U.S. patent application number 13/805323 was filed with the patent office on 2013-08-15 for bubble-based microvalve and its use in microfluidic chip.
This patent application is currently assigned to Tsinghua University. The applicant listed for this patent is Jing Cheng, Tao Deng, Su Guo, Bei Han, Miao Liu, Can Wang, Guoqing Wang, Wanli Xing, Guohao Zhang, Jinxiu Zhang. Invention is credited to Jing Cheng, Tao Deng, Su Guo, Bei Han, Miao Liu, Can Wang, Guoqing Wang, Wanli Xing, Guohao Zhang, Jinxiu Zhang.
Application Number | 20130206250 13/805323 |
Document ID | / |
Family ID | 43261965 |
Filed Date | 2013-08-15 |
United States Patent
Application |
20130206250 |
Kind Code |
A1 |
Zhang; Guohao ; et
al. |
August 15, 2013 |
BUBBLE-BASED MICROVALVE AND ITS USE IN MICROFLUIDIC CHIP
Abstract
Provided are a bubble-based microvalve and a microfluidic chip
using the microvalve. Also provided are methods of using the
microvalve for manipulating fluid in a microfluidic channel by
changing the volume and/or location of the gas in the
microvalve.
Inventors: |
Zhang; Guohao; (Beijing,
CN) ; Guo; Su; (Beijing, CN) ; Wang; Can;
(Beijing, CN) ; Wang; Guoqing; (Beijing, CN)
; Liu; Miao; (Beijing, CN) ; Zhang; Jinxiu;
(Beijing, CN) ; Han; Bei; (Beijing, CN) ;
Deng; Tao; (Beijing, CN) ; Xing; Wanli;
(Beijing, CN) ; Cheng; Jing; (Beijing,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Zhang; Guohao
Guo; Su
Wang; Can
Wang; Guoqing
Liu; Miao
Zhang; Jinxiu
Han; Bei
Deng; Tao
Xing; Wanli
Cheng; Jing |
Beijing
Beijing
Beijing
Beijing
Beijing
Beijing
Beijing
Beijing
Beijing
Beijing |
|
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN |
|
|
Assignee: |
Tsinghua University
Beijing
CN
|
Family ID: |
43261965 |
Appl. No.: |
13/805323 |
Filed: |
July 1, 2011 |
PCT Filed: |
July 1, 2011 |
PCT NO: |
PCT/CN2011/001094 |
371 Date: |
March 4, 2013 |
Current U.S.
Class: |
137/237 |
Current CPC
Class: |
B01L 2200/16 20130101;
F16K 99/0019 20130101; F16K 99/0015 20130101; Y10T 137/4238
20150401; B01L 2400/0633 20130101; B01L 2400/0688 20130101; B01L
3/502738 20130101; B01L 2400/0638 20130101; F16K 99/0001 20130101;
B01L 2200/027 20130101; B01L 9/527 20130101; F16K 99/0044 20130101;
B01L 2300/1827 20130101; F16K 2099/0084 20130101; F04B 43/00
20130101; F16K 99/0034 20130101; B01L 2400/0677 20130101; F16K
99/0028 20130101 |
Class at
Publication: |
137/237 |
International
Class: |
F04B 43/00 20060101
F04B043/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 5, 2010 |
CN |
201010219860.6 |
Claims
1. A bubble-based microvalve, which microvalve comprises a gas
chamber/channel connected to a fluid channel.
2. The microvalve of claim 1, wherein the gas chamber/channel is
directly connected to the fluid channel.
3. The microvalve of claim 1, wherein the gas chamber/channel is
indirectly connected to the fluid channel through a connecting
channel, a gas-permeable membrane, a gas-permeable plate, or a
gas-repellent film.
4. The microvalve of claim 1, further comprising a second gas
chamber/channel connected to the fluid channel.
5. The microvalve of claim 1, wherein the gas chamber/channel
comprises a drying material, and the drying material is selected
from the group consisting of silica gel, calcium chloride, aluminum
oxide and magnesium oxide.
6-7. (canceled)
8. A microfluidic reaction system comprising a microvalve of claim
1.
9. The microfluidic reaction system of claim 8, further comprising
a reaction chamber.
10. The microfluidic reaction system of claim 9, which comprises
multiple reaction chambers and multiple microvalves.
11. The microfluidic reaction system of claim 10, wherein each
microvalve is flanked by two adjacent reaction chambers, and
wherein the reaction chambers are in fluidic connection with the
fluidic channel.
12-13. (canceled)
14. The microfluidic reaction system of claim 8, wherein the size
of the connecting channel is adjustable based on at least the
following parameters: pressure of injection pump or injector
pipette, volume of gas chamber/channel, ambient temperature,
ambient humidity, air humidity inside the fluidic channel, angle of
the fluidic channel and the connecting channel, surface tension of
the fluidic sample, and hydrophobic property of the fluidic
channel.
15-16. (canceled)
17. The microfluidic reaction system of claim 8, wherein the gas
chambers/channels are connected by an interconnecting channel.
18. The microfluidic reaction system of claim 17, further
comprising a means to actuate and/or stop the microvalve.
19. A microfluidic chip comprising a microfluidic reaction system
of claim 8.
20. The microfluidic chip of claim 19, further comprising a heating
device capable of heating the gas chamber/channel, wherein the
heating device comprises a resistance wire, a resistance film or a
metal particle.
21-22. (canceled)
23. The microfluidic chip of claim 19, further comprising a cooling
device capable of cooling the gas chamber/channel, wherein the
cooling device comprises a cooling fluid.
24. (canceled)
25. The microfluidic chip of claim 19, wherein the microfluidic
chip comprises a top layer and a bottom layer.
