U.S. patent application number 12/947266 was filed with the patent office on 2011-03-17 for fluid sample testing system.
This patent application is currently assigned to CHEN & CHEN, LLC. Invention is credited to Shuqi Chen.
Application Number | 20110064613 12/947266 |
Document ID | / |
Family ID | 22222913 |
Filed Date | 2011-03-17 |
United States Patent
Application |
20110064613 |
Kind Code |
A1 |
Chen; Shuqi |
March 17, 2011 |
FLUID SAMPLE TESTING SYSTEM
Abstract
A sample testing vessel may include a flexible plastic tube and
a self-sealing injection channel. The flexible plastic tube may
have a seal defining a first compartment and a second compartment,
wherein the seal comprises a pressure gate providing a fluid-tight
seal between first and second compartments and opening upon
application of a threshold pressure. The injection channel may be
normally substantially free of fluid and capable of fluid
communication with the tubule.
Inventors: |
Chen; Shuqi; (Framingham,
MA) |
Assignee: |
CHEN & CHEN, LLC
Framingham
MA
|
Family ID: |
22222913 |
Appl. No.: |
12/947266 |
Filed: |
November 16, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12036750 |
Feb 25, 2008 |
7833489 |
|
|
12947266 |
|
|
|
|
10863603 |
Jun 8, 2004 |
7337072 |
|
|
12036750 |
|
|
|
|
09910233 |
Jul 20, 2001 |
6748332 |
|
|
10863603 |
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|
09339056 |
Jun 23, 1999 |
6318191 |
|
|
09910233 |
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60090471 |
Jun 24, 1998 |
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Current U.S.
Class: |
422/62 ;
422/68.1 |
Current CPC
Class: |
B01F 13/0818 20130101;
G01N 35/08 20130101; G01N 35/1002 20130101; B01F 15/028 20130101;
B01L 3/505 20130101; B01L 3/5027 20130101; B01F 15/0278 20130101;
B01L 3/0293 20130101; Y10T 436/10 20150115; B01F 15/029 20130101;
B01L 3/50 20130101; Y10T 436/118339 20150115; G01N 35/1079
20130101; B01F 15/0279 20130101; B01F 11/0065 20130101; G01N
35/00009 20130101 |
Class at
Publication: |
422/62 ;
422/68.1 |
International
Class: |
G01N 33/48 20060101
G01N033/48 |
Claims
1. A sample testing vessel comprising: a flexible plastic tube
having a seal defining a first compartment and a second
compartment, wherein the seal comprises a pressure gate providing a
fluid-tight seal between first and second compartments and opening
upon application of a threshold pressure; and a self-sealing
injection channel, the injection channel being normally
substantially free of fluid and capable of fluid communication with
the tubule.
2. The sample testing vessel of claim 1, wherein the threshold
pressure is 2 atmospheres.
3. The sample testing vessel of claim 1, wherein the pressure gate
opens reversibly.
4. A sample testing system, comprising: a housing; a cavity in the
housing, so sized and shaped to receive a vessel comprising at
least two flexible compartments; a sealing apparatus to form a
lateral seal in the vessel; a first contact member, so positioned:
as to be engageable with a first one of the flexible compartments
when the vessel is in the cavity; and as to compress the engaged
first flexible compartment, thereby driving fluid flow from the
engaged first flexible compartment to a second one of the flexible
compartments of the vessel; and a second contact member, so
positioned: as to be engageable with the second flexible
compartment when the vessel is in the cavity; and as to compress
the engaged second flexible compartment, thereby driving fluid flow
from the engaged second flexible compartment to the first flexible
compartment.
5. The sample testing system of claim 4, further comprising a
sensor to sense a condition of a fluid sample in the vessel and to
generate an output signal indicative of that condition.
6. The sample testing system of claim 4, further comprising a
temperature control device to control a temperature of at least one
compartment of the vessel.
7. The sample testing system of claim 4, further comprising a base
member positioned such that the vessel is compressed against the
base member when engaged by a contact member.
8. The sample testing system of claim 4, further comprising a
reagent injector having at least one needle in fluid communication
with a reagent reservoir, the injector positioned to permit
injection of a reagent from the reagent reservoir into a vessel
compartment.
9. The sample testing system of claim 4, further comprising a
computer that controls the first and second contact members to
cause the first and second flexible compartments to be alternately
compressed by the first and second contact members, respectively,
thereby driving fluid flow between the first and second flexible
compartments.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
12/036,750, filed Feb. 25, 2008, now U.S. Pat. No. 7,833,489, which
is a continuation of application Ser. No. 10/863,603, filed Jun. 8,
2004, now U.S. Pat. No. 7,337,072, which is a continuation of
application Ser. No. 09/910,233, filed Jul. 20, 2001, now U.S. Pat.
No. 6,748,332, which is a continuation of application Ser. No.
09/339,056, filed Jun. 23, 1999, now U.S. Pat. No. 6,318,191, which
claims the benefit of U.S. Provisional Application No. 60/090,471,
filed Jun. 24, 1998. Each of the aforementioned applications is
hereby incorporated herein by this reference.
INTRODUCTION
[0002] The present invention is directed to a system for testing a
fluid sample, and, more particularly, to a fluid sample testing
system having improved automation, safety and efficiency.
BACKGROUND
[0003] Collection, transportation and pretreatment of fluid
samples, such as blood samples, are currently done generally in a
manual fashion. Blood is commonly collected in test tubes and
samples from these test tubes are deposited in reaction chambers
for testing. These tubes can be placed in an automated testing
machine to perform testing using various assays. This process can
be expensive, time consuming, and may lead to human error, possibly
leading to false test results. Current automated testing systems
require large capital investment; incur high costs for reagents,
disposables, operation, maintenance, service and training; and do
not provide required sample pretreatment.
