U.S. patent application number 12/552218 was filed with the patent office on 2009-12-31 for thermal device, system, and method, for fluid processing device.
This patent application is currently assigned to APPLIED BIOSYSTEMS, LLC. Invention is credited to David M. Cox, Sean M. Desmond, Janice G. Shigeura, John S. Shigeura.
Application Number | 20090325277 12/552218 |
Document ID | / |
Family ID | 35943774 |
Filed Date | 2009-12-31 |
United States Patent
Application |
20090325277 |
Kind Code |
A1 |
Shigeura; John S. ; et
al. |
December 31, 2009 |
Thermal Device, System, and Method, for Fluid Processing Device
Abstract
A device, system, and method are provided for thermally treating
a fluid processing device. According to various embodiments, a
system is provided that can include a thermal device and a fluid
processing device holder. The thermal device can include a first
block having a thermal conductivity greater than 0.5 Watt per
centimeter Kelvin (W/cmK), a second block having a thermal
conductivity greater than 0.5 W/cmK, and a heat-pump device
disposed between the first block and the second block. The
heat-pump device can transfer thermal energy from at least one of
the first block and the second block to the other of the first
block and the second block. The fluid processing device holder can
hold a fluid processing device in a heat-transfer position with
respect to the first block and the second block. The fluid
processing device can be a microfluidic device.
Inventors: |
Shigeura; John S.; (Portola
Valley, CA) ; Shigeura; Janice G.; (Portola Valley,
CA) ; Desmond; Sean M.; (Moorpark, CA) ; Cox;
David M.; (Foster City, CA) |
Correspondence
Address: |
LIFE TECHNOLOGIES CORPORATION;C/O INTELLEVATE
P.O. BOX 52050
MINNEAPOLIS
MN
55402
US
|
Assignee: |
APPLIED BIOSYSTEMS, LLC
Carlsbad
CA
|
Family ID: |
35943774 |
Appl. No.: |
12/552218 |
Filed: |
September 1, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10926915 |
Aug 26, 2004 |
7585663 |
|
|
12552218 |
|
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Current U.S.
Class: |
435/287.2 |
Current CPC
Class: |
G05D 23/22 20130101;
G05D 23/20 20130101; G05D 23/24 20130101; Y02P 20/129 20151101;
G05D 23/192 20130101; Y10S 435/809 20130101 |
Class at
Publication: |
435/287.2 |
International
Class: |
C12M 1/34 20060101
C12M001/34 |
Claims
1. A system comprising: one or more thermal devices, each thermal
device comprising: a first block having a thermal conductivity
greater than 0.5 Watts per centimeter Kelvin (W/cmK), a second
block having a thermal conductivity greater than 0.5 W/cmK, and a
heat-pump device disposed adjacent the first block and the second
block, and adapted to transfer thermal energy from at least one of
the first block and the second block to the other of the first
block and the second block; and a fluid processing device holder
adapted to hold a fluid processing device in a heat-transfer
position with respect to the first block and the second block.
2. The system of claim 1, further comprising a control device
adapted to control the heat-pump device to provide the first block
with a temperature that is greater than the temperature of the
second block.
3. The system of claim 2, wherein the control device is adapted to
control the heat-pump device to transfer heat from the first block
to the second block and to transfer heat from the second block to
the first block.
4. The system of claim 2, wherein the control device is adapted to
control the temperature of the first block to be at least about
15.degree. C. greater than the temperature of the second block.
5. The system of claim 2, wherein the control device is adapted to
control the temperature of the first block to be at least about
40.degree. C. greater than the temperature of the second block.
6. The system of claim 2, wherein the control device is adapted to
control the heat-pump device to heat the first block to about
95.degree. C. and to control the heat-pump device to keep the
temperature of the second block to be less than about 50.degree.
C.
7. The system of claim 2, wherein the heat-pump device includes
electrodes and a bi-direction power supply electrically connected
to the electrodes, and the control device is adapted to control a
direction of the thermal transfer between the first block and the
second block by inverting a Voltage potential supplied by the
bi-directional power supply.
8. The system of claim 7, wherein the control device includes a
computer system.
9. The system of claim 1, wherein the heat pump device is disposed
between the first block and the second block.
10. The system of claim 2, wherein the control device is adapted to
cycle a temperature of the first block from a first temperature to
a second temperature, and back to the first temperature.
11. The system of claim 1, wherein the heat-pump device comprises a
thermoelectric device.
12. The system of claim 11, further comprising a fluid processing
device, wherein the fluid processing device includes an operative
surface in thermal contact with both the first block and the second
block, in a heat-transfer position, the thermoelectric device
includes an active surface, and the operative surface is disposed
transverse to the active surface in the heat-transfer position when
the fluid processing device is held by the fluid processing device
holder.
13. The system of claim 12, wherein the fluid processing device and
the thermoelectric device do not physically contact one another
when a fluid processing device is held by the device holder.
14. The system of claim 1, wherein at least one of the first block
and the second block comprises a surface, and the thermal device
further comprises a thermal interface material disposed in contact
with the surface.
15. The system of claim 14, wherein the thermal interface material
comprises a material compressible to about 90% of an uncompressed
thickness under an executed pressure of at least one pound per
square inch.
16. The system of claim 1, wherein the first block includes a first
heat-transfer surface and the second block includes a second
heat-transfer surface, and the first heat-transfer surface and the
second heat-transfer surface are co-planar with one another.
17. The system of claim 1, wherein the first block includes a first
heat-transfer surface and the second block includes a second
heat-transfer surface, and the first heat-transfer surface and the
second heat-transfer surface are offset with respect to one
another.
18. The system of claim 17, wherein the thermal device further
comprises a thermal interface material disposed on the second heat
transfer surface.
19. The system of claim 1, further comprising at least one heat
sink in thermal contact with at least one of the first block and
the second block.
20. The system of claim 1, further comprising at least one fan
adapted to create an air-current in thermal contact with at least
one of the first block and the second block.
21. The system of claim 1, further comprising at least one
temperature sensor in thermal contact with at least one of the
first block and the second block.
22. The system of claim 1, further comprising a pressing device
adapted to force at least one of the first block and the second
block into thermal contact with a fluid processing device when a
fluid processing device is held by the fluid processing device
holder.
23. The system of claim 1, further comprising an alignment device
to operatively position the fluid processing device holder and the
heat-transfer device with respect to one another.
24. The system of claim 1, wherein the fluid processing device
holder comprises a plurality of fluid processing device
holders.
25. The system of claim 1, wherein the one or more thermal devices
comprises a plurality of thermal devices.
26. The system of claim 1, further comprising a rotatable platen,
wherein the fluid processing device holder is disposed on or in the
rotatable platen.
27. The system of claim 1, wherein the fluid processing device
holder includes a heat-generating device.
28. The system of claim 1, wherein the fluid processing device
holder includes a thermal insulator.
29. The system of claim 1, further comprising a platform, wherein
the thermal device and the fluid processing device holder are
supported by the platform.
30. The system of claim 1, further comprising a fluid processing
device held by the fluid processing device holder, and a thermally
insulating blanket, wherein the fluid processing device is disposed
between the thermal device and the thermally insulating
blanket.
31. The system of claim 1, further comprising: a second thermal
device comprising: a third block having a thermal conductivity
greater than 0.5 W/cmK, a fourth block having a thermal
conductivity greater than 0.5 W/cmK, and a second heat-pump device
disposed between the third block and the fourth block, the second
heat-pump device being adapted to transfer thermal energy from at
least one of the third block and the fourth block to the other of
the third block and the fourth block.
32. The system of claim 1, wherein the thermal device further
comprises a third block having a thermal conductivity greater than
0.5 W/cmK and a second heat-pump device disposed between the first
block and the third block, the second heat-pump device being
adapted to transfer thermal energy from at least one of the first
block and the third block to the other of the first block and the
third block.
33. The system of claim 32, further comprising a control device
adapted to control the heat-pump device to provide the first block
with a temperature that is greater than the temperature of the
third block.
34. The system of claim 1, further comprising a fluid processing
device held by the fluid processing device holder, the fluid
processing device comprising at least one fluid processing pathway
including at least a first fluid retainment region, a second fluid
retainment region, and a fluid communication between the first
fluid retainment region and the second fluid retainment region;
wherein the first fluid retainment region is operatively positioned
in the heat-transfer position with respect to the first block, and
the second fluid retainment region is operatively positioned in the
heat-transfer position with respect to the second block.
35. The system of claim 34, wherein a first thermal conductance
between the first fluid retainment region and the second fluid
retainment region is less than a thermal conductance between the
first fluid retainment region and the first block, and the first
thermal conductance is less than a thermal conductance between the
second fluid retainment region and the second block.
36. The system of claim 34, further comprising a heat-generating
device in thermal contact with the first fluid retainment
region.
37. The system of claim 34, further comprising a fluid movement
device adapted to transfer a fluid from the first fluid retainment
region to the second fluid retainment region via the fluid
communication.
38. The system of claim 34, further comprising a valve manipulation
device, wherein the fluid processing device further includes a
valve between the first fluid retainment region and the second
fluid retainment region, and the valve manipulation device is
adapted to open and close the valve.
