it is also to be understood that the
present invention may utilize known security and information
processing measures for transmission of electronic data across
networks. Therefore, encryption, authentication, verification,
compression and other security and information processing measures
for transmission of electronic data across both public and private
networks are provided, where necessary, using techniques that are
well known to those skilled in the art.
[0172] Uncapping Station
[0173] One of the advantages of the present vial-based LBP device
and system is that it minimizes operator exposure to the specimens,
which can contain potential biohazards. Referring to FIGS. 26-31,
the LBP device has an uncapping mechanism 400 that first
automatically separates the stirrer 40 in the vial from cover 30,
and then removes and discards the cover--all without intervention
by an operator. See FIG. 26, which shows the stirrer resting on
vial ribs 26 after the cover 30 is removed.
[0174] A closed specimen vial 10 which has arrived at the uncapping
station in its transport receptacle 246 is met by an uncapping head
402 which is lowered onto the cover 30 of the specimen vial. See
FIGS. 27 and 28. Uncapping head 402 has four tapered legs 404 that
form a tapered gripping cavity having chisel-like inner edges 406
spaced and sized to progressively tighten onto cover 30 as head 402
is lowered. Once the cover is tightly engaged by the legs, a
central spindle or plunger 408 is lowered into contact with the
center of cover 30 and applies a downward force to the cover to
cause the stirrer 40 to detach from the cover 30, as described
above, and drop down in the vial onto ribs 26. Then the plunger is
retracted and the uncapping head 402 is rotated counterclockwise
(FIG. 28) to unscrew cover 30 and remove it from container 20.
Thereafter the uncapping head with the removed cover in its grip
moves laterally to the position shown in dashed lines 410 in FIGS.
29 and 11, and plunger 408 is again lowered, this time to eject
cover 30, which falls into a waste chute or bin (not shown) beneath
the uncapping head. Alternatively, a movable waste chute can be
brought beneath the uncapping head to catch the ejected cover, so
that lateral movement of the uncapping head is not required. Covers
are not reused to eliminate the possibility of
cross-contamination.
[0175] The plunger 408 is driven by a pneumatic cylinder 412,
mounted on an L-bracket 415 at the top of the uncapping head, that
can apply a force on the cover of up to about 30 lbs. A coil spring
413 returns the plunger to its retracted position when cylinder 412
is deactivated. The head 402 is capable of applying an uncapping
torque through the gripping legs of up to about 10 lb-ft, which is
sufficient to loosen the cover. The gripping legs can be of the
self-energizing type so that precise alignment with the cover or
small variations in cover geometry do not frustrate their grip.
[0176] The uncapping mechanism has a mounting frame 414 supported
on blocks 416 that slide laterally of the processing path on rails
418. A Y-axis stepper motor 420 and lead screw 422 effect lateral
motion. The uncapping head 402 is rotatably mounted in a bearing
block 424. Bearing block 424 is secured to a C-frame 426 that is
vertically slidable on mounting frame 414. Vertical movement of
C-frame 426 and, hence, uncapping head 402 is effected by Z-axis
stepper motor 428 and lead screw 430. Lead screw 430 can be
vertically compliant to accommodate upward movement of the cover 30
as it is unscrewed. However, it is preferred that stepper motor 428
be actuated during the uncapping sequence so that head 402 rises at
about the same rate as, but no faster than, the unthreading cover.
Uncapping head 402 is rotatably driven by uncapper motor 432
through a gear reduction unit 433, a timing belt 434 and timing
pulleys 436, 438.
[0177] The uncapping head described above would also work with
vials having a conventional "press and turn" bayonet-type coupling
between the container and the cover. The downward force of the
plunger 408 would be sufficient to release the internal anti-turn
lock of the coupling, allowing the gripper to rotate and remove the
cover. Vials having covers that do not require rotation for
removal, e.g., a snap-on cover, would require a differently
designed uncapping head, tailored to the type of cover connection
involved.
[0178] Alternatives to the above-described plunger 408 can be
employed at or upstream of the uncapping station for applying the
required external force to the covered vial to effect separation of
the stirrer from the cover. For example, a cam, lever arm or other
movable mechanical element can contact and press down on the cover.
Alternatively, an abrupt upward external force can be applied to
the vial to yield an acceleration force that overcomes the
frictional retention force between couplers 35 and 47, effectively
pulling the stirrer out of engagement with the cover. This can be
done by, e.g., moving the closed vial rapidly downwardly to rap the
bottom of the container 20 against a rather hard surface, e.g., by
mechanically and/or pneumatically thrusting the closed vial into
the transport carrier 246 that will hold the vial during the
subsequent processing steps, or by dropping the vial down a chute
into the carrier a sufficient distance to dislodge the stirrer.
Another way to exert an abrupt upward external force on the vial is
to strike the bottom of the container 20 with a striking member.
This can be accomplished by, e.g., cradling the container 20 and
momentarily thrusting a striker against the bottom of the
container, e.g. through a bottom opening in the vial carrier 246,
by pneumatic and/or mechanical means. The design of these and other
variants of suitable automated mechanisms for accomplishing these
tasks is within the grasp of those skilled in the mechanical
arts.
[0179] Preprocessing (Primary Stirring) Station
[0180] After uncapping is completed, the transport mechanism
indexes the specimen container to a station where preprocessing
occurs. 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 to the specimen acquisition station. 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. In
this example, the chemical preprocessing station introduces its
dispersing agent through the preprocessing head.