[0004] It is an object of the present invention to provide a sample
testing system which reduces or wholly overcomes some or all of the
aforesaid difficulties inherent in prior known devices. Particular
objects and advantages of the invention will be apparent to those
skilled in the art, that is, those who are knowledgeable or
experienced in this field of technology, in view of the following
disclosure of the invention and detailed description of certain
preferred embodiments.
SUMMARY
[0005] The principles of the invention may be used to advantage to
provide a sample testing system which is highly automated, thereby
increasing efficiency, reducing costs, and increasing safety due to
reduced handling of samples. A sample can be collected in a chamber
which is then divided into a plurality of sealed segments. A
reagent can be added to a segment and the segment can be inspected
to detect a condition of the sample.
[0006] In accordance with a first aspect, a sample testing system
has a chamber sealing apparatus to form a plurality of seals
defining a plurality of fluid-tight segments of the chamber. A
reagent injector cartridge actuator is adapted to receive a reagent
injector cartridge having at least one needle in fluid
communication with a reagent reservoir, and to move a reagent
injector cartridge to inject a quantity of reagent into a segment
of a chamber. A sensor generates an output signal corresponding to
a condition of a fluid sample material within a segment of a
chamber.
[0007] In accordance with another aspect, a sample testing system
has a tube sealing apparatus having a tube compression and sealing
member to laterally seal a flexible plastic tube containing a fluid
sample material, whereby a fluid-tight tubule containing a portion
of the fluid sample material can be formed between axially spaced
lateral seals. A reagent injector cartridge actuator is adapted to
receive a reagent injector cartridge having at least one needle in
fluid communication with a reagent reservoir, and to move a reagent
injector cartridge to inject a quantity of reagent into a tubule. A
flow control device has a contact member movable into contact with
a tubule to effect mechanically induced fluid flow within a fluid
passageway in the tubule. An inspection system has a light detector
to receive light passed through a tubule and to generate an output
signal corresponding to a condition of the fluid sample material
within a tubule.
[0008] In accordance with another aspect, a sample testing system
has a tube sealing apparatus having a tube compression and sealing
member to laterally seal a flexible plastic tube containing a fluid
sample material, whereby a fluid-tight tubule containing a portion
of the fluid sample material can be formed between axially spaced
lateral seals. A reagent injector has at least one needle in fluid
communication with a reagent reservoir, and a needle actuator to
insert the needle into a tubule and inject a quantity of reagent
into a tubule. A flow control device has a contact member movable
into contact with a tubule to effect mechanically induced fluid
flow within a fluid passageway in the tubule. An inspection system
has a light detector to receive light passed through a tubule and
to generate an output signal corresponding to a condition of the
fluid sample material within a tubule.
[0009] In accordance with another aspect, a reagent cartridge has a
housing and at least one reservoir in the housing. At least one
needle in the housing is in fluid communication with one of the
reagent reservoirs. A needle actuator inserts the needle into a
tubule and injects a quantity of reagent.
[0010] In accordance with yet another aspect, a sample testing
tubule has a length of flexible plastic tube having fluid-tight
lateral seals at axially spaced locations to define a fluid-tight
fluid sample chamber between the lateral seals containing a fluid
sample material. A self-sealing injection channel is formed in the
tubule, the injection channel being normally substantially free of
fluid sample material and capable of fluid communication with the
fluid sample material in the tubule.
[0011] In accordance with another aspect, a method of performing a
sample assay includes the following steps: collecting a sample of
fluid material into a length of substantially transparent,
flexible, heat-sealable, plastic tube; inserting the tube into a
sample testing machine having a tube sealing apparatus, a reagent
injector having at least one needle in fluid communication with a
reagent reservoir and a needle actuator to insert the needle into a
tubule and inject a quantity of reagent, a flow control device
having a contact member movable into contact with a tubule to
effect mechanically induced fluid flow within the tubule, and an
inspection system having a light detector to receive light passed
through a tubule and to generate an output signal corresponding to
a condition of the sample material within a tubule; actuating the
tube sealing apparatus to seal lengths of the tube into tubules;
actuating the needle actuator to insert the needle into a selected
tubule and inject reagent to form a mixture of sample material and
reagent in the selected tubule; actuating the flow control device
to mix the mixture of sample material and reagent; and actuating
the inspection system to inspect the mixture and to generate an
output signal corresponding to a condition of the mixture.
[0012] From the foregoing disclosure, it will be readily apparent
to those skilled in the art, that is, those who are knowledgeable
or experienced in this area of technology, that the present
invention provides a significant technological advance. Preferred
embodiments of the fluid sample testing system of the present
invention can provide increased efficiency, reduced costs, and
increase safety. These and additional features and advantages of
the invention disclosed here will be further understood from the
following detailed disclosure of certain preferred embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] Certain preferred embodiments are described in detail below
with reference to the appended drawings wherein:
[0014] FIG. 1 is a partially schematic perspective view of a sample
testing system in accordance with a preferred embodiment of the
present invention;
[0015] FIG. 2 is a schematic representation of the components of
the sample testing system of FIG. 1;
[0016] FIG. 3 is a schematic perspective view, partially in
phantom, of a tube sealing apparatus of the testing system of FIG.
1;
[0017] FIG. 4 is a schematic elevation view, shown partially cut
away, of a tube being compressed by the tube sealing apparatus of
FIG. 3;
[0018] FIG. 5 is a schematic elevation view, shown partially cut
away, of a tube being sealed by the tube sealing apparatus of FIG.
3;
[0019] FIG. 6 is a schematic plan view of a sealing head of the
tube sealing apparatus of FIG. 3;
[0020] FIG. 7 is a schematic plan view of a plurality of tubules
formed in a length of tube by the tube sealing apparatus of FIG.
3;
[0021] FIG. 8 is a schematic plan view of an alternative embodiment
of a sealing head of the tube sealing apparatus of FIG. 3;
[0022] FIG. 9 is a schematic plan view of another alternative
embodiment of a sealing head of the tube sealing apparatus of FIG.