39. The system of claim 34, wherein the at least one fluid
processing pathway comprises a plurality of fluid processing
pathways each including a respective first fluid retainment region,
a respective second fluid retainment region, and a respective fluid
communication between the respective first and second fluid
retainment regions, and wherein the plurality of first fluid
retainment regions are aligned linearly with respect to each
other.
40. The system of claim 39, wherein the second fluid retainment
region comprises a plurality of second fluid retainment regions
aligned linearly with respect to each other.
41. The system of claim 34, wherein the fluid processing device
comprises a microfluidic device.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application is a divisional application of U.S.
patent application Ser. No. 10/926,915, filed Aug. 26, 2004, which
is incorporated herein in its entirety by reference.
FIELD
[0002] The present teachings relate to a thermal energy
manipulation system.
BACKGROUND
[0003] There is a need for a device that can provide efficient
thermal cycling of a fluid in a retainment region of a fluid
processing device while maintaining an adjacent second retainment
region at a different temperature. A device compatible with
biological or chemical reactions, for example, nucleotide
amplification chemistries, and laboratory instrumentation adapted
to process a relatively large number of biological/chemical
reactions, is desirable.
BRIEF DESCRIPTION
[0004] According to various embodiments, a system is provided that
can include a thermal device and a fluid processing device holder.
The thermal device can include a first block having a high thermal
conductivity, a second block having a high thermal conductivity,
and a heat-pump device disposed to transfer thermal energy between
the first block and the second block. Herein, high thermal
conductivity refers to a thermal conductivity of greater than 0.5
W/cmK. The heat-pump device can be disposed physically between or
adjacent the first block and the second block. The heat-pump device
can transfer thermal energy from at least one of the first block
and the second block to the other of the first block and the second
block. The fluid processing device holder can hold a fluid
processing device in a heat-transfer position with respect to the
first block and the second block.
[0005] According to various embodiments, a method is provided that
can include providing a fluid processing device including at least
one fluid processing pathway. Each fluid processing pathway can
include at least a first fluid retainment region, a second fluid
retainment region, and a fluid communication between the first
fluid retainment region and the second fluid retainment region. The
method can include providing a thermal device including a first
block having a high thermal conductivity, a second block having a
high thermal conductivity, and a heat-pump device disposed to
transfer thermal energy between the first block and the second
block. The method can include transferring thermal energy from at
least one of the first block and the second block to the other of
the first block and the second block, using the heat-pump device.
At the same time, the fluid processing device can be held in a
heat-transfer position wherein the first fluid retainment region
can be in thermal contact with the first block and the second fluid
retainment region can be in thermal contact with the second block.
The fluid communication can be sealable, interruptible, closeable,
openable, or the like.
[0006] Additional features and advantages of various embodiments
will be set forth in part in the description that follows, and in
part will be apparent from the description, or can be learned by
practice of various embodiments. Other advantages of the various
embodiments will be realized and attained by means of the elements
and combinations particularly pointed out in the application.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] Various embodiments of the present teachings are exemplified
in the accompanying drawings. The teachings are not limited to the
embodiments depicted in the drawings, and include equivalent
structures and methods as set forth in the following description
and as would be known to those of ordinary skill in the art in view
of the present teachings. In the drawings:
[0008] FIG. 1 is a top view of a thermal system according to
various embodiments;
[0009] FIG. 2 is a side, partial cross-sectional view of a thermal
system including a dual-sided thermal device, according to various
embodiments;
[0010] FIG. 3 is an cross-sectional view a thermal system including
a single-sided thermal device, a fluid processing device, and a
platen, according to various embodiments;
[0011] FIG. 4 is a perspective view of a plurality of blocks
positioned with respect to a plurality of linearly-aligned fluid
retainment regions of a fluid processing device, according to
various embodiments;
[0012] FIG. 5 is a perspective view of a plurality of blocks
positioned with respect to a plurality of linearly-aligned fluid
retainment regions of a fluid processing device, according to
various embodiments;
[0013] FIG. 6 is a bottom view of a fluid processing device
positioned over a thermal device, according to various
embodiments;
[0014] FIG. 7a is a front view of an exemplary system that can be
used to process a fluid processing device;
[0015] FIG. 7b is an exploded view of the system shown in FIG. 7a,
in partial phantom, with the top cover removed;
[0016] FIG. 7c is a side view of the device shown in FIG. 7a;
[0017] FIG. 7d is an exploded view in partial phantom of the device
shown in FIG. 7c with the cover open;
[0018] FIG. 7e is an enlarged view of the assembly loading door of
the system shown in FIG. 7a;
[0019] FIG. 7f is an enlarged view of a portion of the system shown
in FIG. 7a, depicting the positions of the valve actuators, thermal
devices, and electronics;
[0020] FIG. 7g is an enlarged view of a section of the system shown
in FIG. 7a partially cutaway to show the two-assembly platen;
[0021] FIG. 7h is an enlarged view of a section of the system shown
in FIG. 7a including an assembly loaded in the assembly-loading
door;
[0022] FIG. 7i is an enlarged view of a section of the system shown
in FIG. 7a, in partial cutaway to show two assemblies loaded for
spinning while being held to the rotating platen; and
[0023] FIG. 8 is an enlarged, perspective view of a fluid
processing device according to various embodiments;
[0024] FIG. 9 is a perspective view of a fluid processing device
according to various embodiments;
[0025] FIG. 10 is a chart of temperatures, plotting the
temperatures of a first fluid in a first fluid retainment region
and a second fluid in a second fluid retainment region, according
to various embodiments; and
[0026] FIG. 11 is a graph that plots the temperatures of five fluid
retainment regions, versus time, achieved according to various
embodiments.
[0027] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are intended to provide a further
explanation of the various embodiments of the present
teachings.
DESCRIPTION OF VARIOUS EMBODIMENTS
[0028] According to various embodiments, a system is provided that
can include a thermal device and a fluid processing device holder.
The thermal device can include a first block, a second block, and a
heat-pump device disposed to transfer thermal energy between the
first block and the second block. Herein, high thermal conductivity
refers to a thermal conductivity of greater than 0.5 W/cmK. The
heat-pump device can be disposed physically between or adjacent the
first block and the second block. The heat pump can be disposed at
ends of, or end regions of, or otherwise adjacent both the first
block and the second block. The heat-pump device can transfer
thermal energy from at least one of the first block and the second
block to the other of the first block and the second block. The
fluid processing device holder can hold a fluid processing device
in a heat-transfer position with respect to the first block and the
second block.
[0029] Each of the first and second blocks can include a thermally
conductive metal material, such as steel or aluminum.
[0030] According to various embodiments, the system can include a
control device to control the heat-pump device to provide the first
block with a temperature that is greater than the temperature of
the second block. The control device can control the heat-pump
device to transfer heat from the first block to the second block
and to transfer heat from the second block to the first block. The
control device can control the temperature of the first block to be
at least, for example, about 15.degree. C., about 30.degree. C., or
about 40.degree. C., greater than the temperature of the second
block. According to various embodiments, the control device can
control the heat-pump device to heat the first block to about
95.degree. C., and to keep the temperature of the second block to
be less than about 50.degree. C.
[0031] According to various embodiments, at least one of the first
block and the second block can include a surface, and the thermal
device can further include a thermal interface material disposed in
contact with the surface. The first block can include a first
heat-transfer surface and the second block can include a second
heat-transfer surface, where the first heat-transfer surface and
the second heat-transfer surface can be flush with and/or co-planar
with one another. According to various embodiments, the heat
transfer surfaces of the first block and the second block can be
slightly offset from one another. For example, the heat transfer
surface of the first block can be positioned relatively raised or
offset as compared to the heat transfer surface of the second
block. The heat transfer surfaces can lie on planes parallel to one
another, but not co-planar. The offset position of the first block
heat transfer surface can improve thermal contact between a fluid
processing device and the first block heat transfer surface. The
offset between the heat transfer surfaces of the first block and
the second block can be, for example, from about 0.005 inch to
about 0.1 inch, or from about 0.01 inch to 0.020 inches.
[0032] A thermal interface material including a flat surface can be
disposed on the heat transfer surface of either or both of the
first block and the second block. The thermal interface material
can be compressible. In an uncompressed state, thermal interface
material provided at the first block can provide a raised surface
relative to the heat transfer surface of the first block. In
operation, the thermal interface material can be compressed against
a portion of a fluid processing device. The thermal interface
material can be raised relative to the first block heat transfer
surface by from about 0.05 inch to about 0.25 inch, in an
uncompressed state. The heat transfer surface of the first block
can be offset by about 0.015 inch compared to the heat transfer
surface of the second block. When a 0.020 inch thick thermal
interface material is disposed against the heat transfer surface of
the second block, the raised surface of the thermal interface
material can protrude about 0.005 inch or more as compared to the
heat transfer surface of the first block. The thermal interface
material can comprise a heat conductive material, for example,
GAPPAD VO ULTRA SOFT available from Berquist Company, Chanhassen,
Minn.
[0033] According to various embodiments, the system can include at
least one heat sink in thermal contact with at least one of the
first block and the second block. The heat sink can be a metal
block with fins or other features providing a large surface area
for thermal exchange with another thermal mass, for example, air.