26-27. (canceled)
28. The microfluidic chip of claim 25, wherein the top layer
contains the fluidic channel and the bottom layer contains the gas
chamber/channel.
29. The microfluidic chip of claim 25, wherein the microfluidic
chip further comprises a gas-permeable membrane, a gas-permeable
plate, or a gas-repellent film.
30-33. (canceled)
34. The microfluidic chip of claim 29, wherein the gas-permeable
plate comprises pores used for connecting the gas
chamber/channel.
35-37. (canceled)
38. The microfluidic chip of claim 19, further comprising an
interconnecting channel capable of connecting the gas
chambers/channels, wherein the interconnecting channel comprises
gas, liquid or mixture of gas and liquid.
39-40. (canceled)
41. A method for manipulating fluid in a microfluidic channel using
a microvalve of claim 1, wherein the volume and/or location of the
gas in the microvalve is changed.
42. The method of claim 41, wherein the microvalve is actuated by
heating, and the gas chamber/channel is placed in a waterbath or in
close proximity to a heater, optionally a Pt electrode.
43. (canceled)
44. The method of claim 41, wherein the microvalve is actuated by
cooling, and the cooling is by injecting a cooling fluid into a
channel in close proximity to the gas chamber/channel.
45. (canceled)
46. The method of claim 41, wherein the microvalve is actuated by
adding a substance, such as gas, liquid or solid, into the gas
chamber/channel.
47-49. (canceled)
50. The method of claim 41, wherein the microvalve is actuated by
removing a substance from the gas chamber/channel, and the
substance is removed using the second gas channel.
51. (canceled)
52. The method of claim 41, wherein the microvalve is actuated by
exerting force on the gas chamber/channel, and the force leads to
deformation of the gas chamber/channel.
53. (canceled)
54. The method of claim 41, wherein the microvalve is actuated by a
low-humidity gas.
55-59. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention is related to the field of
microfluidic systems. In particular, the invention provides a
bubble-based microvalve and a microfluidic chip using this
microvalve.
BACKGROUND ART
[0002] Microfluidics is a technology that deals with various
chemical and biological progresses, relying on precise control and
manipulation of fluids that are constrained to micro-channel
network exploited on a chip based on MEMS (micro-electro-mechanical
systems) technology. In the early stage, chip-based capillary
electrophoresis is its main research field, structures and
functions of chip are relatively simple. Recently, the demand of
miniaturization and integration has become a new driving force,
which thus extends research field to chemical and biological
reactions, such as nucleic acid amplification, immune reaction and
cell analysis. Accordingly, a number of independent and uniform
reaction chambers, that is a micro-reactor array, need to be
configured on a chip for investigating complex reaction
parameters.
[0003] According to different sampling methods, the construction of
micro-reactor array typically has two types: parallel and serial.
In a parallel type micro-reactor array each chamber has a filling
channel, samples enter into chamber along each filling channel in
parallel manner. In order to avoid non-uniformity of different
chambers, the design accuracy of structures and surface properties
of materials should achieve a higher standard, these requirements
are not easy to be met. By contrast, in a serial type micro-reactor
array all chambers share a filling channel, samples enter into
chambers along this unique filling channel in serial manner. The
uniformity of different chambers is easy to control, but the
independence of different chambers needs to be controlled with
microvalves.
[0004] Microvalves found today include pneumatic microvalves (Unger
et al. (2000) Science 288:113-116), piezoelectric microvalves,
phase change microvalves, torque-actuated microvalves (Chen et al.
(2009) Lab Chip 9:3511-3516) and so on. There are several
disadvantages to these microvalves: they are difficult to produce
and to match with portable instruments, require complicated
operation, and are not friendly to ordinary users.
SUMMARY OF THE INVENTION
[0005] The present invention relates to a bubble-based microvalve
and a microfluidic system and chip using such microvalve, and their
methods of use. Therefore, in one aspect, provided herein is a
bubble-based microvalve, which microvalve comprises a gas
chamber/channel connected to a fluid channel.
[0006] In some embodiments, the gas chamber/channel may be directly
connected to the fluid channel. In some embodiments, the gas
chamber/channel may be connected to the fluid channel through a
connecting channel, a gas-permeable membrane, a gas-permeable
plate, or a gas-repellent film. In some embodiments, the microvalve
may further comprise a second gas channel connected to the fluid
channel. In some embodiments, the gas chamber/channel may comprise
a drying material or a gas-trapping material. In some embodiments,
the drying material may be selected from the group consisting of
silica gel, calcium chloride, aluminum oxide and magnesium oxide.
In some embodiments, the gas chamber/channel may comprise a
nitrogen gas.
[0007] Also provided herein is a microfluidic reaction system
comprising a microvalve, which microvalve comprises a gas
chamber/channel connected to a fluid channel. In some embodiments,
the microfluidic reaction system may comprise a reaction chamber.
In some embodiments, the microfluidic reaction system may comprise
multiple reaction chambers and multiple microvalves. In some
embodiments, each microvalve may be flanked by two adjacent
reaction chambers, wherein the reaction chambers may be in fluidic
connection with the fluidic channel. In some embodiments, the
microfluidic reaction system may be open or closed.
[0008] In some embodiments, the fluid channel may have sections of
different widths. In some embodiments, the size of the connecting
channel may be adjustable based on at least the following
parameters: pressure of injection pump, injector pipette or other
injections devices or methods, volume of gas chamber/channel,
ambient temperature, ambient humidity, air humidity inside the
fluidic channel, angle of the fluidic channel and the connecting
channel, surface tension of the fluidic sample, and hydrophobic
property of the fluidic channel. In some embodiments, the
connecting channel may have a length of .ltoreq.10 cm and a width
of .ltoreq.1 cm. In some embodiments, the fluid channel may have
branches. In some embodiments, the gas chambers/channels may be
connected by an interconnecting channel. In some embodiments, the
microfluidic reaction system may further comprise a means to
actuate and/or stop the microvalve.