3;
[0023] FIG. 10 is a schematic section view of a reagent cartridge
suitable for use in the sample testing system of FIG. 1;
[0024] FIG. 11 is a schematic section view of an alternative
embodiment of a reagent cartridge for the sample testing system of
FIG. 1;
[0025] FIG. 12 is a schematic section view of the reagent cartridge
of FIG. 11 shown injecting reagent into a tubule;
[0026] FIG. 13 is a schematic section view of another alternative
embodiment of a reagent cartridge of the sample testing system of
FIG. 1;
[0027] FIG. 14 is a schematic section view of yet another
alternative embodiment of a reagent cartridge of the sample testing
system of FIG. 1;
[0028] FIG. 15 is a schematic elevation view of a flow control
device and inspection system of the sample testing system of FIG.
1;
[0029] FIG. 16 is a schematic elevation view of an alternative
embodiment of the flow control device of the sample testing system
of FIG. 1;
[0030] FIG. 17 is a schematic elevation view of another alternative
embodiment of the flow control device of the sample testing system
of FIG. 1;
[0031] FIG. 18 is a schematic elevation view of yet another
alternative embodiment of the flow control device of the sample
testing system of FIG. 1;
[0032] FIG. 19 is a schematic elevation view of an alternative
embodiment of the inspection system of the sample testing system of
FIG. 1;
[0033] FIG. 20 is a schematic elevation view of another alternative
embodiment of the inspection system of the sample testing system of
FIG. 1;
[0034] FIG. 21 is a schematic elevation view of a coating being
applied to a tubule of the present invention;
[0035] FIG. 22 is a schematic perspective view of a reagent
cartridge and a tube divided into tubules, suitable for the sample
testing system of FIG. 1;
[0036] FIG. 23 is a schematic perspective view of one preferred
embodiment of a tube of the present invention and a drawing device
into which the tube is placed;
[0037] FIG. 24 is a schematic elevation view of an alternative
embodiment of the tube sealing apparatus of FIG. 1; and
[0038] FIG. 25 is a schematic plan view of an alternative
embodiment of a tubule of the present invention, shown with a
pressure gate between compartments of the tubule.
[0039] The figures referred to above are not drawn necessarily to
scale and should be understood to present a representation of the
invention, illustrative of the principles involved. Some features
of the sample testing system depicted in the drawings have been
enlarged or distorted relative to others to facilitate explanation
and understanding. The same reference numbers are used in the
drawings for similar or identical components and features shown in
various alternative embodiments. Sample testing system as disclosed
herein, will have configurations and components determined, in
part, by the intended application and environment in which they are
used.
DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS
[0040] The present invention has many uses which will become
readily apparent to those skilled in the art, given the benefit of
this disclosure. Sample material to tested may be, e.g., blood,
cell suspensions, biofluids or other fluids. Exemplary tests to be
performed on fluid samples include clinical diagnosis, therapeutic
monitoring, and screening of chemical compounds for discovery of
new drugs. The following discussion will discuss blood testing
specifically for purposes of illustration.
[0041] The present invention provides for a chamber containing a
fluid sample to be divided into a plurality of segments, with
fluid-tight seals separating adjacent segments from one another. It
is considered to be a highly advantageous feature of certain
preferred embodiments that a chamber into which a fluid sample is
drawn, e.g., a tube into which a patient's blood is drawn, can
itself then also be the testing or reaction chamber within which
that blood or other fluid sample is tested, without ever having to
remove the blood or fluid sample from the chamber.
[0042] Referring to FIG. 1, a testing machine according to the
present invention is shown generally by the reference numeral 2.
Testing machine 2 comprises a housing 4 having an entry port 6 on a
front side thereof for receiving a chamber containing a fluid
sample. In the illustrated embodiment, the chamber is a tube 8 from
a blood bag 10. Tube 8 is preferably a flexible, thermoplastic,
substantially transparent tube having an inner diameter of
approximately 1 mm to 5 mm, preferably approximately 3-4 mm. Tube 8
may be formed of polyvinylchloride (PVC) or other suitable
material. A control panel 7 is located on the front of housing 4 to
receive information, such as information read from bar code labels
or keyed data, and a monitor 5 displays operating information, such
as the results of testing. A tube sealing apparatus 12, described
in greater detail below, is contained within housing 4 for sealing
portions of tube 8 into tubules 14. Reagent cartridge 60 is loaded
into a reagent cartridge actuator 49 in housing 4, with reagent
from reservoirs 16 contained within reagent cartridge 60 being
added to tubules 14 (described in greater detail below). A sensor
41 in housing 4 reads a bar code label 73 (seen in FIG. 22) on
reagent cartridge 60 which provides information identifying the
particular reagent or reagents in reagent cartridge 60 as well as
information regarding test procedures associated with the
particular reagent or reagents. Mixing device or flow control
device 18, seen in FIG. 2 and described in greater detail below, is
also contained within housing 4 for creating a fluid passageway to
allow the flow of cells within tubule 14. Computerized microscopic
inspection system 20 is mounted in housing 4 to view and analyze
the flow of cells within tubule 14. In certain preferred
embodiments, multiple testing machines 2 may be connected to
computer analysis and system control components of inspection
system 20, either directly, or via a computer network. In certain
preferred embodiments, flow control device 18 may not be present,
or may not be employed if present. In such an alternative
embodiment, inspection system 20 inspects a sample within tubule 14
without a flow of cells within the sample being created.
[0043] A tube advancement system 3 is provided to support and
control forward movement of tube 8 through testing machine 2.
Suitable tube advancement systems will become readily apparent to
those skilled in the art, given the benefit of this disclosure. In
the embodiment illustrated in FIG. 2, tube advancement system 3
comprises a pair of rotating wheels 22 which rotate in opposite
directions to advance the tube. At least one wheel 22 is connected
to and driven by output shaft 23 of a motor which is not shown.