The system can include at least one fan adapted to create an
air-current in thermal contact with at least one of the first
block, the second block, and if a heat sink is included, the heat
sink.
[0034] The system can include at least one temperature sensor in
thermal contact with at least one of the first block and the second
block. The system can include a pressing device adapted to force at
least one of the first block and the second block into thermal
contact with a fluid processing device when such a fluid processing
device is held by the fluid processing device holder. The system
can include an alignment device to operatively position the fluid
processing device holder and the heat-pump device with respect to
one another.
[0035] According to various embodiments, the system can include a
platform and a second thermal device supported by the platform. The
second thermal device can include a third block, a fourth block,
and a second heat-pump device disposed between the third block and
the fourth block. The second heat-pump device can transfer thermal
energy from at least one of the third block and the fourth block to
the other of the third block and the fourth block. The first block,
the second block, the third block, and the fourth block can be
disposed in respective heat-transfer positions. According to
various embodiments, the first block, the second block, the third
block, and the fourth block can be simultaneously disposed in
respective heat-transfer positions.
[0036] According to various embodiments, the thermal device can
include a third block and a second heat-pump device disposed
between the first block and the third block, where the second
heat-pump device can transfer thermal energy from at least one of
the first block and the third block to the other of the first block
and the third block. The system can include a control device that
can control the heat-pump device to provide the first block with a
temperature that can be greater than the temperature of the third
block. The fluid processing device holder can hold a fluid
processing, for example, a microfluidic card-type device.
[0037] According to various embodiments, the system can include a
fluid processing device held by the fluid processing device holder.
The fluid processing device can include at least one fluid
processing pathway. Each fluid processing pathway can include at
least a first fluid retainment region, a second fluid retainment
region, and a fluid communication between the first fluid
retainment region and the second fluid retainment region. The first
fluid retainment region can be positioned in a heat-transfer
position with respect to the first block of the system, and the
second fluid retainment region can be positioned in a heat-transfer
position with respect to the second block of the system. The system
can include a fluid movement device, unit, or system, adapted to
move or transfer a fluid from the first fluid retainment region to
the second fluid retainment region via the fluid communication. The
system can include a valve manipulation device supported by a
common or a different platform, and the fluid processing device can
include a valve between the first fluid retainment region and the
second fluid retainment region. The at least one fluid processing
pathway can include a plurality of fluid processing pathways each
including a respective first fluid retainment region and a
respective second fluid retainment region. The plurality of first
fluid retainment regions can be aligned linearly with respect to
each other. The plurality of first fluid retainment regions can be
evenly or differently spaced from adjacent first fluid retainment
regions. According to various embodiments, the second fluid
retainment region can include a plurality of second fluid
retainment regions aligned linearly with respect to each other, and
evenly or differently spaced from one another.
[0038] According to various embodiments, a method is provided that
can include manipulating a fluid processing device that includes at
least one fluid processing pathway, wherein the pathway includes at
least a first fluid retainment region, a second fluid retainment
region, and a fluid communication between the first fluid
retainment region and the second fluid retainment region. The
method can include providing a thermal device. The thermal device
can include a first block, a second block, and a heat-pump device
in thermal contact with, for example, disposed between, the first
block and the second block. The method can include transferring
thermal energy from at least one of the first block and the second
block to the other of the first block and the second block using
the heat-pump device, and holding the fluid processing device in a
heat-transfer position. The first fluid retainment region can be in
thermal contact with the first block and the second fluid
retainment region can be in thermal contact with the second
block.
[0039] According to various embodiments, the method can include
controlling the heat-pump device to provide the first block with a
temperature that can be greater than the temperature of the second
block. The controlling can include heating the first block to an
elevated temperature, for example, to a temperature of about
95.degree. C. The method can include maintaining the temperature of
the second block to be less than the elevated temperature, for
example, less than about 50.degree. C. when the elevated
temperature exceeds 50.degree. C. The controlling can include
achieving and maintaining the temperature of the first block to be
at least about 40.degree. C. greater than the temperature of the
second block. The controlling can include inverting a direction of
the thermal transfer with respect to the first block and the second
block. The controlling can include controlling the heat-pump device
to effect heat transfer from the first block to the second block
and/or from the second block to the first block.
[0040] According to various embodiments, the method can include
heating the first block with a heat-generating device. According to
various embodiments, the method can include creating an air-current
in thermal contact with at least one of the first block and the
second block. According to various embodiments, the method can
include cycling a temperature of the first block from a first
temperature to a second temperature, and then back to the first
temperature. According to various embodiments, the method can
include forcing at least one of the first block and the second
block into thermal contact with a fluid processing device.
According to various embodiments, the method can include
positioning the fluid processing device and the thermal device with
respect to one another.
[0041] According to various embodiments, the method can include
providing a second thermal device including a third block, a fourth
block, and a second heat-pump device disposed to transfer heat
between the third block and the fourth block. The second heat pump
can be disposed physically between, at ends of or end regions of,
or otherwise adjacent, the first block and the second block. The
method can include transferring thermal energy from at least one of
the third block and the fourth block to the other of the third
block and the fourth block, and positioning the second thermal
device such that or wherein the third block can be in a
heat-transfer position with respect to the first fluid retainment
region, and the fourth block can be in a heat-transfer position
with respect to the second fluid retainment region.
[0042] According to various embodiments, the method can include
providing the thermal device with a third block and a second
heat-pump device disposed to transfer heat between the first block
and the third block. The second heat-pump device can be adapted to
transfer thermal energy from at least one of the first block and
the third block to the other of the first block and the third
block. The first block can be arranged or disposed, for example,
between the second block and the third block.
[0043] According to various embodiments, the method can include
loading a first set of materials reactive at a first minimum
temperature into the first fluid retainment region and loading a
second material into the second fluid retainment region. The second
material can include a material that can be rendered substantially
ineffective when subjected to the first minimum temperature. The
first set of materials can include nucleic acid amplifying
reagents. The nucleic acid amplifying reagents can include
polymerase chain reaction reagents. The first set of materials can
include oligonucleotide ligase reaction reagents. The second
material can include size-exclusion ion-exchange media. The second
material can include reagents capable of performing purification,
for example, by filtering and/or by ion-exchange.
[0044] According to various embodiments, the method can include
loading a target nucleic acid material and amplifying reagents into
the first fluid retainment region and amplifying the nucleic acid
material by thermal cycling in the first fluid retainment region.
The method can include loading size-exclusion ion exchange media
into the second fluid retainment region. The method can include
loading reagents for a purification reaction into the second fluid
retainment region, for example, ingredients for an ion-exchange
reaction.
[0045] According to various embodiments, the temperature of a fluid
retainment region in a fluid processing device can be controlled by
a thermal cycler that includes a Peltier-effect thermoelectric
device, a heat-pump, an electrical resistance heating element
(Joule heater), fluid flow through channels in a metal block,
reservoirs of fluid at different temperatures, a tempered air
impingement device, or a combination thereof. According to various
embodiments, a plurality of blocks can be maintained at various
temperatures to maintain different temperatures in different fluid
retainment regions of a fluid processing device. The different
temperatures can be maintained in a plurality of areas separated by
imaginary lines drawn between a plurality of fluid retainment
regions in a fluid processing device. According to various
embodiments, a plurality of blocks can be aligned with the
temperatures as desired. Thermal energy can be transferred between
the blocks. Thermal energy can be transferred from the blocks to
the fluid processing device.
[0046] According to various embodiments, cycling of a block
temperature between various temperatures can effect quick changes
in the temperature of a fluid retainment region. More than one heat
pump can be disposed between the blocks to increase the heat
pumping capacity of the system, allowing for faster cooling and/or
heating of the blocks. After achieving a desired temperature for a
block, a temperature sensor can be used to maintain the desired
temperature of a fluid retainment region to be within about
.+-.5.degree. C. of a desired temperature, for example, to be
within about .+-.1.degree. C., or about .+-.0.5.degree. C. A
computer system can be used to control the thermal system. A
computer system can be used to maintain a desired temperature for a
desired time period and for maintaining a desired number of cycles.
Blocks can be placed adjacent one another, without contacting one
another, to achieve and maintain the blocks at disparate
temperatures. A thermal insulator can be placed between two
adjacent blocks to help maintain the two blocks at different
respective temperatures. A thermal insulator can be placed between
two adjacent blocks to maintain the two blocks at the same
temperature.
[0047] According to various embodiments, the system can include a
thermal device in thermal contact with a fluid retainment region of
a fluid processing device. The fluid retainment region can be
included in a substrate, for example, a substrate including a first
and second surface. The thermal device can be disposed along the
first or the second surface, for example, above or below the fluid
retainment region of the fluid processing device. Such a
configuration of a thermal device is herein referred to as a
single-sided thermal cycler.
[0048] According to various embodiments, the system can include two
thermal devices aligned to regulate the temperature of a fluid
retainment region, where one of the two thermal devices is disposed
along a first surface of a fluid processing device and the other of
the two thermal devices is disposed along an opposite, second
surface of the fluid processing device. Such a configuration of
thermal devices is referred to herein as a double-sided thermal
cycler.