[0009] Further provided herein is a microfluidic chip comprising a
microfluidic reaction system described herein. In some embodiments,
the microfluidic chip may further comprise a heating device capable
of heating the gas chamber/channel. In some embodiments, the
heating device may comprise a resistance wire, a resistance film or
a metal particle. In some embodiments, the metal particle may be a
gold nano-particle. In some embodiments, the microfluidic reaction
system may further comprise a cooling device capable of cooling the
gas chamber/channel. In some embodiments, the cooling device may
comprise a cooling fluid.
[0010] In some embodiments, the microfluidic chip may comprise a
top layer and a bottom layer. In some embodiments, the top layer
may contain the microfluidic reaction system. In some embodiments,
the bottom layer may comprise the heating device or cooling device.
In some embodiments, the top layer may contain the fluidic channel
and the bottom layer may contain the gas chamber/channel. In some
embodiments, the microfluidic chip further may comprise a
gas-permeable membrane, a gas-permeable plate, or a gas-repellent
film. In some embodiments, the pore size of the gas-permeable
membrane ranges from about 1 nm to about 1 mm. In some embodiments,
the material of the gas-permeable membrane may be a polymer, which
may be selected from the group consisting of cellulose, cellulose
acetate, cellulose nitrate, mixed cellulose, polyolefin, polyimide,
polyamide, polyether sulfone, polyethylene glycol, sodium alginate,
chitin, and silicone polymer. In some embodiments, the silicone
polymer may be polydimethylsiloxane. In some embodiments, the
gas-permeable plate may comprise pores used for connecting the gas
chamber/channel. In some embodiments, the height of the pores may
be not more than 10 cm, and the diameter of the pores may be not
more than 1 cm. In some embodiments, the material of the
gas-permeable plate may be selected from the group consisting of
metal, glass, quartz, silicon, ceramic, plastic, rubber,
aluminosilicate and a composite/compound thereof. In some
embodiments, the material of the gas-repellent film may be selected
from the group consisting of metal, glass, quartz, silicon,
ceramic, plastic, rubber and a composite/compound thereof. In some
embodiments, the microfluidic chip may further comprise an
interconnecting channel capable of connecting the gas
chambers/channels. In some embodiments, the interconnecting channel
may comprise gas, liquid or mixture of gas and liquid. In some
embodiments, the material of the microvalve may be selected from
the group consisting of metal, glass, quartz, silicon, ceramic,
plastic, rubber, aluminosilicate and a composite/compound
thereof.
[0011] In another aspect, the present invention provides a method
for manipulating fluid in a microfluidic channel using a
microvalve, which microvalve comprises a gas chamber/channel
connected to a fluid channel, wherein the volume and/or location of
the gas in the microvalve is changed.
[0012] In some embodiments, the microvalve may be actuated by
heating. In some embodiments, the gas chamber/channel may be placed
in a waterbath or in close proximity to a heater, optionally a Pt
electrode. In some embodiments, the microvalve may be actuated by
cooling, wherein the cooling may be affected by injecting a cooling
fluid into a channel in close proximity to the gas chamber/channel.
In some embodiments, the microvalve may be actuated by adding
substance, such as nitrogen, into the gas chamber/channel, wherein
the substance may be gas, liquid or solid. In some embodiments, the
gas may be from outside or inside of the fluidic channel, the
microfluidic system or the microfluidic chip. In some embodiments,
the gas from inside of the fluidic channel may be generated by a
physical, electrochemical or chemical method. In some embodiments,
the microvalve may be actuated by removing a substance from the gas
chamber/channel. In some embodiments, the substance may be removed
using the second gas channel. In some embodiments, the microvalve
may be actuated by exerting force on the gas chamber/channel,
wherein the force leads to deformation of the gas chamber/channel.
In some embodiments, the microvalve may be actuated by a
low-humidity gas.
[0013] Further provided herein is a use of a microfluidic chip
described herein for a chemical or biological reaction. In some
embodiments, the biological reaction may be nucleic acid
amplification, immune reaction such as immunoassays, or cell
analysis such as cell culture or lysis, wherein the nucleic acid
amplification may be selected from the group consisting of
polymerase chain reaction (PCR), strand displacement amplification
(SDA), ligase chain reaction (LCR), nucleic acid sequence-based
amplification (NASBA), transcription-mediated amplification (TMA),
loop-mediated isothermal amplification (LAMP), rolling circle
amplification (RCA) and helicase-dependent amplification (HDA).
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a schematic illustration of an embodiment of the
microvalve (the microvalve is not actuated).
[0015] FIG. 2 is a schematic illustration of an embodiment of the
microvalve (the microvalve is actuated).
[0016] FIG. 3 schematically illustrates the serial construction of
micro-reactor array (the microvalve is not actuated).
[0017] FIG. 4 is a schematic illustration of an embodiment of the
microvalve in Example 1 (the microvalve is not actuated).
[0018] FIG. 5 is a schematic illustration of an embodiment of the
microvalve in Example 1 (the microvalve is actuated).
[0019] FIG. 6 schematically illustrates the location of drying
material in Example 3.
[0020] FIG. 7 is a schematic illustration of an embodiment of the
microfluidic chip in Example 2.
[0021] FIG. 8 is a schematic illustration of an embodiment of the
microfluidic chip in Example 5.
[0022] FIG. 9 is a schematic illustration of an embodiment of the
microfluidic chip in Example 6.
[0023] FIG. 10 is a schematic illustration of an embodiment of the
microfluidic chip in Example 7.