Tube 8 is inserted between rotating wheels 22 and advanced into
tube sealing apparatus 12. The volume of sample within each tubule
14 is controlled by compressing tube 8. Specifically, upper plunger
9 and lower plunger 11 are spaced apart from one another and
movable toward one another to partially compress a tubule 14
positioned therebetween prior to it being sealed. An upper, or
first sealing head 24 and a lower, or second sealing head 26
compress a portion of tube 8 and then use radio frequency energy to
seal tube 8, forming lateral seals 13 between adjacent tubules 14.
Lateral seals, as used herein, refer to seals which separate
axially adjacent portions of tube 8. In a preferred embodiment, the
lateral seals extend substantially perpendicular to a longitudinal
axis of tube 8. Seals 13 are fluid-tight seals, that is, seals 13,
under normal operating conditions, prevent the flow of fluid
through the seal. Each tubule 14 contains a sample of blood. The
length of each tubule 14 is preferably approximately 3 to 15 mm,
and more preferably about 5 to 10 mm. Reagent is added to tubule 14
via needle 15 of injector 17.
[0044] Tubules 14 then advance to one of an incubation chamber 19,
a centrifuge 35, or flow control device 18. Flow control device 18
forms a pair of reservoir zones in tubule 14 with a thin fluid
passageway extending between the reservoirs. Light from light
source 28 is projected through the tubule 14 in flow control device
18. A camera with a microscopic lens 30 captures images of blood
cell aggregates flowing from one reservoir zone to the other
through the thin passageway. It sends the images to a frame grabber
32, which in turn sends the images to programmable control system
or computer 34 for analysis. The results of the testing done in
computer 34 may be transmitted to display 7, seen in FIG. 1, for
reading by an operator. In other preferred embodiments, the results
of the testing may be stored for later retrieval, or forwarded to
another computer or other device, e.g. a printer for preparing a
hard copy of the results.
[0045] Centrifuge 35 is provided to separate components of the
sample in a length of tube 8 in a known fashion. A length of tube
8, typically longer than a typical tubule 14, is conveyed to
centrifuge 35 via suitable conveying means. Once the components of
the sample in the length of tube 8 have been separated, the length
of tube is sealed into tubules 14 providing a fluid-tight seal
between the different components. The length of tube is sealed
either by a tube sealing apparatus at centrifuge 35, or it may be
advanced to tube sealer 12 by suitable conveying means for sealing.
Centrifuge 35 may also be used during testing in order to perform
certain assays.
[0046] In certain preferred embodiments, selected tubules 14 may be
stored in incubation chamber 19 prior to advancing to flow control
device 18. Incubation chamber 19 may provide temperature control of
tubules 14, and may allow the addition of a second reagent to
tubules 14. Temperature controlling means 21 is connected to
incubation chamber 19 to heat and/or cool incubation chamber 19. It
is to be appreciated that the temperature of tubules 14 may be
controlled directly, such as with a temperature sensor detecting
the temperature of tubules 14 and maintaining a desired setpoint
temperature. Alternatively, the temperature of the tubules could be
controlled indirectly by sensing and controlling the temperature of
incubation chamber 19. Temperature controlling means 21 may include
a heating element and may also include a cooling device. Other
suitable temperature controlling means will become readily apparent
to those skilled in the art given the benefit of this
disclosure.
[0047] Turning now to FIG. 3, tube sealing apparatus 12 will be
shown in greater detail. Tube sealing apparatus 12 comprises upper,
or first sealing head 24 and lower, or second sealing head 26.
Upper sealing head 24 has conductors 36 extending from an upper
surface 38 to a lower sealing surface 40. Lower sealing head 26
also has conductors 36 extending from an upper sealing surface 42
to a lower surface 44. Conductors 36 are connected by cables 45 to
a power source 46 which creates a radio frequency (RF) electrical
field between the conductors 36 of upper sealing head 24 and lower
sealing head 26 which heat seals tube 8. Conductors 36 are
preferably formed of a material having high electrical and heat
conductivity. Suitable materials for conductor 36 are, for example,
metals such as copper. Other suitable materials for the sealing
heads will become readily apparent to those skilled in the art,
given the benefit of this disclosure. Upper sealing head 24 and
lower sealing head 26 are preferably formed of a substantially
rigid insulating material having high heat conductivity. Suitable
materials for the sealing heads include plastics such as nylon.
Other suitable materials for the sealing heads will become readily
apparent to those skilled in the art, given the benefit of this
disclosure. Resilient pads 48 are preferably located at the outer
edges of lower sealing surface 40 and upper sealing surface 42.
Resilient pads 48 may be formed of rubber, silicone rubbers,
teflon, fluoropolymers, or any other suitable resilient material.
In certain preferred embodiments, a central bar 50 may be located
between a pair of conductors 36. As seen in FIG. 4, both upper
sealing head 24 and lower sealing head 26 have a central bar 50. It
is to be appreciated that in certain preferred embodiments, only
upper sealing head 24 may have a central bar 50, while lower
sealing head 26 has a single conductor 36.
[0048] As seen in FIG. 4, tube 8, containing fluid sample 51, e.g.,
whole blood, is passed between upper sealing head 24 and lower
sealing head 26. The volume of a portion of tube 8, or tubule 14,
is adjusted by compressing upper bar 9 and lower bar 11 together
about tubule 14. In certain preferred embodiments, the volume of
tubule 14 is approximately 20 .mu.l. The tubule 14 may contain, for
example, approximately 5 .mu.l of whole blood or approximately 15
.mu.l of plasma. Upper and lower sealing heads 24, 26 are then
squeezed together under pressure, compressing a portion of tube 8
and pushing fluid sample 51 outwardly in the direction of arrows A.