[0049] According to various embodiments, any of the blocks
described above can be shaped as a disk, a cylinder, a cuboid, a
rectanguloid, a bar, or as any other shape. In the accompanying
drawings, and for the sake of simplicity, a rectanguloid block is
depicted. A surface of the block can be designed to complement a
region of a fluid processing device that is to be thermally
regulated. Shapes of the blocks used herein can be altered to match
a shape of a thermally regulated region of a fluid processing
device. The shape of the block can include a flat surface to
thermally contact a heat-transfer surface of a heat-pump, for
example, a heat absorbing surface of a thermoelectric device.
[0050] With reference to the drawings, FIG. 1 is a top view of a
thermal system 160. The thermal system 160 can include a carriage
152 that is capable of sliding along rails in a plurality of
directions. The carriage 152 can be capable of latitudinal and/or
longitudinal movements. Rails 154 and 156 can be included to
provide guidance for the latitudinal and/or longitudinal movements.
According to various embodiments, the carriage 152 can be
permanently affixed, for example, to a base or platform, such as to
base 150 as shown. A first block 102, can be configured as a
relatively hot block, and can be thermally coupled to one or more
thermoelectric device 130, 131. The thermoelectric device 130, 131
can be thermally coupled to a second block 104 and to a third block
105, that can be configured to be relatively cold blocks. One or
more alignment pins 103 can be disposed at or near an end of the
first block 102. The alignment pins 103 can align the first block
102 with a fluid retainment region such as a reaction well (not
shown) formed in or on a fluid processing device (not shown). Heat
sinks 106, 107, for example, each including a plurality of cooling
fins, can be in thermal contact with the second block 104 and the
third block 105. A fan 155 can be provided to create an air flow in
the direction indicated to thus flow over and cool the heat sink
106. A fan 153 can be provided to create an air flow in the
direction indicated to thus flow across and cool the heat sink 107.
The thermoelectric device 130, 131 can be thermally coupled to and
disposed between the first block 102 and the second block 104, as
shown at 130, and between the first block 102 and the third block
105, as shown at 131. According to various embodiments, a plurality
of thermoelectric devices like 130 and 131 can be thermally coupled
to at least the first block 102.
[0051] FIG. 2 is a side, partial cross-sectional view of a thermal
system 100 including two thermal devices 140 and 142, that together
form a dual-sided thermal cycler. The two thermal devices 140, 142
can be made to be in thermal contact with a fluid processing device
120. Each thermal device 140, 142 respectively includes a first
block 102, a thermoelectric device 130, a second block 104, a third
block 105, and two heat sinks 106. Each thermal device 140, 142 can
be assembled using articles known in the art, for example, bolts
132. Each second block 104 can include a thermal interface material
124. The thermal interface material 124 can be a compressible
material. A second thermal interface material (not shown) can be
disposed on the first block 102. The fluid processing device 120
can include a first fluid retainment region 121 and a second fluid
retainment region 122. The first fluid retainment region 121 can be
subjected to higher temperatures than the second fluid retainment
region 122. The first block 102 can include a heat-transfer surface
114 that can be aligned into a heat-transfer position with respect
to the first fluid retainment region 121 of the fluid processing
device 120. The third block 105 can include a heat-transfer surface
110 that can be aligned into a heat-transfer position with respect
to the second fluid retainment region 122. The heat transfer
surface 114 can be co-planar or flush with the heat-transfer
surface 110. The heat transfer surface 114 can be offset from the
plane of the heat-transfer surface 110. The thermal interface
material 124 can provide a heat-transfer surface that is co-planar
with the heat-transfer surface 124. The fluid processing device 120
can be compressed between the thermal devices 140 and 142 using a
pressing assembly 144. The pressing assembly 144 can include, for
example, a clamping device, a set of bolts, a pneumatic press, a
hydraulic press, or a multiplicity or combination thereof. The
pressing assembly 144 can include a device that is capable of
moving either the fluid processing device 120 or the heat-transfer
assembly, in relation to one another, and between a
pressure-application position and a release position.
[0052] According to various embodiments, the thermal system can
include two thermal devices, including a lower thermal device and
an upper thermal device. The lower thermal device can include a hot
block sandwiched between two thermoelectric devices and two cold
blocks, each thermal device sandwiching a respective thermoelectric
device between the respective cold block and the hot block. The
upper thermal device can be identical to and/or a mirror image of,
the lower thermal device. The upper thermal device can be disposed
above the lower thermal device, as a mirror or as an inverted
version of, the lower thermal device. According to various
embodiments, during the heating portion of a thermal cycle, the
thermoelectric devices, in both the upper and lower thermal
devices, can transfer heat from the upper and lower flanking cold
blocks to the respective upper and lower hot blocks. According to
various embodiments, during the cooling portion of the thermal
cycle, the direction of the heat transfer by the upper and lower
thermoelectric devices can be reversed, and the upper and lower
thermoelectric devices can transfer heat from the upper and lower
hot blocks to the respective upper and lower flanking cold
blocks.
[0053] According to various embodiments, a fluid processing device
including at least one plurality of linearly aligned fluid
retainment regions can be positioned between the upper and lower
thermal devices whereby the plurality of linearly aligned fluid
retainment regions can be disposed centered on the hot block of at
least one of the upper and lower thermal devices. A fluid
retainment region in the at least one plurality of linearly aligned
reaction reactions can be used for, for example, a nucleotide
amplification reaction, a nucleotide sequencing reaction, an
oligonucleotide synthesis reaction, or the like. According to
various embodiments, the hot blocks of the upper and lower
assemblies can clamp the fluid processing device therebetween.
According to various embodiments, the cold blocks of the upper and
lower assemblies can clamp the fluid processing device
therebetween. According to various embodiments, the pressing device
can include the lower thermal device and the upper thermal device
to press against the fluid processing device during operation. The
pressing device and the two thermal devices can operate at the same
time or at different start and/or stop times.
[0054] According to various embodiments, the heat capacity
(Joules/Kelvin) of the cold blocks can be larger than the heat
capacity of the hot blocks, for example, about 5-times, about
10-times, or about 50-times. The cold blocks can use the
surrounding environment, for example, air, as a heat source or as a
heat sink depending on the direction of heat-transfer by the
thermoelectric device, by using heat sinks thermally coupled to the
cold blocks. The control device can control the temperature of the
hot block to be at least about 10.degree. C., at least about
15.degree. C., at least about 20.degree. C., at least about
30.degree. C., at least about 40.degree. C., or at least about
50.degree. C., greater than the temperature of the cold block.
[0055] According to various embodiments, the terms "cold block" and
"hot block" exemplify the relative temperatures of the blocks
relative to one another. The cold block can be hotter than the
ambient environment. The hot block can be cooler than the ambient
environment. In operation, the hot block can be hotter than the
cold block. This can occur, for example, when the hot block is
heated to a temperature of about 95.degree. C. and the cold block
is heated to a temperature of only about 50.degree. C. or less. In
operation, the hot block can be cooler than the cold block. This
can occur, for example, when after completion of a heating cycle
the hot block is cooled to a temperature of about 25.degree. C.
while the cold block maintains or reduces to a temperature of above
about 25.degree. C.
[0056] According to various embodiments, each thermal device can
include a fan to direct air-flow over heat sinks and/or a cold
block to assist in a heat transfer between blocks. According to
various embodiments, the thermal conductivity of a fluid processing
device can be less than the thermal conductivity of a block.
According to various embodiments, the thermal conductivity of the
block can be greater than the thermal conductivity of an ambient
environment, for example, air at about one atmosphere of pressure
at about 300.degree. K.
[0057] The thermal conductivity of a material is equivalent to the
quantity of heat that passes in a unit time through a unit area of
a plate, when the material's opposite faces are subject to a unit
temperature gradient, such as, a one degree temperature difference
across a thickness of one unit. Thermal conduction is the transfer
of heat or thermal energy from one substance to another.
[0058] According to various embodiments, the block or bar can
include a material having a high thermal conductivity, for example,
diamond or metal, for example, aluminum, copper, steel, stainless
steel, alloys or combinations thereof. At temperatures of about
273.degree. K to about 300.degree. K various materials having a
typical thermal conductivity of at least about 0.5 Watts per
centimeter Kelvin (W/cmK), for example, at least about 1.9 W/cmK,
or at least about 5 W/cmK, can be used to form a block. According
to various embodiments, a block can be a high thermal conductivity
block when the block has a thermal conductivity of at least about
0.5 W/cmK, for example, at least about 1.9 W/cmK, or at least about
5 W/cmK. at temperatures of about 273.degree. K to about
300.degree. K.
[0059] According to various embodiments, a heat-pump can be a
machine, that moves heat from a low level of temperature to a
higher level of temperature under supply of work, for example, gas
compression heat-pumps, phase change heat-pumps, or thermoelectric
heat-pumps that use the Peltier effect. A heat-pump can include a
vapor-cycle device, for example, a Freon-based vapor compression or
absorption refrigerator. Vapor-cycle devices can include moving
mechanical parts and require a working fluid, while thermoelectric
elements can be totally solid state.