[0181] In the illustrated preferred embodiment preprocessing occurs
at the primary stirring station 500, which uses a specified or
instructed stirring protocol to stir the specimen, if needed, using
the stirrer 40 in the container, at a specified speed (rpm) for a
specified duration. The stirring protocol chiefly depends on the
specimen, as described above, and is normally intended to
disaggregate any mucous material and disperse it and/or other
particulate material in the specimen liquid.
[0182] Referring to FIGS. 32-35, the primary stirring station 500
has a stirring head 502 in the form of an expanding steel collet.
The collet is formed at the lower end of a shaft 503 which splits
into six flexible fingers 504 defined by six equally spaced slits
506. Shaft 503 is rotatable in a bearing block 508 secured to a
C-frame 510 that is vertically slidable on a mounting frame 512.
Vertical movement of C-frame 510 and, hence, stirring head 502 is
effected by a Z-axis stepper motor 514 and a lead screw 516.
Stirring head 502 is rotatably driven by a stirring motor 518
through a timing belt 520 and timing pulleys 522, 524.
[0183] The inner surfaces of the collet fingers 504 taper uniformly
inwardly toward the lower end of the collet. A central plunger 526,
movable vertically by a pneumatic cylinder 528 atop a bracket 530,
expands the fingers 504 outwardly when it descends and encounters
the narrowing passage defined by the tapering fingers. Thus the
diameter of the lower end of the stirring head (collet) 502
increases when the plunger descends. This end is sized to fit
loosely but closely within the annular wall 47 at the top of
stirrer 40 when the collet is not expanded. When plunger 526
descends, the fingers 504 expand outwardly to wedge against the
inside of wall 47, in manifold M, securely engaging the
stirrer.
[0184] In operation, the stirring head 502 is first lowered so that
the collet enters the manifold M. The dashed motor and bracket
lines in FIGS. 33 and 34 indicate this lowered position. Then
plunger 526 descends to lock the stirring head to the stirrer. Then
the stepper motor 514 is operated to slightly raise the stirring
head and the attached stirrer 40. This vertical movement need only
be very small, such as 0.050 in., just to free the stirrer from the
ribs 26 and prevent interference with the container during
stirring. Then DC stirring motor 518 is operated in accordance with
the specimen-specific stirring protocol. Stirring speed can vary,
and is usually in the range of about 500 rpm to about 3,000 rpm.
The stirring time can vary from about 5 seconds to about 90
seconds. The base or bottom wall 41 of the stirrer acts as a
slinger to thrust any liquid that may rise along the stirrer
against the container wall, and prevents the escape of liquid from
the container. Withdrawing the plunger 526 from the collet releases
the stirrer 40 from the collet 502 so the specimen container can
move on to the next station.
[0185] A contracting collet could be used instead of expanding
collet 502. In that case, the collet fingers would fit around the
outside of annular wall 47, and would be squeezed together to clamp
around the wall by a descending sleeve that surrounds the
fingers.
[0186] Filter Placement Station
[0187] At the filter placement station 600 an appropriate filter
assembly F (see FIG. 5) is loaded into the open manifold M at the
top of the stirrer 40. Filter assemblies can come in different
filter configurations for automated machine recognition. For
example, one set of filter assemblies can be colored red (5
micrometers), another set white (8 micrometers), each having
different filtering properties, and a color sensor can detect which
type of filter is before it and cause the proper filter to be
loaded. The filter assemblies are dispensed by a pusher from a
magazine having multiple filter tubes.
[0188] FIGS. 36-40 show the structure and operation of the filter
placement station. Referring to FIGS. 37 and 40, a filter
dispensing head 610 comprises a filter magazine in the form of a
turret 612 rotatable on a spindle 614 by a stepper motor 616.
Vertical post 611 provides the main support for the turret. Turret
612 has a top support plate 618 with eight equally spaced holes 620
near its periphery, each hole opening through the edge of the plate
618 with a slot 622. A bottom guide plate 624 on spindle 614 has a
similar arrangement of holes that are aligned with the holes and
slots in the top support plate.
[0189] Eight steel filter tubes 626, each having an upper support
shoulder 628, are supported vertically in holes 620 and the aligned
holes beneath them, with shoulders 628 resting on the top of top
plate 618. Each filter tube 626 has a full-length slot 630, and its
bottom portion is split into four springy fingers 632 by slots 634.
Just above the bottom end the fingers 632 curve inwardly, forming
rounded inner shoulders 636 against which a filter assembly F
rests. The filter tube is dimensioned such that the shoulders 636
keep up to a full stack of filter assemblies F from falling out of
the tube, but deflect to allow a filter assembly to pass when the
stack is pushed downwardly without damage to the filter assembly.
Fingers 632 thus form a springy choke.
[0190] FIG. 39 shows the position of the filter magazine 612 in
relation to the processing path and the adjacent processing
stations, namely the primary stirring station 500 to the left, and
the specimen acquisition station 700 to the right, all located on
one side of the processing path as defined by guide rails 250. On
the other side of the processing path opposite the filter magazine
612 is the assembly that supports and drives a pusher arm 640. This
assembly comprises a support post 642 supporting a Z-axis lead
screw 644 driven by a stepper motor (not shown) which moves a
shuttle 646 that carries pusher arm 640. A filter sensor 650
positioned opposite bottom guide plate 624 monitors the passage
(drop) of the lowest filter assembly F in the filter tube presented
to (i.e., directly above) the specimen container. Sensor 650 also
detects when the filter tube is empty. A second sensor 651 monitors
filter type.