As sealing heads 24, 26 compress tube 8, a sample free zone 52 is
created, that is, a zone is created within tube 8 which is
substantially free of any fluid sample 51. The pressure must be
sufficient to squeeze fluid sample 51 out of sample free zone 52 as
well as sufficient to prevent pressure in tubule 14 from forcing
fluid sample 51 back into sample free zone 52, especially during
sealing. The required pressure forcing sealing heads 24, 26
together is dependent on the material of tube 8, as well as its
diameter and wall thickness. In certain preferred embodiments,
fluid sample 51 is approximately 2 mm away from conductors 36 which
provide the sealing of tubule 14.
[0049] As seen in FIG. 5, central bar 50 is then raised, releasing
the pressure in a central area of sample free zone 52 and creating
an injection channel 54 which is also free of fluid sample 51.
Power source 46 then supplies RF power through cables 45 to
conductors 36 which seals tube 8 forming seal 13. In certain
preferred embodiments, the frequency of the RF power supplied is
approximately 40 MHz. The RF power is supplied for a time period
typically less than one second. The power and duration of the
supplied RF energy may vary based on the size of tube 8 and the
material of which it is constructed. Upper sealing member 24 is
then raised, tube 8 is advanced to the left as seen in FIG. 4, and
tube 8 is sealed again, forming a tubule 14 between seals 13. By
creating sample free zone 52, fluid sample 51 is kept a safe
distance from conductors 36 when the RF power is applied, thereby
reducing negative effects on fluid sample 51 from the RF power and
the heat it generates.
[0050] In the embodiment illustrated in FIG. 4, lower sealing head
26 is fixed and upper sealing head 24 moves downwardly in the
direction of arrows B toward lower sealing head 26. In other
preferred embodiments, upper sealing head 24 may be fixed with
lower sealing head 26 moving toward upper sealing head 24, or both
upper and lower sealing heads 24, 26 may move toward one
another.
[0051] In the embodiment illustrated in FIGS. 4, 5, lower sealing
surface 40 and upper sealing surface 42 have a substantially convex
profile. Thus when sealing heads 24, 26 are brought together, tube
8 is compressed a maximum amount in the central area of heads 24,
26, that is, in sample free zone 52, and compresses to a lesser
extent outside of sample free zone 52.
[0052] In certain preferred embodiments, as seen in FIG. 6, central
bar 50 has an L shaped, or inverted L shaped profile. In the
embodiment illustrated, central bar 50 of first sealing head 24 has
an inverted L shape and central bar 50 of second sealing head 26
has an L shape. Conductor 36 is formed of conductor element 36A and
conductor element 36B, spaced apart by central bar 50. Conductor
element 36A extends along the long leg of central bar 50 and
terminates at its short leg. Conductor element 36B extends along
the length of the long leg of central bar 50. Lines W represent the
width of a tube 8 which is sealed by sealing heads 24, 26. It can
be seen that the sealing heads extend beyond the edge of the tube
such that the seal, when formed, extends across the entire width of
the tube. When the RF power is applied, as seen in FIG. 7, seal 13,
comprising first portion 13A and second portion 13B is formed only
in the areas where conductor elements 36A, 36B lie, creating L
shaped injection channel 54 which is capable of being in fluid
communication with tubule 14. However, tension in the area of seal
13 prevents fluid sample 51 from entering injection channel 54.
Reagent is added to injection channel 54 through needle 15, seen in
FIG. 2 and described in greater detail below. The amount of reagent
added to tubule 14 is preferably approximately 1-15 .mu.l depending
on the assay being performed. By maintaining injection channel 54
free of fluid sample 51, any leakage from tubule 14 is prevented
when a needle punctures the side wall of the tube to inject reagent
into the tubule through injection channel 54. In certain preferred
embodiments, the needle puncture in injection channel 54 has been
found to be able to withstand pressure of up to approximately 3
atm. without leaking.
[0053] The specific configuration of injection channel 54 is not
critical, except that it must be sufficiently large to receive the
reagent injection needle. Also, in accordance with a highly
advantageous aspect, indicated above, it is sufficiently small so
as to be self-sealing. That is, the bore, length, and configuration
of the injection channel are such that the passageway is normally
substantially devoid of fluid sample. Given the benefit of this
disclosure of the general concept and principles of the injection
channel, it will be within the ability of those skilled in the art
to select suitable dimensions and configurations for the injection
channel, taking into account the size, wall thickness and
resiliency of the flexible plastic tube. Thus, while the injection
channel is normally closed or collapsed so as to be devoid of fluid
sample, it still provides fluid communication into the main fluid
chamber within the tubule. That is, reagent or other fluid injected
into the injection channel under suitable injection pressure passes
through the injection channel to the main chamber. Once the
injection needle is withdrawn, however, the injection channel
returns to its closed or collapsed condition such that leakage does
not occur during normal operating conditions through the hole in
the wall formed at the end of the passageway by the needle.
[0054] In another preferred embodiment, seen in FIG. 8, central bar
50' has a T shaped profile with conductor 36 comprising conductor
elements 36B, 36C, and 36D. In yet another preferred embodiment,
seen in FIG. 9, conductor 36 is formed of a single conductor
element 36E. In this embodiment, a single lateral seal 13 is formed
across tube 8. Alternatively, tube 8 or tube sealing apparatus 12
can be repositioned after a first seal 13A is formed, creating a
second seal 13B as seen in FIG. 7 to form an injection channel
54.
[0055] As shown in FIG. 2, needle 15 is inserted into tubule 14,
preferably into injection channel 54, to add reagent to fluid
sample 51 into tubule 14. In a preferred embodiment, the reagent is
added through injection channel 54 prior to upper and lower sealing
heads 24, 26 being fully released. In other preferred embodiments,
the reagent is added just prior to the tubule 14 entering flow
control device 18, so that the inspection of the sample is done
soon after the reagent has been added. Reagent can be drawn from
reservoir 16 by releasing upper and lower bars 9, 11, creating
vacuum pressure within tubule 14 and drawing reagent into tubule
14. Central bar 50 may then be depressed, forcing any reagent
remaining in injection channel 54 into tubule 14.