[0060] According to various embodiments, a thermoelectric device
can be used as a heat-pump, for example, an XLT module available
from Marlow Industries, Inc. of Dallas, Tex. Controls for a
thermoelectric device can include an adjustable-bipolar DC output
current power supply. The power supply can provide programmable PID
control/ramp set points to control the thermoelectric device,
deviation alarms, and automatic and manual operating modes. In
reactions, for example, a Polymerase Chain Reaction (PCR),
thermoelectric devices can both heat and cool fluid retainment
regions at a predetermined rate by using a bi-directional power
supply under computer control. Thermoelectric devices can be
specifically designed to withstand the continuous temperature
excursions required in PCR use.
[0061] According to various embodiments, a thermoelectric device
can include a heat absorbing surface. The thermoelectric device can
include a heat dissipating surface. The heat absorbing surface
(cooling surface) can be in thermal contact with a cool block. The
heat dissipating surface (heating surface) can be in thermal
contact with a hot block. A control device can reverse the polarity
of a voltage being applied to the thermoelectric device to reverse
a direction of the heat flow effectively swapping the heat
absorbing surface with the heat dissipation surface. When power is
supplied to a thermoelectric device, the heat absorbing surface and
the heat dissipating surface are activated, and each surface can be
referred to as an active surface.
[0062] According to various embodiments, a thermal interface
material (TIM) can provide a good thermal contact between two
surfaces. The TIM can include silicone-based greases, elastomeric
pads, thermally conductive tapes, thermally conductive adhesives,
or a combination thereof. Zinc-oxide silicone can be a common TIM.
An elastomeric pad compressible to about 90% of an uncompressed
thickness under an exerted pressure of at least 0.5 pounds per
square inch (PSI), for example, at least about one (1) PSI, at
least about five (5) PSI. According to various embodiments, Gap-Pad
products, for example, the GAP PAD VO ULTRA SOFT available from
Berquist Company of Chanhassen, Minn. can be used as a thermal
interface material. A TIM is described in U.S. Pat. No. 5,679,457
to Bergerson, which is incorporated herein in its entirety.
[0063] According to various embodiments, a thermal connect, a
thermal contact, or a thermal conduct can be a physical contact of
two objects, for example, a fluid processing device surface with a
block surface. According to various embodiments, a TIM can be
disposed between the fluid processing device surface and the block
surface, on the fluid processing device surface, or on the block
surface to optimize the thermal contact. According to various
embodiments, the block surface can be pressed against the fluid
processing device surface to optimize the thermal contact.
[0064] According to various embodiments, a thermal insulator can
provide low thermal conductivity. A thermal insulator can be used
to prevent heat transfer from a temperature regulated volume to a
temperature unregulated volume, for example, a thermal insulator
can be used to prevent heat transfer from a heated volume to a
cooled or unregulated volume. A thermal insulator can include wood,
plastics, air, or gases. According to various embodiments, a
thermal insulator can be disposed between or adjacent a heated
fluid retainment region in a fluid processing device, and the fluid
processing device holder or platen holding the fluid processing
device.
[0065] According to various embodiments, a pressing device surface
can exert a pressure against a first or operative surface of a
fluid processing device. The pressing device surface can be
provided by a thermal device. According to various embodiments, the
pressing device surface can press the fluid processing device
across different imaginary zones or regions of the fluid processing
device. The pressing device surface can apply a compression force
of, for example, from about one (1) lbs to 500 lbs, about 10 lbs,
about 20 lbs, about 50 lbs, about 100 lbs, or about 200 lbs. The
average force over the thermal cycled area can be approximately 20
lbs per square inch. Pressure exerted over a fluid retainment
region can prevent leakage of a fluid retained in the fluid
retainment regions. A single-sided thermal device can press against
the fluid processing device. A dual-sided thermal device can press
against the fluid processing device. A fluid processing device
holder or platen can press against the fluid processing device.
[0066] According to various embodiments, a fluid processing device
can move relative to a thermal device by shifting the fluid
processing device, shifting the thermal device, or shifting both
the fluid processing device and the thermal device. The shifting
can be performed by placing either the fluid processing device or
the thermal device on a movable fluid processing device holder. The
fluid processing device holder can be included or disposed in a
carriage. The fluid processing device holder can be movable by a
robotic arm, other devices well known in the art, or the fluid
processing device can be manually transferred. The fluid processing
device holder can move along a single-axis, two-axes, or all
three-axes. According to various embodiments, the fluid processing
device and/or the thermal device can move to heat or cool a
plurality of fluid retainment regions formed in or on a fluid
processing device as desired. According to various embodiments, a
platen can be spun to align a desired fluid retainment region with
a heat-transfer position with respect to a thermal device.
According to various embodiments, the fluid processing device
holder can be used to force the fluid processing device and/or the
thermal device against one another to provide a pressing force.
According to various embodiments, the fluid processing device
holder can be moved to allow another system, for example, a valve
manipulation system, a fluid depositing system, an output retrieval
system, a fluid movement system, a detection system, or a
combination thereof, to access the fluid processing device.
[0067] According to various embodiments, an alignment system can
generate a signal upon detecting a fluid processing device in a
heat-transfer position. A control system can begin a thermal cycle
based on the signal. The signal can be generated by using, for
example, optical alignment, mechanical alignment, electrical
alignment, manual alignment, or an on/off switch. According to
various embodiments, alignment pins included in the thermal device
can be solenoids. According to various embodiments, the alignment
system can indicate an error in the fluid processing device
placement by generating an error signal, for example, by beeping,
by lighting an error light, or by indicating an alignment error on
a computer screen.
[0068] According to various embodiments, a fluid processing device
can include an alignment device, for example, a hole, a notch, a
pin, a chamfered edge, a chamfered corner, or combinations thereof.
The alignment device can assist in the correct placement of the
fluid processing device in the fluid processing device holder.
According to various embodiments, a fluid processing device holder
can include an alignment device, for example, a hole, a notch, a
pin, a chamfered edge, a chamfered corner, for correct operative
alignment of the fluid processing device holder with respect to a
thermal device. A plurality of exemplary alignment devices can be
disposed in or on the fluid processing device and/or the fluid
processing device holder. For example, two alignment pins in the
fluid processing device holder can align a fluid processing device
into a heat transfer position wherein the fluid device can include
two holes or notches.
[0069] According to various embodiments, a thermal device can
supplement heat from one or more thermoelectric devices by using a
heat generating device, for example, a heat resistive wire. The
heat generating device can be eliminated to reduce cost. According
to various embodiments, a temperature sensor can include, for
example, a thermometer, a thermistor, or a thermocouple sensor.
[0070] According to various embodiments, a region of the fluid
processing device holder operatively in a good or high thermal
contact with a fluid retainment region can include a heating
element, for example, a thin-resistive heater. During a thermal
cycling protocol, the heating element can raise and maintain the
temperature of the reaction region at a fixed or uniform
temperature, for example, about 40.degree. C., about 50.degree. C.,
or about 55.degree. C., while the thermal device can be used to
oscillate the temperature of the reaction region from about
60.degree. C. to about 95.degree. C. The heating element can reduce
the thermal gradient of the fluid processing device. This reduction
in the thermal gradient due to the use of a heating element can be
greater than a reduction in the thermal gradient when a thermal
insulator is operatively disposed in good or high thermal contact
with the fluid retainment region. The heating element can be used
in conjunction with a thermal insulator. The heating element can
have a low mass. The heating element can have a long lifetime. The
heating element can be of durable construction.
[0071] According to various embodiments, a thermal device can
provide one or more thermoelectric devices that can transfer heat
between two blocks. According to various embodiments, one, two, or
more thermal devices can surround a fluid processing device.
According to various embodiments, a thermal system can provide one,
two, or more thermal assemblies, wherein a thermal assembly is one
or more thermal devices configured to operate cooperatively on a
fluid processing device disposed in a fluid processing device
holder. The thermal assemblies in a thermal system can correspond
to the number of fluid processing device holders in a thermal
system. The dual-sided thermal system described above is an example
of a thermal assembly including two thermal devices.
[0072] According to various embodiments, a thermal cycling system
using a single-sided thermal device can reduce the mechanical
complexity of the thermal cycling and platen sub-assemblies. The
single-sided thermal device can lead to a fluid processing device
holder or platen design that can be more aerodynamic and
structurally sound.