[0191] Filter assemblies of the same type are stacked in the proper
orientation, with the membrane filter side (beveled edge) facing
down, in each tube. For example, 54 filter assemblies can be housed
in each tube; thus a total of 432 filter assemblies can be loaded
into the magazine. Fifty-four filter assemblies can be prepackaged
in a stack that is inserted into a filter tube with a wrapper tab
projecting from slot 630, and unwrapped by pulling the tab
outwardly. Alternatively, filter assemblies of the same type can be
dumped onto a vibratory feeder, which can recognize their
orientation by geometric configuration, and properly orient and
feed the filter assemblies onto the tubes. Several of these feeders
can be used, one for each type of filter assembly.
[0192] In operation, with the pusher arm 640 in its home (top)
position, indicated by the dashed shuttle outline in FIG. 38, the
filter magazine 612 is rotated by stepper motor 616 until sensor
650 detects the presence of the specified type of filter assembly
in the filter tube before it. Shuttle 646 then moves downwardly
with pusher arm 640 moving through slot 630 to press the stack of
filter assemblies in that tube downwardly, until the lowest filter
assembly drops from the tube into the manifold M in stirrer 40.
When filter drop is sensed, the shuttle 646 with its pusher arm 640
stops its advance. In an alternative arrangement, a weight sensor
can be used to monitor the weight of the filter stack, and detect
by weight change when a filter assembly has dropped from the stack
and when the filter tube is empty.
[0193] The use of eight filter tubes 626 in magazine 612 enables
unattended processing of all of the specimens housed in the trays
of the vial autoloader 300. For a counter-top model of the type
described above, however, a single filter tube supported in a fixed
position above the processing path would suffice for processing
specimens that require the same type of filter.
[0194] Specimen Acquisition and Cell Deposition Station
[0195] Referring to FIG. 41, specimen acquisition station 700 has a
suction head 702 that descends to engage the upper portion of the
stirrer 40. Before drawing a vacuum on the specimen through the
filter assembly F, the suction head grips, slightly lifts and
rotates the stirrer 40, this time more slowly than at the primary
stirring station (typically no more than 500 rpm for a 5 second
interval), to re-suspend the particulate matter in the specimen
liquid. The re-stir motor can be a Maxon 24 volt DC planetary
gear-reduced type. Then suction is applied through suction line 750
to aspirate specimen liquid from the container 20 through suction
tube 43, into the particulate matter separation chamber (manifold)
46 and through the filter assembly F, leaving a monolayer or thin
layer of uniformly deposited cells on the bottom surface of the
filter as described above. It may also be possible to rotate the
stirrer slowly while the specimen liquid is being aspirated.
[0196] FIG. 6 shows how the suction head cooperates with the
annular wall 47 of the stirrer manifold and the filter assembly F
therein. The outer portion 704 of the suction head envelops the
wall 47 and has an O-ring 760 that seals against the outside of
wall 47. The inner portion 706 of the suction head has two
concentric O-rings 762, 764 that seal against the top of filter
holder 200. Suction applied through port 750 creates a vacuum
around central opening 204 and within filter holder 200, which
draws liquid into the manifold 46 and through the filter 202. An
O-ring 766 is interposed between the inner and outer portions of
the suction head.
[0197] Referring to FIG. 42, when aspiration of the specimen is
complete, the suction head 702 is raised. The inner portion 706 of
the suction head is extended at the same time by action of a
pneumatic cylinder (not shown) mounted above the suction head. As
the suction head 702 is raised, the outer portion 704 disengages
from the stirrer 40, but the filter assembly F is retained on the
inner portion 706 by application of a vacuum through suction line
752 to the annular space between O-rings 762 and 764. Thus the
suction head 702 removes filter assembly F from the stirrer, and
can continue to apply light suction via suction line 750 through
the filter to effect a desired degree of moisture control of the
cellular material on the filter.
[0198] The suction head 702 then moves laterally away from the
transport conveyor by pivoting 90.degree. about a vertical axis to
the cell transfer position "P" shown in FIG. 46, to position the
filter assembly F over a microscope slide S delivered from a slide
cassette at slide presentation station 900. This pivoting movement
of suction head 702 can also be seen in FIGS. 11 and 39. The inner
portion 706 of the suction head 702 then moves downwardly to press
the filter against the slide S with a tamping force in the range of
4 to 8 lbs. and transfer the monolayer of cells thereto. The
phantom lines in FIG. 42 show this change in position of suction
head 702 and contact of the filter with slide S. Instead of being
pivotally mounted, the suction head 702 could be mounted for
rectilinear movement to and from a different deposition site where
slides are presented, e.g., above the processing path.
[0199] Referring to FIGS. 43-46, suction head 702 is rotatably
mounted on a boom 716 that also carries the re-stirring motor 718,
which rotates suction head 702 through a timing belt 720. Boom 716
is pivotally supported about a vertical axis 721 on a slide 722,
which is vertically movable along frame support 724 by means of a
Z-axis stepper motor 726 and a lead screw 728. Motor 726 thus moves
the entire suction head vertically. Pivoting motion of boom 716 is
effected by stepper a motor 717 operating through a gear train (not
shown). Vertical motion of the inner portion 706 of the suction
head is effected by a pneumatic cylinder and return spring (not
shown) mounted above the suction head to an L-bracket 719,
substantially identical to the arrangement 412, 413, 415 (see FIG.
29) used to move the plunger 408 of the uncapping head 402.