[0024] FIG. 11 is a schematic illustration of an embodiment of the
microfluidic chip in Example 8.
[0025] FIG. 12 is a schematic illustration of an embodiment of the
microvalve in Example 9 (the microvalve is actuated).
[0026] FIG. 13 is a schematic illustration of an embodiment of the
microvalve in Example 10 (the microvalve is not actuated).
[0027] FIG. 14 is a schematic illustration of an embodiment of the
microvalve in Example 10 (the microvalve is actuated).
[0028] FIG. 15 is a schematic illustration of an embodiment of the
microvalve in Example 10 (the microvalve is actuated again).
DETAILED DESCRIPTION OF THE INVENTION
[0029] One object of the present invention is to provide a
bubble-based microvalve, which could control the flow of fluids
efficiently and conveniently, and ensure the independence of
different chambers of a micro-reactor array.
A. Definitions
[0030] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art to which this invention belongs. All
patents, applications, published applications and other
publications referred to herein are incorporated by reference in
their entirety. If a definition set forth in this section is
contrary to or otherwise inconsistent with a definition set forth
in the patents, applications, published applications and other
publications that are herein incorporated by reference, the
definition set forth in this section prevails over the definition
that is incorporated herein by reference.
[0031] As used herein, the singular forms "a", "an", and "the"
include plural references unless indicated otherwise. For example,
"a" dimer includes one or more dimers.
[0032] As used herein, the term "microfluidic device" generally
refers to a device through which materials, particularly fluid
borne materials, such as liquids, can be transported, in some
embodiments on a micro-scale, and in some embodiments on a
nanoscale. Thus, the microfluidic devices described by the
presently disclosed subject matter can comprise microscale
features, nanoscale features, and combinations thereof.
[0033] Accordingly, an exemplary microfluidic device typically
comprises structural or functional features dimensioned on the
order of a millimeter-scale or less, which are capable of
manipulating a fluid at a flow rate on the order of a .mu.L/min or
less. Typically, such features include, but are not limited to
channels, fluid reservoirs, reaction chambers, mixing chambers, and
separation regions. In some examples, the channels include at least
one cross-sectional dimension that is in a range of from about 0.1
.mu.m to about 500 .mu.m. The use of dimensions on this order
allows the incorporation of a greater number of channels in a
smaller area, and utilizes smaller volumes of fluids.
[0034] A microfluidic device can exist alone or can be a part of a
microfluidic system which, for example and without limitation, can
include: pumps for introducing fluids, e.g., samples, reagents,
buffers and the like, into the system and/or through the system;
detection equipment or systems; data storage systems; and control
systems for controlling fluid transport and/or direction within the
device, monitoring and controlling environmental conditions to
which fluids in the device are subjected, e.g., temperature,
current, and the like.
[0035] As used herein, the terms "channel," "micro-channel,"
"fluidic channel," and "microfluidic channel" are used
interchangeably and can mean a recess or cavity formed in a
material by imparting a pattern from a patterned substrate into a
material or by any suitable material removing technique, or can
mean a recess or cavity in combination with any suitable
fluid-conducting structure mounted in the recess or cavity, such as
a tube, capillary, or the like.
[0036] As used herein, the terms "flow channel" and "control
channel" are used interchangeably and can mean a channel in a
microfluidic device in which a material, such as a fluid, e.g., a
gas or a liquid, can flow through. More particularly, the term
"flow channel" refers to a channel in which a material of interest,
e.g., a solvent or a chemical reagent, can flow through. Further,
the term "control channel" refers to a flow channel in which a
material, such as a fluid, e.g., a gas or a liquid, can flow
through in such a way to actuate a valve or pump.
[0037] As used herein, "chip" refers to a solid substrate with a
plurality of one-, two- or three-dimensional micro structures or
micro-scale structures on which certain processes, such as
physical, chemical, biological, biophysical or biochemical
processes, etc., can be carried out. The micro structures or
micro-scale structures such as, channels and wells, electrode
elements, electromagnetic elements, are incorporated into,
fabricated on or otherwise attached to the substrate for
facilitating physical, biophysical, biological, biochemical,
chemical reactions or processes on the chip. The chip may be thin
in one dimension and may have various shapes in other dimensions,
for example, a rectangle, a circle, an ellipse, or other irregular
shapes. The size of the major surface of chips of the present
invention can vary considerably, e.g., from about 1 mm.sup.2 to
about 0.25 m.sup.2. Preferably, the size of the chips is from about
4 mm.sup.2 to about 25 cm.sup.2 with a characteristic dimension
from about 1 mm to about 5 cm. The chip surfaces may be flat, or
not flat. The chips with non-flat surfaces may include channels or
wells fabricated on the surfaces.
[0038] It is understood that aspects and embodiments of the
invention described herein include "consisting" and/or "consisting
essentially of" aspects and embodiments.
[0039] Other objects, advantages and features of the present
invention will become apparent from the following specification
taken in conjunction with the accompanying drawings.
B. Bubble-Based Microvalve, Microfluidic System and Chip
[0040] In one aspect, the present invention provides a bubble-based
microvalve and a microfluidic system and chip using such
microvalve, which comprises a gas chamber/channel connected to a
fluid channel. According to some embodiments, the gas
chamber/channel may be directly connected to the fluid channel. In
some embodiments, the gas chamber/channel may be connected to the
fluid channel through a connecting channel, a gas-permeable
membrane, a gas-permeable plate, or a gas-repellent film. In some
embodiments, the microvalve may further comprise a second gas
channel connected to the fluid channel. In some embodiments, the
gas chamber/channel may comprise a drying material or a
gas-trapping material. In some embodiments, the drying material or
the gas-trapping material may be selected from the group consisting
of silica gel, calcium chloride, aluminum oxide and magnesium
oxide. In some embodiments, the gas chamber/channel may comprise a
nitrogen gas. In some embodiments, the material of the microvalve
may be selected from the group consisting of metal, glass, quartz,
silicon, ceramic, plastic, rubber, aluminosilicate and a
composite/compound thereof. The gas chamber/channel may have any
shape that is suitable for its function.