[0073] FIG. 3 a side partial cross-section of a thermal system 601
including a thermal device 600 and a platen 630. The thermal device
600 can include a plurality of thermoelectric devices 612, 622,
624, 628. The plurality of thermoelectric devices 612, 622, 624,
628 can be thermally coupled to a fluid processing device 620. The
thermal device 600 can include a first block 610. The first block
610 can be used to thermally regulate a fluid retainment region 635
of the fluid processing device 620. The first block 610 can be a
cold block. A cooling fan 609 can direct an air flow across the
first block 610. The thermoelectric device 612 can include a heat
absorbing surface 613 in contact with the first block 610, and can
be disposed adjacent or between the first block 610 and a second
block 606. The second block 606 can be used to thermally regulate a
fluid retainment region 633 of the fluid processing device 620. The
second block 606 can be a hot block. The thermoelectric device 622
can include a heat absorbing surface 623 in contact with a third
block 602, and can be disposed adjacent or between the second block
606 and the third block 602. The third block 602 can be used to
thermally regulate a fluid retainment region 634 of the fluid
processing device 620. The third block 602 can be a cold block. A
cooling fan (not shown) can be disposed to direct an air flow
across the third block 602. The thermoelectric device 624 can
include a heat absorbing surface 625 in contact with the third
block 602, and can be disposed adjacent or between the third block
602 and a fourth block 604. The fourth block 604 can be used to
thermally regulate a fluid retainment region 632 of the fluid
processing device 620. The fourth block 604 can be a hot block. The
thermoelectric device 628 can include a heat absorbing surface 629
in contact with a fifth block 608, and can be disposed adjacent or
between the fourth block 604 and the fifth block 608. The fifth
block 602 can be used to thermally regulate a fluid retainment
region 631 of the fluid processing device 620. The third block 602
can be a cold block.
[0074] The fluid processing device 620 can be a microfluidic
device, for example, the microfluidic device 500 as illustrated in
FIG. 8, or the microfluidic device 800 of FIG. 9. The fluid
processing device 620 can be placed in a fluid processing device
holder 638 that is disposed in the platen 630. The fluid processing
device holder 638 can be a recess in the platen 630. The fluid
processing device 620 can be secured in, on, or to the fluid
processing device holder 638 using locks tabs, adhesive, tape,
friction, or other devices well known in the art. Fluid retainment
regions 632, 633 can be subjected to higher temperatures than fluid
retainment regions 631, 634, 635. The fluid processing device
holder can include a channel 636, 637. The channel 636, 637 can
complement and align with a shape of a desired fluid retainment
region. The channel 636, 637 can have a thermal insulator disposed
therein. The platen 630 can be rotatable.
[0075] The channel 636, 637 can include a heating element (not
shown) disposed therein. In operation, a control unit 640 can use
the heating element included in the channel 636, 637 to add heat to
the fluid processing device 620. The added heat can regulate the
temperature of fluids contained in fluid retainment regions 632,
633.
[0076] The control unit 640 can transfer heat from blocks 602, 608,
610 to blocks 604, 606 using thermoelectric devices 612, 622, 624,
628. The control unit 640 can reverse a polarity of a voltage
supplied to the thermoelectric devices 612, 622, 624, 628 to
reverse a direction of the thermal energy transfer, i.e., to
transfer heat from blocks 604, 606 to blocks 602, 608, 610. The
control unit 640 can use a signal from a temperature probe 644. The
temperature probe 644 can be a plurality of temperature probes. The
temperature probe 644 can include one or more temperature probes
measuring temperatures across a block, for example, blocks 602,
604, 606, 608, 610. The control unit 640 can independently operate
thermoelectric devices 612, 622, 624, 628. The control unit 640 can
control a movement of the thermal device 600 to place the thermal
device 600 in thermal contact with the fluid processing device 620,
for example, between a pressure application position and a pressure
release position. Arrows in FIG. 3 illustrate possible directions
of movement for the thermal device 600. The control unit 640 can
control a pressing device 642 to press the thermal device 600
against the fluid processing device 620.
[0077] According to various embodiments, a system can include a
plurality of thermal devices to regulate temperatures of a
plurality of fluid retainment regions. The plurality of fluid
retainment regions can be disposed in one substrate. The plurality
of fluid retainment regions can be disposed in a plurality of
substrates.
[0078] According to various embodiments, the thermal device,
single-sided or dual-sided, can be very effective in performing
many types of chemical reactions requiring various thermal
protocols. According to various embodiments, the thermal device can
be used for a plurality of reactions: amplification reactions, for
example, PCR or Oligonucleotide Ligation Assay (OLA); labeling
reactions, for example, sequencing and SnaPshot; or enzymatic
purifications, for example, by using Exol, EXO-SAP-IT, or
Lambda-Exo nuclease (Lambda-Exo). Exol or Exolnuclease I, and
Lambda-Exonuclease are available from New England Biolabs of
Beverly, Mass. (see www.neb.com). EXO-SAP-IT is a registered
trademark of and available from USB Corporation of Cleveland, Ohio
(see www.usweb.com). SnaPshot is a trademark of and available from
Applied Biosystems of Foster City, Calif. (see
www.appliedsystems.com). The chemical reactions can be completed in
microfluidic devices. The chemical reactions can utilize a dual
sided vertical Peltier thermal cycler.
[0079] According to various embodiments, a fluid retainment region
can be pre-loaded with a reagent. The pre-loaded reagents can be,
for example, dried-down probes, primers, tags, labels, reactants,
buffers, or other reagents useful in nucleic acid sequence
amplification, sequencing, ligation, or the like, reactions as
known to those of ordinary skill in the art. Examples of reagents
that can be used and/or preloaded include: for example, reducing
agents (e.g. dithiothreitol, tris[2-carboxyethyl]phosphine
hydrochloride), alkylating agents (e.g. iodoacetic acid,
iodoacetamide), derivatization reagents (e.g. N-hydroxysuccinamide
activated biotin,
sulfosuccinimidyl-4-O-[4,4'-dimethoxytrityl]butyrate,
2-iminothiolane hydrochloride, fluorescein isothiocyanate),
cross-linking reagents (e.g. dimethyl pimelimidate hydrochloride,
disuccinimidyl suberate,
1-ethyl-3-[3-dimethylaminopropyl]-carbodiimide hydrochloride),
lyophilized enzymes (e.g. trypsin, chymotrypsin, pepsin, papain),
immobilized enzymes (e.g. immobilized trypsin), catalysts, enzyme
inhibitors, enzyme substrates, dyes, immobilized reagents, or
combinations thereof.
[0080] According to various embodiments, the system can include one
or more fluid processing device holders, each fluid processing
device holder adapted to support a fluid processing device
including a reaction region. A system can include a plurality of
fluid processing device holders, for example, one, two, four, six,
or six or more. The system can include a plurality of thermal
devices, for example, one, two, four, six, or six or more. The
system can include thermal devices equal in number to the number of
fluid processing device holders included in the system. The system
can include thermal devices less in number than the number of fluid
processing device holders included in the system. The plurality of
fluid processing devices disposed in the one or more fluid
processing device holders can be thermally regulated by the system
in a desired order.
[0081] According to various embodiments, the system can include a
platen to support a fluid processing device. The platen can be
divided into platen regions, for example, two, four, six, eight, or
eight or more. Each platen region can include a fluid processing
device holder. The platen regions can be geometric or non-geometric
divisions of a plane. The platen can include a first surface. Fluid
processing device holders and fluid processing devices therein can
be distributed evenly or irregularly in the plurality of platen
regions.
[0082] According to various embodiments, the platen can limit
thermal variation through the thickness of the microfluidic device.
A portion of the platen region can thermally contact the reaction
region of the fluid processing device. The reaction region can be
in thermal contact with a hot region of the thermal device. The
portion of the platen region in thermal contact with the reaction
region can include a thermal insulator, for example,
black-glass-filled polycarbonate, plastics, air, a polyamide
blanket, or gas. The thermal insulator can be moveably disposed in
thermal contact with the reaction region. The thermal insulator, a
material or material composition with poor thermal conductivity,
can be included in the platen region, for example, in a groove in
the platen, a circular groove in the platen, a groove complementing
the form of a reaction region, or a groove complementing an surface
area of a plurality of reaction regions on a fluid processing
device. The thermal insulator could be included in the platen such
that pockets of air are disposed in thermal contact with the
reaction region.
[0083] FIG. 4 is a perspective schematic 10 of a plurality of
blocks positioned with respect to a plurality of linearly-aligned
fluid retainment regions. A first block 24 can be in thermal
contact with a plurality of fluid retainment regions 42, for
example, aligned in a linear fashion. A first gap 28 can be
disposed between the first block 24 and a second block 22. The
second block 22 can be disposed to conduct thermal energy to/from a
plurality of fluid retainment regions 31, 33, 35, 37. A second gap
29 can be disposed between the second block 22 and a third block
26. The third block 26 can be disposed to conduct thermal energy
to/from a plurality of fluid retainment regions 45, for example,
aligned in a linear fashion. The fluid retainment regions can be
formed in or on a fluid processing device 20. Non-thermally
regulated fluid retainment regions 41 can also be disposed in the
fluid processing device 20. Thermoelectric devices (not shown) can
be disposed in the first gap 28 and/or the second gap 29. A control
device (not shown) can control the thermoelectric devices to
achieve and maintain various temperatures for the first, second and
third blocks 24, 22, 26. The blocks can in turn achieve and
maintain various temperature zones, zones formed by imaginary lines
sectioning the fluid processing device 20, and the wells contained
in the temperature zones. According to various embodiments, the
control device can transfer heat among the first block 24, the
second block 22, and the third block 26, with the second block 22
acting as an intermediate temperature zone.