[0200] The frame support 724 is mounted on a slide 730 so as to be
movable laterally of the transport path. A Y-axis stepper motor 732
and a lead screw 734 effect this movement. After the slide is
printed the suction head is raised by the Z-axis motor, and the
Y-axis stepper motor 732 advances the entire assembly to the dashed
line position "X" shown in FIG. 43. Then the suction head pivots
back to its original orientation, transverse to the transport path
(position "S" in FIG. 46). The Y-axis stepper motor 732 then pulls
the entire assembly back toward its original position (solid lines
in FIG. 43). As the suction head 702 moves (to the right as seen in
FIG. 43), the still-retained filter assembly F is "scraped" off the
suction head by the edge 736 of an open-top used filter (waste)
tube 738 (see also FIGS. 11 and 39). This leaves suction head 702
free to engage a fresh filter assembly.
[0201] The vacuum source that communicates with the suction head
702 pulls a slight vacuum, e.g., in the range of 3 in. to 10 in. Hg
(adjustable by a regulator), through suction line 750 to aspirate
specimen liquid and draw it through the filter assembly F. The
separately regulated vacuum applied through suction line 752 for
holding the filter assembly to the suction head 702 is higher, on
the order of 20 in. Hg.
[0202] Formation of high-quality specimens on microscope slides
depends critically on the deposition of a monolayer of cells of
specified concentration (i.e., number of cells per unit area) on
the surface of the filter that will contact the slide. That, in
turn, depends critically on the aspiration rate and/or the
aspirated flow volume. Since cell concentration on the filter
surface is a function of the number of filter pores blocked by the
solids suspended in the specimen liquid, the percent of flow
reduction from the maximum open filter condition correlates to the
blockage or amount of accumulation on the filter. Because of the
nature of biological specimens, solid particle concentration is a
significant variable in the process and must be taken into
consideration. Also, it is important to identify the total volume
of material filtered on a real time basis for other processing
operations.
[0203] The specimen acquisition station thus further includes a
deposition control system for controlling the liquid draw vacuum
duration by monitoring the flow rate and/or aspirated volume. The
monitored flow rate or aspirated volume can be used to signal
vacuum cut-off and/or suction head retraction, which correlates to
the specified concentration of cells collected on the membrane
filter surface. If a specified concentration factor is not achieved
before a specified volume of fluid is aspirated, the system can
also issue a retract signal.
[0204] Different types of deposition control systems or modules can
be used for these purposes. FIG. 47 schematically shows one such
system, which has a meter in the form of a digital level detector
positioned along a fluid column. This "bubble flow" system can use
sensors in the form of a plurality of LED emitters and
corresponding number of photosensors, such as Omron sensor,
EE-SPX613 GaAs infrared LED, placed along the length of the column.
Any other type of sensors may be used. Alternatively, LED sensors
such as the Omron sensors mentioned above can be used without
corresponding emitters when they are positioned just at the edge of
a glass tube. The meniscus edge of the liquid in the tube diffracts
the light passing through the tube, and the sensor will detect the
shifted light pattern when the rising meniscus edge reaches the
sensor.
[0205] The fluid column is formed in a vertically extending
transparent tube or cylinder 770, e.g., one made of Pyrex glass 9
mm in diameter by 1 mm thick. The aspirated specimen fluid is drawn
from the specimen container through the membrane filter, and pulled
into the glass cylinder 770 via suction line 750 and a 3-way valve
778, by means of a vacuum source 772 connected to the top of the
cylinder. The sensors 774 are positioned evenly along the length of
the cylinder 770, preferably at 1.5 ml capacity intervals, and are
interfaced with a controller or microprocessor 776.
[0206] In operation, in the normal state, with no fluid in the tube
770, the sensor relay line is "low." Vacuum begins to draw fluid
into the tube through the filter, and the controller marks the
beginning of the draw sequence. When the fluid reaches the first
sensor, the first sensor relay line goes "high." The controller
marks the time it took for the fluid to reach the first sensor,
indicating the nearly free-flow condition of the filter, and the
relative viscosity of the fluid in the test. When an additional 1.5
ml of fluid is drawn into the tube, the second sensor relay line
goes "high." The time interval for the first 1.5 ml of fluid
(between the first and second sensors) is noted by the controller,
and this becomes the reference time base. As each additional 1.5 ml
of fluid is drawn into the system (and is detected by succeeding
sensors), the time base for that increment is computed. When the
incremental time base reaches an empirically derived percentage
(e.g., 120%) of the original (reference) time base, the controller
indicates that cell collection is completed, and a stop signal is
transmitted, preferably to retract the suction head 702 from the
manifold in the specimen container. The empirically derived figure
mentioned above is variable with the protocol and directly controls
the cellularity of the specimen sample.
[0207] The best approximation of the free-flow condition of the
filter is obtained if the time it takes for the fluid to reach the
first sensor 774 is kept to a practical minimum. This can be
accomplished by incorporating the first sensor into the suction
head itself, as schematically illustrated in FIG. 47a. In this
embodiment, inner portion 706 of the suction head carries an
emitter 774a and an opposed sensor 774b, which detects the leading
edge of the fluid column very close to the filter assembly F. The
outer portion 704, which has teeth 775 engaged by timing belt 720
(not shown), is rotatable about the inner portion 706 (note
interposed bearing 773) to rotate the stirrer (not shown) and stir
the specimen prior to aspiration.