[0041] The microvalve may not only be suitable for liquid samples,
but also for solid-liquid mixed samples. The liquid samples may
have a high surface tension coefficient (e.g., water), or a lower
coefficient, such as an enzyme reaction solution, a nucleic acid
amplification system solution, or a sodium dodecyl sulfate (SDS)
solution.
[0042] Also provided herein is a microfluidic reaction system
comprising a microvalve, which microvalve comprises a gas
chamber/channel connected to a fluid channel. In some embodiments,
the microfluidic reaction system may comprise a reaction chamber.
In some embodiments, the microfluidic reaction system may comprise
multiple reaction chambers and multiple microvalves. According to
some embodiments, the gas chambers and/or said gas channels may not
be linked to one another. According to some embodiments, the gas
chambers and/or said gas channels may be interconnected through an
interconnecting channel. In some embodiments, each microvalve may
be flanked by two adjacent reaction chambers, wherein the reaction
chambers may be in fluidic connection with the fluidic channel. In
some embodiments, the microfluidic reaction system may be open or
closed. Opening and closing of the system may be controlled by the
sealing of the outlet(s) of the fluidic channel.
[0043] In some embodiments, the fluid channel may have sections of
different widths. In some embodiments, the size of the connecting
channel may be adjustable based on at least the following
parameters: pressure of injection pump or injector pipette, volume
of gas chamber/channel, ambient temperature, ambient humidity, air
humidity inside the fluidic channel, angle of the fluidic channel
and the connecting channel, surface tension of the fluidic sample,
and hydrophobic property of the fluidic channel. In some
embodiments, the connecting channel may have a length of .ltoreq.10
cm and a width of .ltoreq.1 cm. In some embodiments, the fluid
channel may have branches. In some embodiments, the gas
chambers/channels are connected by an interconnecting channel.
[0044] In some embodiments, the microfluidic reaction system may
further comprise a means to actuate and/or stop the microvalve. Any
suitable means to actuate and/or stop the bubble-based microvalve
may be used, e.g., introducing a substance into the microvalve or
exerting force to the microvalve, wherein the substance may be a
gas, liquid or solid substance, and wherein the force may be a
piezoelectric, electric, pneumatic or magnetic force.
[0045] Exemplary actuation means of the microvalve may be: 1)
low-humidity gas, wherein the low-humidity gas may be atmospheric
air or gas trapped in the microfluidic system, and the latter may
be produced by a drying material, such as silica gel, calcium
chloride, aluminum oxide or magnesium oxide; 2) heating, wherein
the object of heating may be the microvalve or the whole
microfluidic system, and heating methods may relate to heat
conduction, resistance, electromagnetic, ultrasonic, laser or
infrared; 3) cooling, wherein the object of cooling may be
microvalve or the whole microfluidic system, and the cooling medium
may be water, air or oil; 4) adding a substance, wherein the
substance may be gas, liquid or solid; 5) removing a substance,
wherein the substance may be gas, liquid or solid; and 6) exerting
a force, wherein the force may deform the gas chamber/channel or
change the internal pressure, which may lead to bubble
generation/removal. These actuation means disclosed herein may be
used alone or in combination.
[0046] In some embodiments, outside gas may be introduced into the
microfluidic system. In some embodiments, inside gas may be
introduced into the gas chamber and/or gas channel. The inside gas
may be stored in the microfluidic system already, or may be new gas
generated though, for example, physical method (e.g., heating of
solid or liquid regents), electrochemical method (e.g.,
electrolysis of salt solution), or chemical method (e.g., acid-base
reaction). In some embodiments, a substance outside may be removed
to induce a low pressure, which thus leads to bubble because of gas
expansion. In some embodiments, forces can be piezoelectric,
electric, pneumatic or magnetic. The object exerting the forces may
be the gas chamber/gas channel or other parts of the microfluidic
system, and the device exerting the forces may be outside or inside
the microfluidic system.
[0047] In some embodiments, the microfluidic reaction system may
further comprise a means to stop the microvalve. Generally the stop
means may be the reverse operation of the actuation means, e.g.,
stop heating, stop cooling, remove filled substances, or stop
exerting the force. Other stop means may be directly manipulating
the bubble, e.g., extracting bubble with a syringe needle, or
reducing bubble volume by a chemical or biological reaction. These
stop means can be used alone or in combination.
[0048] Further provided herein is a microfluidic chip comprising a
microfluidic reaction system described herein. In some embodiments,
the microfluidic chip may further comprise a heating device capable
of heating the gas chamber/channel. In some embodiments, the
heating device may comprise a resistance wire, a resistance film or
a metal particle. In some embodiments, the metal particle may be a
gold nano-particle. Any suitable heating means may be used, such as
heat conduction, electromagnetic, ultrasonic, laser or infrared. In
some embodiments, the microfluidic reaction system may further
comprise a cooling device capable of cooling the gas
chamber/channel. In some embodiments, the cooling device may
comprise a cooling fluid.
[0049] In some embodiments, the microfluidic chip may comprise a
top layer and a bottom layer. In some embodiments, the top layer
may contain the microfluidic reaction system. In some embodiments,
the bottom layer may comprise the heating device or cooling device.