[0056] As seen in FIG. 24, tube sealing apparatus 55 may comprise a
pair of rotatable wheels 57 having a plurality of circumferentially
disposed teeth 59. The outer surface of each tooth 59 is
substantially planar or curvoplanar. A conductor 61 operably
connected to power source 46 by cables (not shown) is located
within each tooth 59. The surface 63 of wheels 57 extending between
teeth 59 is substantially concave. Wheels 57 rotate in opposite
directions to progress tube 8 through tube sealing apparatus 55,
with surfaces 63 preferably being configured to compress each
portion of tube 8 between the seals to a desired volume. As an
opposed pair of teeth 59 meet, radio frequency energy or heat, etc.
is transmitted through conductors 61, forming seal 13 in the manner
described above.
[0057] In other preferred embodiments, sealing of the chamber or
tube 8 can be accomplished by other suitable sealing means.
Examples of other sealing means include, for example, mechanical
clamps, a fold lock, ultrasound fusion, and direct application of
heat to the tube. Tube 8 may, in certain preferred embodiments, be
a heat shrinkable tube and the tube sealing apparatus may be a
device for applying focused heat to each of the seal locations
along the length of the tube.
[0058] In another preferred embodiment, shown in FIG. 10, reagent
reservoir 16 may be contained in a reagent cartridge 60 having
housing 62. Bladder 64 is disposed within housing 62 and is secured
to an inner wall of housing 62 by ring 66. Reagent is thus
contained within bladder 64. Needle 15 extends from housing 62 and
is preferably covered by resilient cover 68. Vent 70 is provided in
an upper surface of housing 62 and a filler plug 71 is provided in
housing 62 for adding reagent. In certain preferred embodiments,
magnetic stirrer 72 is positioned in reservoir 16 on a bottom
surface of housing 62. A magnetic field generator 74 positioned
outside housing 62 creates rotation of magnetic stirrer 72, mixing
the reagent, e.g. a cell suspension, prior to injection into tubule
14. The reagent may also be mixed by other means such as shaking.
Tube 76 of piezoelectric material surrounds needle 15 and serves as
a drop generator as described more fully in U.S. Pat. No.
4,329,698, the contents of which are incorporated herein by
reference. Multiple reservoirs 16 of reagent may be contained
within reagent cartridge 60, allowing different reagents to be
added to different tubules 14 as they pass through testing machine
2.
[0059] One preferred embodiment is shown in FIG. 22. In the
illustrated embodiment, reagent cartridge 60 contains 12 reservoirs
of different reagents, each reservoir having its own needle 15, and
each reagent being used for a specific test. A bar code label 73 on
reagent cartridge 60 provides information to identify particular
reagents contained therein and test procedure necessary for
programming the sample test system. Tubules 14 are moved in an
axial direction, preferably in step-wise fashion, past reagent
cartridge 60. Reagent cartridge 60 is movable in a direction
transverse to a longitudinal axis of the tubules in order to
position the proper needle 15 corresponding to a desired reagent,
at the injection channel of each tubule in turn. Once reagent
cartridge 60 is properly positioned, needle 15 is injected into
tubule 14 to inject the desired reagent.
[0060] Another preferred embodiment is shown in FIG. 11, where
reagent cartridge 60A has housing 62A with an adapter 78 located on
an upper surface of housing 62A to receive air nozzle 80. In use,
as seen in FIG. 12, needle 15 extends through resilient cover 68
and penetrates the wall of tubule 14. In the preferred embodiment
illustrated, needle 15 extends into injection channel 54. Air
pressure is introduced onto bladder 64 through air nozzle 80,
causing reagent from reservoir 16 to be forced into tubule 14. In
the embodiment illustrated, needle 15 is fixed with respect to
reagent cartridge 60A, and the entire reagent cartridge 60A is
moved vertically by actuator 49 (seen in FIG. 1) in order to inject
needle 15 into tubule 14. In other preferred embodiments, needle 15
may be independent of reagent cartridge 60A such that only needle
15 moves in order to inject reagent into tubule 14.
[0061] Another preferred embodiment is shown in FIG. 13, where
reagent cartridge 60B comprises housing 62B having piston 82
disposed therein above reservoir 16 containing reagent. A pair of
resilient annular rings 84 are positioned between piston 82 and an
inner wall of housing 62B, providing a seal between piston 82 and
housing 62B. Shaft 86 is in contact with the upper surface of
piston 82 and pressure is introduced into reservoir 16 as shaft 86
causes piston 82 to be lowered. The pressure in reservoir 16 forces
reagent through needle 15 into tubule 14.
[0062] Yet another embodiment is shown in FIG. 14, where reagent
cartridge 60C comprises housing 62C having resilient sac 88 forming
reservoir 16 therein. Shaft 86 engages an outer surface of sac 88,
introducing pressure into reservoir 16 in order to force reagent
through needle 15.
[0063] In other preferred embodiments, multiple reagent cartridges,
each having a single reservoir or reagent, may be chained together
with a flexible connector such that a large number of reagent
cartridges may be connected together. The connected reagent
cartridges can then, for example, be rolled up to facilitate
storage and delivery.
[0064] In certain preferred embodiments, a reagent cartridge with
multiple needles in fluid communication with a single, or
corresponding multiple reservoirs, may be used to inject, or
deposit reagent simultaneously, or sequentially, into multiple
different tubules. The reagent cartridge may also be used to inject
or deposit reagent into other chambers or containers. For example,
a reagent cartridge with multiple needles in fluid communication
with a single, or corresponding multiple reservoirs, can be used to
simultaneously, or sequentially, inject or deposit reagent into a
plurality of containers, such as the recesses of a ninety-six well
microplate.