[0208] During the specimen drawing operation, the controller
records the cumulative or total aspirated volume. If the cumulative
volume reaches a predetermined level before reaching the
predetermined flow rate reduction from the reference flow, the
controller will also issue a stop signal and a flag indicating that
the stop signal issued not as a result of desired reduced flow, but
by reaching the maximum liquid draw limit. A slide formed under the
flagged condition will likely form a hypo-cellular condition. The
controller can imprint the slide and indicate to the DMS that a
hypo-cellular condition likely exists. Accordingly, if the flagged
condition exists, the controller issues a signal to purge the
liquid in the cylinder 770 and initiate a second draw. The cylinder
is purged of all liquid after each sample is taken.
[0209] Referring to FIG. 48, the deposition control system can have
a purge value so that when the draw cycle is completed, the stop
signal generated by the controller 776 will open the purge valve to
vent the vacuum supply line to the atmosphere and divert the liquid
remaining in the cylinder 770 into a waste container. The cylinder
770 can be maintained under a negative pressure. The system is then
ready for the next cycle. Specifically, the system can have a 2-way
solenoid valve V-3 in the suction line with one port 780 open to
the atmosphere. The bottom of the cylinder 770 is connected to a
valve manifold 782 with two solenoid valves V-2, V-4. The solenoid
valves can be Lee LF series designed for use in vacuum systems,
2-way valve LFVA 2450110H, viton seal, 24 volt and 3-way valve,
LFRX 0500300B, viton seal, 24 volt. The 2-way valve V-4 can port
the specimen liquid to the bubble flow cylinder 770, or to vacuum
by-pass 784. The 2-way valve V-2 can control the filter dehydration
vacuum source. FIG. 49 illustrates the valve logic.
[0210] The deposition control system can use an analog level
indicator instead of the digital sensors 774. The analog level
indicator senses capacitance of the aspirated liquid. The
difference is only in the method of sensing the volume and fill
rate of the liquid in the cylinder 770. Here two spaced electrodes
are used, one around the outside of the cylinder 770 and the other
positioned down the center of the cylinder the cylinder, separated
from the aspirated liquid by a dielectric. A high frequency, such
as 10 kHz, low voltage current is applied across the electrodes.
Capacitance in this system is measured by a bridge circuit, which
provides an analog indication of capacitance in the circuit. As
fluid fills the column, capacitance in the circuit increases. A
10.times. differential in direct capacitance is easily obtained
with this system. Capacitance is indicated on a real time basis and
can be sampled frequently enough to provide control of the sampling
system. This arrangement, like the first two, uses a computer or
microprocessor and a bubble flow technology to measure the flow
rate and the total fluid volume in real time. The predetermined
volume increment for these arrangements can be in the range of
about 0.1 ml to 5.0 ml, and preferably is in the range of about 1.0
to 2.0 ml.
[0211] A different system can use an ultrasonic indicator for
measuring fluid movement through a tube. The ultrasonic system uses
ultrasonic wave propagation through a moving liquid. In this
regard, the third system employs an ultrasonic emitter and detector
clamped across the liquid draw tube (suction line 750) operating on
the distal end of the filter assembly F. This system provides a
digital indication of fluid flow in the tube, the total volume
aspirated through the tube being calculated by a flow interval
calculation. It measures phase shift from the ultrasonic wave
generator source to a detector for measuring flow speed.
[0212] Another way to measure aspirated fluid volume and control
the duration of the specimen draw is to detect the change in the
weight of the specimen vial. This can be accomplished by using a
sensor that makes a high-precision measurement of the weight or
mass of the vial containing the specimen that is being aspirated.
Vial weight or mass is repeatedly measured at a high frequency such
that the rate of change of the weight or mass of the vial is
accurately determined. Specimen aspiration is completed when the
rate of change in weight or mass has diminished by a predetermined
amount or percentage from the initial rate. The weight sensor can
be, e.g., a load cell in each conveyor receptacle 246, or a single
load cell beneath the conveyor at the specimen acquisition head
that rises to engage the container above it. In either case, the
specimen acquisition head can be raised slightly during aspiration
to unload the container so that the load cell can measure only the
combined weight of the container and the remaining specimen.
[0213] Although specimen acquisition preferably is accomplished
through aspiration (using a vacuum), it can also be accomplished by
pressurizing the container 20 through an appropriate head that
seals against the top of the container and forces specimen liquid
up through tube 43 and through the filter assembly by means of
positive pneumatic pressure. The fluid volume control schemes and
mechanisms described above would also work in conjunction with such
a pressurized specimen acquisition system.
[0214] The cell concentration can be selected from low to high by
defining flow control cut-off. For a typical low cellularity
result, the cut-off can be 80% of the 120% reference discussed
above, and for high cellularity the cut-off can be set at 60% of
the reference, selectable in 5% increments. The number of slides
per specimen can range from one to three. Some of the typical
default protocols are as follows:
[0215] GYN: 1,000 RPM stir, 30 second interval, 8-micrometer
filter, 60%-high cellularity, one slide.
[0216] Urine: 1,000 RPM stir, 20 second interval, 5-micrometer
filter, 70%-medium cellularity, one slide.
[0217] Lung sputum: 3,000 RPM stir, 120 second interval,
5-micrometer filter, 80%-high cellularity, two slides.
[0218] Re-Capping Station
[0219] After completing the specimen processing cycle, the specimen
container is resealed with the stirrer still inside the container.
It is preferred to use a thin, polypropylene-coated aluminum foil
to form the new cap, which is available in roll form. The foil is
drawn across the open end of the specimen container, thermally
bonded to the container at a seal temperature of about 365.degree.