In some embodiments, the top layer may contain the fluidic channel
and the bottom layer may contain the gas chamber/channel. In some
embodiments, the microfluidic chip further may comprise a
gas-permeable membrane, a gas-permeable plate, or a gas-repellent
film. In some embodiments, the pore size of the gas-permeable
membrane ranges from about 1 nm to about 1 mm. In some embodiments,
the material of the gas-permeable membrane may be a polymer, which
may be selected from the group consisting of cellulose, cellulose
acetate, cellulose nitrate, mixed cellulose, polyolefin, polyimide,
polyamide, polyether sulfone, polyethylene glycol, sodium alginate,
chitin, and silicone polymer. In some embodiments, the silicone
polymer may be polydimethylsiloxane. In some embodiments, the
gas-permeable plate may comprise pores used for connecting the gas
chamber/channel. In some embodiments, the height of the pores may
be not more than 10 cm, and the diameter of the pores may be not
more than 1 cm. In some embodiments, the material of the
gas-permeable plate may be selected from the group consisting of
metal, glass, quartz, silicon, ceramic, plastic, rubber,
aluminosilicate and a composite/compound thereof. In some
embodiments, the material of the gas-repellent film may be selected
from the group consisting of metal, glass, quartz, silicon,
ceramic, plastic, rubber and a composite/compound thereof. In some
embodiments, the microfluidic chip may further comprise an
interconnecting channel capable of connecting the gas
chambers/channels. In some embodiments, the interconnecting channel
may comprise gas, liquid or mixture of gas and liquid.
[0050] In order to prevent a fluidic sample from entering into gas
chamber and/or gas channel, the size of the connecting channel
(width/height/length, etc.) may be adjusted based on at least the
following parameters: pressure of injection pump or injector
pipette, volume of gas chamber and/or gas channel, ambient
temperature, ambient humidity, air humidity inside the fluidic
channel, angle of the fluidic channel and the connecting channel,
surface tension of the fluidic sample, and hydrophobic property of
the fluidic channel. The length and width of the connecting channel
may be set according to actual needs, for example, the connecting
channel may have a length of .ltoreq.10 cm, and a width of
.ltoreq.1 cm.
[0051] According to some embodiments, the gas chamber/channel may
be connected to the fluid channel through a connecting channel, a
gas-permeable membrane, a gas-permeable plate, or a gas-repellent
film. According to some embodiments, a gas-permeable membrane may
be located between the gas chamber and/or gas channel and the
fluidic channel. This may prevent the fluidic sample from entering
into gas chamber and/or gas channel, and may ensure the connection
between the gas chamber and/or gas channel and the fluidic channel
in the meanwhile. The pore size of the gas-permeable membrane may
be adjusted according to actual needs, for example, the pore size
may range from about 1 nm to about 1 mm. According to some
embodiments, a gas-permeable plate may be located between the gas
chamber and/or gas channel and the fluidic channel. The role of
gas-permeable plate may be similar to the gas-permeable membrane.
The length and diameter of the pores of the gas-permeable plate may
be set according to actual needs, for example, length may be
.ltoreq.10 cm, diameter may be .ltoreq.1 cm. In some embodiments,
the diameter may be 10 nm. According to some embodiments, a
gas-repellent film may be located between the gas chamber and/or
gas channel and the fluidic channel, wherein the gas-repellent film
may be used to actuate the microvalve in some cases. The material
of the gas-permeable plate, gas-permeable membrane and
gas-repellent film may be selected from the group consisting of
metal, glass, quartz, silicon, ceramic, plastic, rubber,
aluminosilicate, and a composite/compound thereof.
[0052] According to some embodiments, a connecting channel, a
gas-permeable membrane, a gas-permeable plate, and a gas-repellent
film may also be used in combination, and the spatial relationship
between the gas chamber/channel and the connecting channel,
gas-permeable membrane, gas-permeable plate, and gas-repellent film
is not limited.
[0053] The microfluidic devices of the present invention may
comprise a central body structure in which various microfluidic
elements are disposed. The body structure includes an exterior
portion or surface, as well as an interior portion which defines
the various microscale channels and/or chambers of the overall
microfluidic device. For example, the body structure of the
microfluidic devices of the present invention typically employs a
solid or semi-solid substrate that may be planar in structure,
i.e., substantially flat or having at least one flat surface.
Suitable substrates may be fabricated from any one of a variety of
materials, or combinations of materials. Often, the planar
substrates are manufactured using solid substrates common in the
fields of microfabrication, e.g., silica-based substrates, such as
glass, quartz, silicon or polysilicon, as well as other known
substrates, i.e., gallium arsenide. In the case of these
substrates, common microfabrication techniques, such as
photolithographic techniques, wet chemical etching, micromachining,
i.e., drilling, milling and the like, may be readily applied in the
fabrication of microfluidic devices and substrates. Alternatively,
polymeric substrate materials may be used to fabricate the devices
of the present invention, including, e.g., polydimethylsiloxanes
(PDMS), polymethylmethacrylate (PMMA), polyurethane,
polyvinylchloride (PVC), polystyrene, polysulfone, polycarbonate
and the like. In the case of such polymeric materials, injection
molding or embossing methods may be used to form the substrates
having the channel and reservoir geometries as described herein. In
such cases, original molds may be fabricated using any of the above
described materials and methods.
[0054] The channels and chambers of the device are typically
fabricated into one surface of a planar substrate, as grooves,
wells or depressions in that surface. A second planar substrate,
typically prepared from the same or similar material, is overlaid
and bound to the first, thereby defining and sealing the channels
and/or chambers of the device. Together, the upper surface of the
first substrate, and the lower mated surface of the upper
substrate, define the interior portion of the device, i.e.,
defining the channels and chambers of the device. In some
embodiments, the upper layer may be reversibly bound to the lower
layer.