[0084] FIG. 5 is a perspective schematic 50 of a plurality of
blocks positioned with respect to a plurality of linearly-aligned
fluid retainment regions. A first block 64 can be in thermal
contact with a plurality of fluid retainment regions 82. A second
block 62 can be disposed to conduct thermal energy to/from a
plurality of fluid retainment regions 71, 75, 77. A third block 66
can be disposed to conduct thermal energy to/from a plurality of
fluid retainment regions 85. The fluid retainment regions can be
formed in or on a fluid processing device 60. The blocks can bring
various regions or sections of the fluid processing device 50 to
different temperatures, and maintain the regions at those
temperatures. Non-thermally regulated blocks 92, 94, 96 can assist
in cooling and/or heating of respective fluid retainment region in
thermal contact with the first block 64, the second block 62, and
the third block 66. Each non-thermally regulated block 92, 94, 96
can include a high conductivity material, for example, if the fluid
retainment region in thermal contact with the non-thermally
regulated block 92, 94, 96 is to be kept cooler than an adjacent
fluid retainment region. Each non-thermally regulated block 92, 94,
96 can complement the functionality of the opposing first block 64,
second block 62, and third block 66, respectively. For example, if
the first block 64 and the third block 66 are to be used as cold
blocks, the non-thermally regulated blocks 94, 96 can include a low
conductivity material or a thermal insulator when, for example, the
fluid retainment region in thermal contact with the non-thermally
regulated block 94, 96 is to be kept warmer or hotter than an
adjacent fluid retainment region. One or more cooling fans (not
shown) can be disposed to create an air flow in thermal contact
with the non-thermally regulated blocks 94, 96. The non-thermally
regulated block 92 can be disposed opposite a hot block (second
block 62), and can include a thermal insulator such as plastic.
[0085] Each non-thermally regulated block 92, 94, 96 can reduce a
thermal load on a heat-pump or a heating element. The non-thermally
regulated block 92, 94, 96 can be integrally formed by using a
single-piece of thermal insulation to control the thermal load. The
single-piece of thermal insulation can include a thermal insulation
pad, for example, a polyamide blanket. According to various
embodiments, the control device can use the thermoelectric devices
to transfer heat among the first block 64, the second block 62, and
the third block 66, with the second block 62 acting as an
intermediate temperature zone.
[0086] FIG. 6 depicts a fluid processing device 566 thermally
coupled with a thermal device 550 including a first cold block 552
and a second cold block 556 arranged around a hot block 554. A
first thermoelectric device 557 can be disposed between the cold
block 552 and the hot block 554. A second thermoelectric device 559
can be disposed between the cold block 556 and the hot block 554.
The fluid processing device 566 can be aligned with the thermal
device 550 by disposing an alignment pin 560 in an alignment notch
562. The alignment notch 562 can be included in the fluid
processing device 566. A fluid retainment region 570 can be
thermally coupled to the hot block 554, while fluid retainment
regions 568, 572 can be thermally coupled to the first cold block
552 and the second cold block 556, respectively. Fluid retainment
region 574 is not thermally regulated. A fluid input manifold 551
can distribute a fluid and/or reagents to the fluid retainment
region 568. A second alignment notch 564 can be disposed in the
fluid processing device 566. According to various embodiments, the
fluid processing device 566 can be thermally coupled with the
thermal device 550. By disposing the pin 560 in the second
alignment notch 564, the fluid retainment region 572 can be
thermally coupled with the cold block 552 and the fluid retainment
region 574 can be thermally coupled with the hot block 554. An
alignment pin 558 can be disposed in a separate alignment notch
(not shown) in the fluid processing device 566.
[0087] FIGS. 7a through 7i depict a system according to various
embodiments. The system 410 includes an electronics unit 412, a
rotating platen 414, a thermal assembly 416, a cover 418, and an
enclosure basin 420. The device 410 also includes an assembly
processing unit 370 shown in FIGS. 7e-7h.
[0088] The assembly processing component 370 includes a tray
loading door 372, electronics 412, a valve actuator 376, and two
thermal assemblies 377 and 378. Each thermal assembly 377, 378 can
include two thermal devices. Each thermal device can include a hot
block and at least one cold block. The component 370 shown
particularly in FIG. 7g includes a two-assembly platen 380 for
processing two assemblies simultaneously. The non-labelled arrows
shown in FIG. 7i depict the direction of centripetal force applied
to the assembly resulting from rotation of the platen 380 about a
central axis 386 thereof. FIG. 7h shows tray loading door 372 in an
open position and an assembly 381 loaded in the door and ready to
be supported by the two-assembly platen 380 upon closure of the
loading door 372.
[0089] FIG. 8 is an enlarged, perspective view of a microfluidic
device 500 according to various embodiments that can be used to
manipulate fluids, for example, micro-sized fluid samples. The
microfluidic device 500 can include a substrate 510 that can
include a plurality of fluid-containment features or fluid
retainment regions formed therein or thereon, for example, a
plurality of fluid retainment regions 514, 516, 518, 520, 522, 524.
The fluid retainment regions 514, 516, 518, 520, 522, 524 can be
formed in or on the microfluidic device 500. Other
fluid-containment features, for example, reservoirs, recesses,
channels, vias, appendices, input wells and ports, output wells,
purification columns, or valves, can be interconnected by
deformable valves, and can be included in or on the microfluidic
device 500. According to various embodiments, a deformable valve
536, for example, a Zbig valve, can be arranged between the fluid
retainment regions 514, 516, 518, 520, 522, 524 to selectively
control fluid communication between the fluid retainment regions
514, 516, 518, 520, 522, 524. The deformable valve as described in
U.S. patent application Ser. No. 10/808,228, filed Mar. 24, 2004,
which is incorporated herein in its entirety by reference.
[0090] According to various embodiments, the substrate 510 of the
microfluidic device 500 can be at least partially formed of a
deformable material, for example, an inelastically deformable
material. The substrate 510 can include a single layer of material,
a coated layer of material, a multi-layered material, or a
combination thereof. The substrate 510 can be formed as a single
layer and made of a non-brittle plastic material, for example,
polycarbonate, for example, a TOPAS material, a plastic cyclic
olefin copolymer material available from Ticona (Celanese AG),
Summit, N.J., USA. The thermal conductivity of the TOPAS cyclic
olefin copolymer can be about 0.16 Watt per meter Kelvin. The
substrate 510 can be in the shape of a disk, a rectangle, a square,
or any other shape. The substrate 510 can provide an operative
surface for a thermal device to thermally contact the microfluidic
device 500.
[0091] According to various embodiments, an elastically deformable
cover sheet 508 can be adhered to at least one of the surfaces of
the substrate 510. The cover sheet 508 can be made of, for example,
a plastic, elastomeric, or other elastically deformable material.
The microfluidic device 500 can include a central axis of rotation
534. The cover sheet 508 can provide an operative surface for a
thermal device to thermally contact the microfluidic device 500. An
input fluid-containment feature 530 can be fluidly connected to a
manifold 532 for the introduction of one or more fluids to the
fluid processing pathway 512 via a branch channel (not shown) or
opening a valve (not shown). For example, one or more fluids can be
introduced by piercing through the cover sheet 508 in the area of
the input fluid-containment feature 530 and injecting one or more
fluids into the input fluid-containment feature 530. The fluid can
be collected in output fluid retainment regions 526, 528 after
being processed through the fluid processing pathway 512. According
to various embodiments, the fluid processing pathway 512 can be
arranged generally linearly. According to various embodiments, and
as shown in FIG. 8 and FIG. 9, more than one fluid processing
pathway 512 can be arranged side-by-side in or on the substrate
510. A plurality of samples or a plurality of reactions on the same
sample can be processed in the fluid processing pathway 512. The
processing can be serial or simultaneous. For example, 12, 24, 48,
96, 192, or 384 of the fluid processing pathways 512 can be
arranged side-by-side to form a set of fluid processing pathways on
a single microfluidic device 500. Moreover, two or more sets of
fluid processing pathways can be arranged on a single microfluidic
device 500. One or more output fluid retainment regions 526, 528
can be provided for each fluid processing pathway 512.
[0092] According to various embodiments, the microfluidic device
500 can be rotated through a central axis of rotation 534, to
selectively force fluids between the fluid retainment regions 514,
516, 518, 520, 522, 524 of the microfluidic device 500, by way of
applying a centripetal force. For example, by spinning the
microfluidic device 500 around the central axis of rotation 534, a
fluid can be selectively forced to move from at least the input
fluid-containment feature 530 to the output fluid retainment
regions 526, 528 along the fluid processing pathway 512. The fluid
flow can be controlled by manipulation of valves 536. According to
various embodiments, a platen 502, or a microfluidic device holder
built-in the platen 502, can be arranged to support and rotate the
microfluidic device 500 about the axis of rotation 534 of the
platen and/or holder 502. According to various embodiments and as
shown in FIG. 8, the axis of rotation of the platen 502 can be
coaxial with the central axis of rotation 534 of the microfluidic
device 500. An alignment notch 504 can be disposed in the
microfluid processing device 500 to complement an alignment pin 506
in the platen 502.
[0093] According to various embodiments, the ability to achieve
disparate temperature zones in nearly abutting fluid retainment
regions can allow adjacent fluid retainment regions of a fluid
processing device to be loaded with reagents activated at disparate
temperatures. Alternatively or additionally, temperature sensitive
reagents can be disposed in a fluid retainment region while an
adjacent fluid retainment region can be subjected to temperatures
that would render the temperature sensitive reagents inoperative.