F. applied for about 3 seconds with a seal force of 3 pounds, and
cut from the roll. Of course, any other type of re-capping material
can be used as long as it is compatible with the vial material and
creates a safe and reliable seal. For example, a foil backed with a
thermosetting resin adhesive could be used; a sticky-backed foil
could be used that does not require heat to effect a seal; or a
plastic seal material can be bonded to the container
ultrasonically. To enhance unattended operation, an automatic
threader could be included for threading a new roll of sealing
material into the re-capping mechanism. Cutting caps from a roll
can be eliminated if roll-mounted pre-die-cut closures having
peel-off tabs are fed to the re-capping mechanism.
[0220] Referring to FIGS. 50 and 52, the re-capping mechanism 800
has a side support plate 802 secured to the machine base plate. The
side support plate carries a main frame 810 having a top plate 812
with slots 814, 816, and two side plates 818, 820. A driver capstan
822 is journaled in side plates 818, 820. A foil advance motor 824,
mounted on a bracket 826, drives the capstan. A pressure roller 828
is pivotally mounted to the main frame 810 and resiliently engages
the capstan under the influence of a spring 830. Capstan 822 and
pressure roller 828 define between them a throat through which the
foil runs, and have resilient surfaces which grip the foil for
positive feed. A handle 832 allows the throat to be opened manually
to allow the end of the foil to be fed into the throat after first
passing through slot 814. A spindle 804, carried side support plate
802, supports a replaceable roll of foil.
[0221] FIG. 51 shows the foil path 834 through the throat. An
L-shaped cutter 836 is pivoted at its elbow to the rear of main
frame 810. One end of a single-acting pneumatic cutter actuator
cylinder 838 is mounted on a bracket 840, and the other end of the
cylinder is linked to the upper leg 842 of cutter 836. The lower
leg of the cutter has a blade 844 that normally rests above the
foil path downstream of the throat, held in that position by a
spring 845 linked between the upper leg 842 and the support plate
802.
[0222] A rear post 850 pivotally supports an arm 852 that extends
forwardly toward main frame 810. Arm 852 carries a heated platen
854 and a foil guide fork 856 having two tines that extend toward
the throat and are spaced apart so as to allow the platen 854 to
pass between them. Arm 852 is kept elevated, in the rest position
shown in FIG. 51, by a spring 858. During the re-capping operation
a single-acting pneumatic cylinder 860 pulls down on the arm 852 to
lower the platen 854 and the guide fork 856. Note the position of a
container 20 in a transport receptacle (not shown) beneath the
platen 854.
[0223] In operation, the foil advance motor turns the capstan 822
to feed a measured length of foil past the cutter blade 844, into
the fork 856, and to the position shown by the dashed line in FIG.
51. A photocell 862 detects the leading edge of the foil and
signals the motor to stop. Then cylinder 838 is actuated to cut the
foil, and cylinder 860 is actuated to pull arm 852 down to the seal
position. The cut length of foil is sandwiched between the platen
854 and the container 20, and the container is sealed. After about
three seconds cylinder 860 is deactivated and the arm 852 rises,
returning to its rest position. A vacuum assist (not shown)
optionally may be used to help hold the cut length of foil in
position on the platen prior to sealing.
[0224] The foil caps applied by the re-capping mechanism are
approximately square in shape. The corners of the foil caps can
protrude from the vials and interfere with other re-capped vials
that are returned to the trays 330. Accordingly, a foil folding
ring 870 (seen in phantom lines in FIG. 51) preferably is provided
which acts to fold the edges and corners of each foil cap down
along the side of the container. The foil folding ring 870
preferably is mounted to act on the vial in the transport position
immediately downstream of the re-capping mechanism, i.e., position
"FF" in FIG. 51, and may be mounted on the re-capping mechanism
itself, e.g., to main frame 810, so that actuation of cylinder 860
serves simultaneously to apply a foil cap to one container and fold
the edges and corners of the foil cap of the preceding (downstream)
container. Alternatively, the foil folding ring or an equivalent
foil folding mechanism can be mounted further downstream of the
re-capping mechanism so as to act independently thereof.
[0225] Foil folding ring 870 is a metal ring having an inner
diameter that is slightly larger than the outside diameter of the
threaded portion of the container 20. The ring 870 is mounted on an
arm (not shown) that moves downwardly when actuated to lower the
ring 870 over the upper end of the container. As the ring encircles
the container, it folds the overhanging portions 872 of the foil
cap against the side of the container. When the ring rises after
folding the foil, the container is held in position in its
transport receptacle by a pin (not shown) that is mounted on a leaf
spring (not shown) and is situated in the center of the ring 870.
The leaf spring is carried by the arm that holds the ring, so the
pin resiliently presses down against the center of the foil cap
until the arm and the ring retract fully.
[0226] The foil seals applied to the processed containers are
easily punctured by a syringe or a pipette to obtain further liquid
specimen samples. The seals are very durable, however, withstanding
rough handling and preventing leakage in low ambient pressure
conditions, e.g., in aircraft flying as high as 40,000 ft. Further,
the appearance of the foil seal makes it readily distinguishable
from the cover of an unprocessed vial, making handling by
low-skilled operators virtually foolproof. To avoid the potential
of puncturing the foil seal inadvertently, the re-sealed container
can be capped with an unused screw-on cover of a distinct
color.