[0055] In the exemplary devices described herein, at least one main
channel, also termed an analysis channel, is disposed in the
surface of the substrate through which samples are transported and
subjected to a particular analysis. Typically, a number of samples
are serially transported from their respective sources, and
injected into the main channel by placing the sample in a
transverse channel that intersects the main channel. This channel
is also termed a "sample loading channel." The sample sources are
preferably integrated into the device, e.g., as a plurality of
wells disposed within the device and in fluid communication with
the sample loading channel, e.g., by an intermediate sample
channel.
[0056] The systems of the invention may also include sample sources
that are external to the body of the device per se, but still in
fluid communication with the sample loading channel. In some
embodiments, the system may further comprise an inlet and/or an
outlet to the micro-channel. In some embodiments, the system may
further comprise a delivering means to introduce a sample to the
micro-channel. In some embodiments, the system may further comprise
an injecting means to introduce a liquid into the micro-channel.
Any liquid manipulating equipments, such as pipettes, pumps, etc.,
may be used as an injecting means to introduce a liquid to the
micro-channel.
C. Methods of Manipulating Fluid Using the Microvalve
[0057] In another aspect, the present invention provides a method
for manipulating fluid in a microfluidic channel using a
microvalve, which microvalve comprises a gas chamber/channel
connected to a fluid channel, wherein the volume and/or location of
the gas in the microvalve is changed.
[0058] In some embodiments, the microvalve may be actuated by
heating. In some embodiments, the gas chamber/channel may be placed
in a waterbath or in close proximity to a heater, optionally a Pt
electrode. In some embodiments, the microvalve may be actuated by
cooling, wherein the cooling may be by injecting a cooling fluid
into a channel in close proximity to the gas chamber/channel. In
some embodiments, the microvalve may be actuated by adding
substance, such as nitrogen, into the gas chamber/channel, wherein
the substance may be gas, liquid or solid. In some embodiments, the
gas may be from outside or inside of the fluidic channel, the
microfluidic system or the microfluidic chip. In some embodiments,
the gas from inside of the fluidic channel may be generated by a
physical, electrochemical or chemical method. In some embodiments,
the microvalve may be actuated by removing a substance from the gas
chamber/channel. In some embodiments, the substance may be removed
using the second gas channel. In some embodiments, the microvalve
may be actuated by exerting force on the gas chamber/channel,
wherein the force leads to deformation of the gas chamber/channel.
In some embodiments, the microvalve may be actuated by a
low-humidity gas.
[0059] Further provided herein is a use of a microfluidic chip
described herein for a chemical or biological reaction. In some
embodiments, the biological reaction may be nucleic acid
amplification, immune reaction or cell analysis such as cell
culture or lysis, wherein the nucleic acid amplification may be
selected from the group consisting of polymerase chain reaction
(PCR), strand displacement amplification (SDA), ligase chain
reaction (LCR), nucleic acid sequence-based amplification (NASBA),
transcription-mediated amplification (TMA), loop-mediated
isothermal amplification (LAMP), rolling circle amplification (RCA)
and helicase-dependent amplification (HDA).
D. Examples
[0060] The following examples are offered to illustrate but not to
limit the invention.
REFERENCE NUMERAL LIST
[0061] 101 fluidic channel [0062] 102 connecting channel [0063] 103
gas chamber [0064] 201 sample [0065] 202 gas [0066] 301
bubble-based microvalve [0067] 302 reaction chamber [0068] 401
narrow branch channel [0069] 402 wide branch channel [0070] 403
necked channel [0071] 701 silica gel bead [0072] 801 Pt electrodes
[0073] 901 cooling channel [0074] 1001 interconnecting channel
[0075] 1002 gas outlet [0076] 1101 pyramid [0077] 1201
channel-bubble-based microvalve [0078] 1201 gas channel [0079] 1301
combined bubble-based microvalve
EXAMPLE 1
Low-Humidity Environment, Open System (Outlet is Not Sealed After
Injection), the Microvalve is Actuated by Low-Humidity Air
[0080] The device is composed of two layers, a 1 mm thick PMMA
cover layer and a 2 mm thick PMMA bottom layer. The bottom layer is
embedded with one channel (101) (w=0.5 mm), one narrow branch
channel (401) (w=0.2 mm) connecting the channel (101), and one wide
branch channel (402) (w=0.5 mm) connecting the channel (101)
through a necked channel (403) (w=0.2 mm). It further contains the
bubble-based microvalve (301), in which a gas chamber (103)
(l.times.w.times.h=2.2 mm.times.0.5 mm.times.1.5 mm) with a
hydrophobic Teflon (PTFE) coating is directly connected to the
channel (101). All channels are 0.2 mm deep.
[0081] The device is fabricated through conventional techniques in
the microfluidic area, i.e., firstly micro-structures on the PMMA
bottom layer are exploited by laser engraving machine or milling
machine, then a PTFE solution (0.1% V/V) is coated into gas chamber
using a injector pipette, and finally the cover layer and the
bottom layer are thermally bonded into a complete chip.
[0082] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 16%. When injecting water sample
to channel (101) in 5 .mu.L/min, most of the sample is entering
into the wide branch channel (402) because of the bigger fluid
resistance of narrow branch channel (401) (FIG. 3). Three minutes
later, the volume increase of gas chamber (202) induces a bubble
into the channel (101), thus held by the necked channel (403), so
the wide branch channel (402) is blocked while sample can only
enter into narrow branch channel (401) (FIG. 2, 5).
[0083] The working principle is: since PTFE coating is hydrophobic
and water sample has a high surface tension, water does not fill
the gas chamber (103) and leaving trapped low-humidity air inside
the gas chamber (103). After priming, a part of sample (201) will
spontaneously evaporate into gas (202) to increase the humidity and
pressure, which generate a bubble to block the downstream flow.