[0065] Flow control device 18 is seen in FIG. 15 and comprises
transparent base member 90 upon which tubule 14 is placed.
Transparent central plunger 92 is positioned above tubule 14 and
lowered onto tubule 14 such that tubule 14 is sandwiched between
central plunger 92 and base member 90, creating first and second
reservoir zones 94, 96 in tubule 14, with a narrow flow passage 98
extending therebetween through which a thin layer of sample flows.
A first outer plunger 100 is positioned above first reservoir zone
94 and a second outer plunger 102 is positioned above second
reservoir zone 96. First and second outer plungers 100, 102 are
alternately raised and lowered (shown by arrows D), engaging and
disengaging tubule 14, creating a flow of fluid sample 51 back and
forth through narrow flow passage 98. By sensing the pressure
needed to cause the flow of fluid sample 51 through passage 98, the
specific molecular binding strength between cells or particles in
the sample can be determined. The number of particles or cells in
the sample can be counted, and cell properties such as size and
light intensity can be measured. In a preferred embodiment, the
height of, or gap created by, flow passage 98 is approximately 10
.mu.m to 100 .mu.m, depending on the assay performed. Through such
a narrow passageway, the flow of fluid sample 51 can be analyzed by
computerized microscopic inspection system 20. Light from light
source 28, shown by arrows C, is projected through central plunger
92 and passage 98. Images of fluid sample 51 as it flows through
passage 98 are captured by camera with microscopic lens 30 which
then transfers the images through frame grabber 32 to computer 34
(seen in FIG. 2) for analysis through known signal processing
algorithms. It is to be appreciated that operation of flow control
device 18 may, in certain preferred embodiments, include portions
of time where no flow is generated through passage 98, and camera
30 may capture images of fluid sample 51 during these non-flow
periods. Camera 30 is, in certain preferred embodiments, a
charged-coupled device (CCD) camera. Cell interaction kinetics can
be analyzed by computer 34 by monitoring cell motion and/or
location as well as optical properties of the cells such as light
scattering.
[0066] Cell-cell interaction occurs in tubule 14 when any of
certain known reagents are added to a blood sample. Molecular
interactions occur when the reagent is added to the sample.
Aggregates may be formed in the sample, and the size and
distribution of the aggregates varies depending on the type of
reagent added to fluid sample 51, the shear flow of the sample, and
the time period elapsed after injection of the reagent. In a known
fashion, the size and quantity of aggregates passing through flow
passage 98 allows various types of screening or analysis to be
performed on fluid sample 51. For example, immunodiagnosis such as
blood typing, antibody screening and infectious disease testing can
be performed using the present invention by selecting suitable
known reagents to be injected into one or more tubules.
Specifically, blood forward typing can be performed by adding a
related antibody as the reagent to fluid sample 51 comprising whole
blood. Blood reverse typing can be performed by adding a cell
suspension as the reagent to fluid sample 51 comprising plasma.
Blood reverse typing can also be performed by adding cell
suspension as the reagent to fluid sample 51 comprising whole
blood. Hematology tests for blood components such as red and white
blood cell counts, coagulation and aggregation time testing, and
platelet function tests can be performed as well. The reagent may
comprise anti-analyte coated beads in order to detect specific
analyte in the sample. Other tests such as nucleic acid
amplification and DNA analysis may also be performed in the manner
disclosed here. Blood chemistry analysis can detect, for example,
sugar levels, cholesterol levels, etc. Drug compound testing can
also be performed using the present invention. Other testing which
can be performed using the present invention will become readily
apparent to those skilled in the art, given the benefit of this
disclosure.
[0067] The present invention provides many advantages. A testing
machine can be used cost effectively for many different tests and
groups of tests. The testing machine has high throughput and low
complexity for ease of operation. Bio-safety is increased due to
reduced handling of samples such as blood.
[0068] Computer 34, in certain preferred embodiments, may be
operably connected to tube advancing system 3, tube sealing
apparatus 12, flow control device 18, incubation chamber 19,
centrifuge 35, and inspection system 20 by cables (not shown).
Computer 34 can provide control and coordination of the operating
parameters of the components of testing machine 2 in a known
fashion, and further description of the control of the components
of testing machine 2 need not be provided here.
[0069] In another preferred embodiment, shown in FIG. 16, flow
control device 18A comprises transparent cylindrical plunger 92A
having a longitudinal axis L and a beveled surface 104 formed on
lower surface 106 of plunger 92A. A reservoir 94A is formed beneath
beveled surface 104 and passage 98A is formed beneath lower surface
106. As plunger 92A is rotated about longitudinal axis L, flow
through passage 98A can be observed in the same manner described
above.
[0070] Another preferred embodiment is shown in FIG. 17, where flow
control device 18B comprises transparent plunger 92B having first
and second beveled surfaces 108, 110 formed on a lower surface
thereof. First and second reservoirs 94B, 96B are formed beneath
beveled surfaces 108, 100, respectively, with narrow passage 98B
extending therebetween. As plunger 92B is rocked back and forth,
fluid sample 51 passes back and forth from first reservoir 94B to
second reservoir 96B through passage 98B. The flow of fluid sample
51 is observed by camera 30 as described above.
[0071] Yet another embodiment is shown in FIG. 18, where flow
control device 18C comprises transparent plunger 92C whose lower
surface 112 has an arcuate profile. The arcuate profile of lower
surface 112 creates a narrow flow passage 98C extending between a
first reservoir 94C and a second reservoir 96C. Plunger 92C is
rolled back and forth, forcing fluid sample 51 back and forth from
first reservoir 94C to second reservoir 96C through flow passage
98C. The flow of fluid sample 51 through flow passage 98C is
observed by camera 30 as described above.