According to various embodiments, the temperature sensitive
reagents can maintain their effectiveness, even as the adjacent
fluid retainment region is subjected to temperatures incompatible
with the temperature sensitive reagents. Temperature sensitive
reagents can be reagents that can lose their effectiveness or be
rendered inoperable if subjected to a temperature above a lower
limit. According to various embodiments, a fluid retainment region
and an adjacent temperature sensitive reagent region can be
disposed nearly abutting on a fluid processing device, for example,
separated by from about 1 mm to about 50 mm, separated by about 10
mm, separated by about 3 mm, or separated by about 2 mm.
[0094] According to various embodiments, the fluid movement device
can provide for movement of fluids within features of a fluid
processing device by, for example, spinning, suctioning, or
pneumatics.
[0095] According to various embodiments, the valve manipulation
device can comprise, for example, a deformer, a flap, or a
solenoid. Further information about valve manipulation devices can
be found in U.S. patent application Ser. No. 10/808,229 filed Mar.
24, 2004, which is incorporated herein in its entirety.
[0096] According to various embodiments, FIG. 9 is a top view of an
exemplary microfluidic device 800 having two input ports 801, 802
for distributing a fluid sample to respective flow distributors
804, 806, each flow distributor being in fluid communication with,
or being designed to be in interruptible communication with a
pathway 803. The microfluidic device 800 can include 384 output
ports 808. Each pathway 803 can include a PCR chamber 814, a PCR
purification chamber 816, a flow restrictor, a vertical
flow-splitter that leads to a forward sequencing chamber 818 and a
reverse sequencing chamber 820, a forward sequencing product
purification chamber 822, a reverse sequencing product purification
chamber 824, a purified forward sequencing product output chamber
826, a purified reverse sequencing product output chamber 828, a
plurality of opening and closing valves, or a combination thereof.
The thermal device 600 of FIG. 3 can thermally regulate fluids
disposed in the various chambers of the microfluidic device 800.
The thermal device 600 of FIG. 3 can thermally regulate fluids
disposed in the PCR chamber 814 and the PCR purification chamber
816 for each pathway 803. The thermal device 600 of FIG. 3 can
thermally regulate fluids disposed in the forward sequencing
chamber 818, the reverse sequencing chamber 820, the forward
sequencing product purification chamber 822, and a reverse
sequencing product purification chamber 824, for each pathway 803.
Exemplary volumes for each of the chambers can be from 0.01 micro
liters to about 100 micro liters.
[0097] According to various embodiments, the thermal device can be
an assembly. The assembly can include several components that can
be stacked or assembled together to form a single-side thermal
device. The assembly can include, for example, a cold block, one or
more thermoelectric devices, a first hot block, one or more
thermoelectric devices, and another cold block. This embodiment of
the thermal device can provide one hot region and two cold regions
on fluid processing device, for example, thermal device 140 of FIG.
2. The thermal device assembly can be augmented by adding one or
more thermoelectric devices, a first hot block, one or more
thermoelectric devices, and another cold block to the thermal
device as desired, for example, thermal device 600 of FIG. 3. A
system can include a thermal device providing a plurality of hot
blocks, for example, one, two or three hot blocks for the device of
FIG. 8 for heating, two, four or six hot blocks for the device of
FIG. 9. The hot blocks can correspond to a PCR chamber, a forward
sequencing chamber and/or a reverse sequencing chamber of the
microfluidic devices illustrated in FIG. 8 and FIG. 9, as desired.
The hot blocks can be heated by operating adjacent thermoelectric
devices, as desired.
[0098] The chart 620 of FIG. 10 is an example of a fluid being
subjected to a thermal protocol such as PCR. A temperature plot 622
tracks the fluid temperature over time. The fluid was disposed in a
fluid retainment region of a fluid processing device, for example,
fluid retainment region 121 of FIG. 2, or fluid retainment region
514 of FIG. 8. A dual-sided thermal device, for example, the
dual-sided thermal system 100 of FIG. 2, was utilized to obtain the
plot. The fluid retainment region was in thermal contact with two
hot blocks, for example, hot blocks 102 of FIG. 2. The fluid
temperature plot 622 cycles in the range from about 55.degree. C.
to about 95.degree. C. The temperature plot 624 depicts the
temperature of a fluid in a second fluid retainment region, for
example, a purification region. The second fluid retainment region,
for example, fluid retainment region 122 of FIG. 2, fluid
retainment region 516 of FIG. 8, can be in contact with two cold
blocks, for example, cold blocks 106 of FIG. 2. The temperature of
the second fluid retainment region can fluctuate in the range of
from about 40.degree. C. to about 45.degree. C. According to
various embodiments, the temperature measured for the fluid
retainment region can fluctuate in a range of at least, for
example, about 20.degree. C., or about a 40.degree. C. range, while
the temperature of the second fluid retainment region fluctuates
over a range of, for example, less than about 5.degree. C., or less
than about 10.degree. C.
[0099] Example. FIG. 11 is a chart of temperatures obtained using
five thermocouples embedded or buried within a plastic card. The
thermocouples were obtained from Omega Engineering. Data was
acquired using LabView software from National Instruments of
Austin, Tex. using their off-the shelf data acquisition PC board
(see, www.ni.com/labview). A depression was machined in a surface
of the substrate. The depression allowed for a flush placement,
with respect the machined surface, of thermocouples and their
respective signal wires in the substrate. A cover film was placed
over the thermocouples. A single-sided thermal device including a
hot block and a cold block was placed in thermal contact with the
cover film. The thermal device was thermo-cycled by a control
device to follow the PCR protocol. Data tracks designated Chan4,
Chan6, and Chan8 tracked temperatures reported by some of the
thermocouples, linearly arranged, in thermal contact with the hot
block. Data tracks designated Chan5 and Chan7 tracked temperatures
reported by some of the thermocouples, linearly arranged, in
thermal contact with the cold block. The hot block was offset from
the cold block by about 6 mm. A pressing device was used to
sandwich the plastic card with the embedded thermocouples. A
single-sided thermal device was disposed on one side of the plastic
card. A device including a first aluminum block, a plastic hot
block, a second aluminum block, and two fans directing air flow
over the first and second aluminum blocks, was disposed on the
other side or opposing surface of the plastic card.
[0100] According to various embodiments, a fluid processing device
can be used to manipulate a fluid, for example, a micro-sized fluid
sample. The fluid sample can be subjected to at least two reactions
in at least two respective reactions wells formed in the fluid
processing device. The at least two reactions can transpire
serially. A latter reaction within the set of the at least two
reactions can use the product of the preceding reaction. The latter
reaction well can be loaded with some reagents prior to activating
a first reaction of the at least two reactions. According to
various embodiments, to remain operative some of the reagents in
the latter reaction well can require that the latter reaction well
be maintained at a preservative temperature range exclusive and/or
partially overlapping of thermal parameters of a reaction
transpiring in the first well. According to various embodiments, a
thermal device adapted to maintain the at least two reaction wells
at different thermal parameters is described herein.
[0101] According to various embodiments, a fluid processing device
can be used to manipulate at least two fluid samples, for example,
at least two micro-sized fluid samples. The at least two fluid
samples can be subjected to at least two reactions in at least two
respective reaction wells formed in the fluid processing device.
The at least two reactions can require mutually exclusive and/or
partially overlapping thermal parameters to transpire in parallel
or at the same time.
[0102] According to various embodiments, in a PCR device a PCR
sample can be cycled in the temperature range of about 50.degree.
C. to about 95.degree. C. A second fluid retainment region on the
fluid processing device can concomitantly contain some
size-exclusion ion-exchange (SEIE) beads. The SEIE beads can be
rendered inoperative or less effective, when subjected to
temperatures above about 50.degree. C. Alternatively or
additionally, the inadvertent heating of adjacent fluid retainment
regions, for example, a second fluid retainment region, in the
fluid processing device can expand any air contained therein. The
air expansion can cause the adjacent fluid retainment regions
and/or a seal disposed in the adjacent fluid retainment regions to
burst or "blow-out." Similar thermal parameters can be imposed by a
sequencing device including a sequencing-fluid retainment region
and a sequencing purification fluid retainment region containing
SEIE beads. The thermal parameter requirements for a plurality of
reactions can proliferate as an increasing number of reactions can
transpire in a fluid processing device, for example, a fluid
processing device including a PCR fluid retainment region, a
PCR-purification fluid retainment region, a sequencing fluid
retainment region, a sequencing purification fluid retainment
region. The fluid processing device can additionally or
alternatively include a forward sequencing fluid retainment region,
a forward sequencing purification fluid retainment region, a
reverse sequencing fluid retainment region, a reverse sequencing
purification fluid retainment region. According to various
embodiments, a fluid processing device can include a reaction
region for an Oligonucleotide Ligation Assay isothermal biological
assay.
[0103] Other embodiments will be apparent to those skilled in the
art from consideration of the present specification and practice of
various embodiments disclosed herein. It is intended that the
present specification and examples be considered as exemplary only
with a true scope and spirit indicated by the teachings and
equivalents thereof.
* * * * *
References