[0227] Slide Handling and Presentation
[0228] The LBP device can use 30 and 40 slide plastic magazines
(cassettes), which can accept standard 25 mm.times.75 mm.times.1 mm
and 1.times.3.times.0.040 in. slides. Metric and inch based slides
can be used interchangeably. FIGS. 52-55 show a 40-slide cassette C
suitable for use in the LBP device. The slide cassette is in some
respects similar to that disclosed in U.S. Pat. No. 5,690,892
(incorporated herein by reference), but is specially adapted for
use in other devices as well, such as an automated stainer, an
automated image analyzer, and a pathology work station, so that the
slides do not have to be unloaded and reloaded into different
magazines for use in those devices. Machine-readable indicia on the
cassette, such as a bar code or an embedded microchip, provides
cassette information that can be linked by the DMS to the bar codes
on the slides in the cassette so that the location and status of
any cassette and any slide in that cassette can be tracked in a
laboratory system. The cassettes are stackable for compact storage
and easy retrieval.
[0229] Specifically, the slide cassette is molded of plastic and
has a generally rectangular shape with an open front 902, a rear
wall 904, a top wall 906, a bottom wall 908 and side walls 910. The
top wall 906 bears bar-coded information 909. A guide flange 912
extends laterally outwardly from each side wall. Rear wall 904 has
a rectangular central opening 914 through which a slide shuttle can
pass (see below) to extract and return one slide at a time. An
inwardly projecting ridge 916 around the central opening acts as a
stop against which the slides abut when they are inserted into the
cassette. The preferred material for the cassette is ABS plastic;
alternative choices include polyurethane, thermoplastic polyester,
and polypropylene. The open front face is sized to accommodate the
rear of another like cassette so as to be stackable.
[0230] The slides are supported on shelves 918 at each side of the
cassette. In the illustrated embodiment there are 41 pairs of left
and right shelves, and each pair (except for the top pair) supports
one slide that spans the space between the shelves. Referring to
the detailed view in FIG. 53, each shelf (except for the top and
bottom shelves) has a raised top ledge 920 on which the slide rests
and an underside beam spring 922 for applying a force to pinch and
thereby frictionally restrain the slide against the top ledge
directly beneath it. This arrangement keeps the slides from falling
out of the cassette, even when the cassette is held face down, yet
enables each slide to be moved out of and back into the cassette by
the slide presentation apparatus, described below, without
blocking, scratching or interfering with the slide-mounted
specimens. Each shelf 918 also has a lead-in ramp 924 which guides
the slide during insertion into the cassette. Each shelf 918
(including spring 922) preferably is integrally molded into the
cassette and is attached to both the rear wall 904 and a side wall
910. However, separately fabricated springs, plastic or metal, may
be inserted between the shelves instead.
[0231] Each side wall is provided with multiple drainage ports 926
which allow fluid to drain from the cassette after removal from a
staining bath. The last (top and bottom) drainage ports 923 on each
side also cooperate with a hanger assembly of a stainer for moving
the cassette from one staining bath to another. During the staining
operation the cassette is oriented generally on its side, hung from
the last two drainage ports on the upper side. An all-plastic
construction makes the cassette compatible with acid baths and all
types of staining bath compositions.
[0232] Referring to FIG. 54, rear wall 904 has two rows of
apertures 927 that form two integrally molded gear racks 928, which
are adapted to engage pinion gears 936 (see below) for moving the
cassette longitudinally so that each slide can be accessed by the
slide shuttle. Two spaced parallel racks and two pinion gears
enhance the smoothness and accurate positioning of the cassette, as
compared to a single rack and single pinion. Also integral with the
rear wall is a row of 40 cassette position sensing slots 929
extending through the rear wall and coincident with the positions
of the slides to allow for optical sensing of each slide. Further,
rear wall 904 has a row of 40 blind recesses 925 (these do not
extend completely through the rear wall) that allow for accurate
sensing of cassette position when it is driven via the gear racks
928.
[0233] The molded cassette preferably is supplied wrapped in sealed
plastic for cleanliness, with slides installed. It is therefore
well suited for shipping, relatively low in cost, disposable yet
reusable. It has a high storage capacity and is stackable with
others, thus providing high density storage for specimen
samples.
[0234] Slide cassettes populated with slides are manually loaded
into the LBP device in an elevated in-feed track 930 (see FIG. 11)
located behind the filter loading station 600 and the specimen
acquisition station 700. No latching is required to enter cassettes
into the system. Up to ten unprocessed cassettes can be loaded in
the LBP device at any one time, but only in a single orientation.
The cassettes can be marked with a top indicator, and will not be
accepted if they are installed backwards or upside down. The
cassettes are loaded with their open fronts facing to the right as
seen in FIG. 11, with the lead cassette between vertical rails
932.
[0235] The lead cassette moves down incrementally whenever a new
slide is to be withdrawn from the cassette for specimen printing.
This is accomplished by a stepper motor (not shown) driving pinion
gears 936 that engages the racks 928 on the back of the cassette C
(see FIG. 54). When all slides in the cassette have been processed,
the cassette descends all the way to outfeed track 940, and a
stepper motor/lead screw pusher 938 moves the cassette to the right
into outfeed track 940, and then retracts. Then the next cassette
in the infeed track 930 is advanced by a motor/lead screw pusher
(not shown) to the front position between vertical rails 932, where
it is engaged by the pinion gears 936 and moved downwardly until
the first (lowest) slide comes into position for extraction. Each
of the feed tracks can have a home sensor, which can be Omron
self-contained shutter type, and a cassette full sensor, which can
be Keyence fiber optic.
[0236] FIGS. 11, 56 and 57 show the slide presentation system,
which uses a slide shuttle feed system 960, e.g. AM Part No.