[0072] In certain preferred embodiments, as seen in FIG. 19, a
first electrode 120 and a second electrode 122 are inserted into
tubule 14 and are connected by cables 124 to voltage source 126
which creates a voltage difference between first and second
electrodes 120, 122. Red blood cells in fluid sample 51 within
tubule 14 are negatively charged so that by electrophoresis they
are attracted to the positively charged electrode 122. An
electrochemiluminescent reagent is added to tubule 14 by reagent
cartridge 60 or other suitable means, creating an
electrochemiluminescent reaction near the surface of electrode 122
which causes a particular light to be emitted (shown by arrows E)
from electrode 122 based on the type of reagent added to tubule 14.
Sensor 128 receives the transmitted light and generates a
corresponding electrical signal which is sent to computer 34 for
analysis, display, recording, etc. In other preferred embodiments,
a current is passed by first and second electrodes 120, 122 through
the sample. In this embodiment, certain electrochemical properties
of the sample can be measured by analyzing the voltage difference
between the first and second electrodes 120, 122.
[0073] Another preferred embodiment is shown in FIG. 20. First and
second electrodes 130, 132 are inserted into tubule 14. Second
electrode 132 is a fiberoptic sensor. As described above with
respect to FIG. 19, an electrochemiluminescent reaction occurs near
the surface of electrode 132 causing light to be generated. The
light travels through fiberoptic electrode 132 to a fiber optic
sensor, or reader 134 which captures and interprets the information
provided by the type of light generated. Second electrode 132
preferably has a diameter between approximately 0.4 mm and 1 mm.
Second electrode 132 is formed of a material or is coated with a
material suitable for providing sufficient conductivity.
[0074] In certain preferred embodiments, a coating may be deposited
on tubule 14 to increase visibility through the wall of tubule 14.
As seen in FIG. 21, a coating material 140 is transferred through
conduit 142 from coating supply 144 and deposited on the outer
surface of tubule 14. If the walls of tubule 14 are translucent,
the addition of coating 140 to the outer surface of tubule 14 can
make the walls of tubule 14 substantially transparent, increasing
the effectiveness of viewing the flow of fluid sample 51 through
flow passage 98. Coating 140 preferably has the same optical
refractive index as that of the walls of tubule 14. Suitable
materials for coating 140 are dependent on the material of tubule
14 and include, for example, oil.
[0075] Suitable methods for filling a tube with a sample will be
apparent to those skilled in the art, given the benefit of this
disclosure. Exemplary methods include injecting sample fluid into
one end of a tube or drawing sample into a tube by creating a
vacuum in the tube. A suitable tube 150 is shown in FIG. 23, having
a self-sealing head 152 at a first end thereof for needle
penetration. Tube 150 may have a label 154 to assist in identifying
the source of the sample, e.g., a patient's name when the sample is
blood. Label 154 may be, e.g., a bar code label. Tube 150 is
inserted into a tube-like drawing device 156 through an aperture
158 at a first end of drawing device 156. To draw a sample into
tube 150, the tube-like drawing device 156 is plugged into a needle
holder commonly used for drawing blood into a vacuum tube, and
slide handle 160 is moved downwardly along drawing device 156. A
pair of opposed rollers (not shown) within drawing device 156 and
operably connected to slide handle 160 compress a portion of, and
roll downwardly along, tube 150, pumping or drawing a sample of
blood into tube 150.
[0076] In some cases a multiple stage reaction within a segment of
a chamber may be desired. In one embodiment, the reagent is
injected through an injection channel in the segment, reacted with
the contents therein, and then, later, a second reagent is added
and reacted with the contents. In an alternative preferred
embodiment, the segment may be formed with a pressure gate,
separating the volume of the segment into two compartments between
which there is fluid communication only at pressure levels achieved
by application of external pressure. Pressure for moving sample
material from one compartment into an adjacent compartment may be
applied, e.g., by hand or by automatic mechanical pressure devices
such as those shown in FIGS. 2, 4, 5 and adapted to apply pressure
to a single compartment.
[0077] One preferred example is shown in FIG. 25, where a segment
or tubule 168 is separated by a seal 170 into first compartment 172
and second compartment 174. Seal 170 is formed in a manner as
described above with respect to seal 13. Seal 170 forms a pressure
gate 176, which, under normal operating conditions, provides a
fluid-tight seal between first and second sub-segments or
compartments 172, 174. In a preferred embodiment, pressure gate 176
opens upon application of pressure greater than a certain value,
for example, approximately 2 atm. When external pressure is applied
to one of the compartments, pressure gate 176 opens, allowing fluid
to flow from the high pressure compartment to the low pressure
compartment. One preferred application is in a two stage antibody
screening wherein first compartment 172 of tubule 168 is pre-filled
with plasma. A first reagent is injected through injection channel
54 into second compartment 174. External pressure is then applied
to second compartment 174, forcing the first reagent into first
compartment 172. A second reagent is added to second compartment
174 through injection channel 54. Tubule 168 is then conveyed by
suitable means to incubation chamber 19 for a predetermined time
period of incubation. Tubule 168 is then conveyed by suitable means
to centrifuge 35 where tubule 168 is spun such that the cells of
the first reagent accumulate proximate pressure gate 176. In
certain preferred embodiments, the second reagent may be added
after tubule 168 has been incubated in incubation chamber 19 or
spun in centrifuge 35. External pressure is applied to first
compartment 172 such that cells of the first reagent are passed to
second compartment 174. Tubule 168 is then conveyed to flow control
device 18 and inspected by inspection system 20 in the manner
described above.
[0078] In light of the foregoing disclosure of the invention and
description of the preferred embodiments, those skilled in this
area of technology will readily understand that various
modifications and adaptations can be made without departing from
the true scope and spirit of the invention. All such modifications
and adaptations are intended to be covered by the following
claims.
* * * * *