5000-1, for extracting one slide at a time from the cassette along
the X-axis and placing it on a Y-axis handler, which moves the
slide to the pressing (print) position. The aforementioned U.S.
Pat. No. 5,690,892 discloses a similar slide cassette and shuttle
arrangement used in a pathology work station (microscope). The
Y-axis handler 962 has a slide platen 964 secured to a follower
966, 967. The handler is driven by a stepper motor 970 and a lead
screw 972, guided along a rail 968. A slide is held to the platen
under a fixed shoulder 974 (against a spring 976) and a pivoted arm
978 which is spring-biased in the counterclockwise direction as
seen in FIG. 56.
[0237] When the handler 962 moves to the left, arm 978 moves off an
adjustable stop 980 and rotates over the slide. The full Y-axis
slide travel (shown as "T" in FIG. 57) brings the center of the
slide to the print position "P" (note the dashed line position of
the slide and the handler in FIG. 56). On its way to the print
position the bar code number on the slide is acquired by a bar code
reader 982 and transmitted to the host data base. When the print
position is reached the suction head 702, which has pivoted along
arc "A" about axis 721, lowers the filter assembly F into contact
with the slide, as described above, depositing (printing) the
specimen on the slide. Vacuum on the filter is maintained
throughout the printing cycle to prevent over-hydration of the
sample and unintentional dripping.
[0238] After printing the slide moves back to the right, pausing
under a fixative dispensing head 984. Here a solenoid-driven pump
(not shown), such as Lee LPL X 050AA, 24V, 20 microliter per pulse,
yielding 12 microliters per pulse (maximum of 2 pulse/second),
applies fixative to the specimen. The total volume can be
determined by the number of solenoid cycles. The total fixative
volume dispensed is programmable in 20 microliter increments. It
can have a flexible connection to a dispensing sapphire jet nozzle
with a 0.030 in. orifice. The liquid can be gravity-fed from a
reservoir to the pump. The reservoir can be a tank and can have a
"fluid low" sensor connected to the operating system. More than one
fixative dispenser can be employed to provide alternative fixatives
as determined by processing protocols.
[0239] After the specimen is fixed, the completed slide moves all
the way to the right, where it is transferred by the slide shuttle
mechanism back to its original position in the cassette. When the
cassette is fully processed, the entire cassette is ejected into
the outfeed track 940, as described above.
A Complete Laboratory System
[0240] The present LBP device does not require that specimens be
pre-processed before loading, and can automate every step of the
slide preparation process. Moreover, the device does not require
the operator to open any of the specimen containers--an important
operator safety feature. The LBP device can automatically prepare
high quality cytology slides from all specimen types, including
mucous-containing GYN and non-GYN specimens, using the integral
high-speed, high-shear mixing station that facilitates mucous
disaggregation. The incorporated dual-flow filter system allows
production of slides with optimal cell separation, cell
concentration, cell dispersion, and optimal preservation of
antigens, DNA, and morphologic characteristics to enhance the
performance of subsequent testing. The slide cassettes, containing
up to 40 slides each, will be utilized in the follow-on laboratory
processing devices to avoid the labor-intensive need to transfer
slides to different racks before continuing with slide processing.
Data on the patient, the specimen, the vial, the cassette and the
slide can be transferred automatically to the LIS over the user's
network, via a DMS software interface.
[0241] The present LBP device can provide eight hours of unattended
operation. Thus, if the operator re-loads the device before leaving
for the day, a single-shift laboratory can produce two shifts of
output per day without added personnel or equipment costs. The
total throughput can exceed 160,000 slides per year, at a per-test
cost significantly below that of the current leading LBP
system.
[0242] The LBP device also has the capability to process specimens
for current and future molecular diagnostic tests including
quantitative DNA analyses, and tests utilizing markers &
probes. Features built into the device include the capacity to
employ multiple fixative dispensers in order to provide non-routine
fixatives that may be required for special molecular diagnostic
tests.
[0243] The complete laboratory system, illustrated, e.g., in FIG.
21a, includes a pathology review station, a computer-aided
microscopy work station used by pathologists to review specimen
slides and sign out cytology cases. As with all components of the
laboratory system, the pathology review stations are networked to
the DMS and thereby to all other devices on the system, for rapid
access to patient data and specimen processing information. The
pathology review station accepts slide cassettes for automated
loading and review of specimen slides. Computerized, fully
automated image analyzers will perform quantitative analyses of DNA
and molecular diagnostic tests, receiving their operating
instructions and reporting their results via specimen bar codes
using the integral DMS. See, for example, AccuMed/MDI U.S. Pat.
Nos. 5,963,368; 6,091,842; and 6,148,096, which are incorporated
herein by reference.
[0244] The laboratory system will also include, for example, slide
autostainers and autocoverslippers (and/or combination automated
stainer/coverslipper devices) controlled via the DMS that utilize
the same slide cassette as the present LBP device. Cassettes
containing processed slides can be utilized directly in these
additional devices without the need to unload slides and reload
them into separate racks.
[0245] The inter-connectivity and high degree of automation of the
processing and analytical devices making up the laboratory system
will enable high-quality, high-throughput specimen processing and
analysis at relatively low cost.
INDUSTRIAL APPLICABILITY
[0246] The above disclosure presents a safe, effective, accurate,
precise, reproducible, inexpensive, efficient, fast and convenient
vial-based system and method for collecting, handling and
processing liquid-based cellular specimens, providing fully
integrated specimen and information management in a complete
diagnostic cytology laboratory system.
* * * * *