EXAMPLE 2
Low-Humidity Environment, Closed System (Outlet is Sealed After
Injection), the Microvalve is Actuated by Low-Humidity Air
[0084] The microfluidic chip is composed of two layers, a 1 mm
thick PMMA cover layer and a 2 mm thick PMMA bottom layer. The
bottom layer is embedded with a micro-reactor array, in which a
channel (101) and 24 reaction chambers (302) are arranged serially
in a ring pattern and the distance between each chamber (diameter=3
mm, depth=1 mm) is uniform (FIG. 6). It further contains the
bubble-based microvalve (301), in which each gas chamber (103)
(diameter=1.8 mm, depth=1.5 mm) between reaction chambers (302) is
connected to the channel (101) through a connecting channel (102)
(l=0.75 mm). All channels are 0.2 mm deep, 0.4 mm wide.
[0085] The fabrication technology of this device is similar to
Example 2.
[0086] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 16%. When injecting PCR system
solution (201) to channel (101) in 60 .mu.L/min, this sample
serially enters into each reaction chamber (302), then the inlet
and outlet are sealed. Three minutes later, the volume increase of
gas chamber (202) induces a bubble into the channel (101), thus
blocking the channel (101) and isolating the reaction chamber
(302).
[0087] The working principle is: since fluid pressure is relatively
high and PCR system solution has a low surface tension, a
connecting channel (102) is necessary to prevent the sample from
filling the gas chamber (103). After priming, a part of sample
(201) will spontaneously evaporate into gas (202) to increase the
humidity and pressure, which generate a bubble to isolate the
reaction chamber (302).
EXAMPLE 3
High-Humidity Environment, Closed System (Outlet is Sealed after
Injection), the Microvalve is Actuated by Low-Humidity Gas Trapped
in Chip
[0088] The microfluidic chip is the same as the one in Example 2,
except that each gas chamber (103) contains a silica gel bead (701)
(FIG. 7).
[0089] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 75%. Silica gel beads (701) are
added into each chamber and the inlet and outlet are sealed for one
hour. After that, a PCR system solution (201) is injected to the
channel (101) in 60 .mu.L/min, then the inlet and outlet are sealed
once again. Three minutes later, the volume increase of gas chamber
(202) induces a bubble into the channel (101), thus blocking the
channel (101) and isolating the reaction chamber (302).
[0090] The working principle is: the principle is the same as the
one in Example 2, except that the low-humidity air is instead of
low-humidity gas dried by silica gel beads.
EXAMPLE 4
High-Humidity Environment, Closed System (Outlet is Sealed after
Injection), the Microvalve is Actuated through Heating the Whole
Microfluidic Chip
[0091] The microfluidic chip is the same as the one in Example
2.
[0092] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 75%. When injecting PCR system
solution (201) to channel (101) in 60 .mu.L/min, this sample
serially enters into each reaction chamber (302), then the inlet
and outlet are sealed. The chip is placed into the thermostat water
bath at 65.degree. C., which raises the temperature of the whole
microfluidic chip through heat conduction. Two minutes later, the
volume increase of gas chamber (202) induces a bubble into the
channel (101), thus blocking the channel (101) and isolating the
reaction chamber (302) (FIG. 2).
[0093] The working principle is: because of heating, a part of
sample (201) will evaporate into gas (202), which raises the
saturation vapor pressure and reduces the liquid volume, thus a
bubble is generated to isolate the reaction chamber (302). It is
should be noted that the chip are sealed in the progress, thermal
expansion of the gas does not increase the gas volume, but increase
the pressure.
EXAMPLE 5
High-Humidity Environment, Open System (Outlet is Not Sealed after
Injection), the Microvalve is Actuated through Heating the Gas
Chamber
[0094] As shown in FIG. 8, the microfluidic chip is composed of two
layers, a 4 mm thick PDMS cover layer and a 2 mm thick glass bottom
layer (the dashed line in the bottom layer represents the
projection of cover layer). The cover layer is embedded with a
micro-reactor array, in which a channel (101) and 42 reaction
chambers (302) (diameter=3 mm, depth=1 mm) are arranged serially in
a snake pattern and the distance between each reaction chamber
(diameter=4 mm, depth=1 mm) is uniform. It further contains the
bubble-based microvalve (301), in which each gas chamber (103)
(l.times.w.times.h=3 mm.times.3 mm.times.1.5 mm) between reaction
chambers (302) is connected to the channel (101) through a
connecting channel (102) (l=1 mm). The bottom layer contains a
heater, Pt meander traces (801) aligned with gas chambers (103).
All channels are 0.2 mm deep, 0.2 mm wide.
[0095] The cover layer of the microfluidic chip is fabricated in
polydimethylsiloxane (PDMS) using a rapid prototyping technique and
Pt electrodes of the bottom layer are lithographically patterned
onto a glass slide. Pt electrodes (801) are connected to an
external power for heating gas chambers (103) alone, that will
avoid thermal denaturation of sample in reaction chambers
(302).
[0096] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 75%. When injecting SDS solution
(201) (10% W/V) to channel (101) at 360 .mu.L/min, this sample
serially enters into each reaction chamber (302), the inlet and
outlet are not sealed. Gas chambers (103) are heated to 70.degree.
C. by Pt electrodes (801) while the pressure of gas chamber (202)
is rising. Two minutes later, the volume increase of gas chamber
(202) induces a bubble into the channel (101), thus blocking the
channel (101) and isolating the reaction chamber (302) (FIG.
2).
[0097] The working principle is: since flow rate is higher than the
ones in Examples 2-4, and SDS solution has a lower surface tension
than PCR system solution, the connecting channel (102) should be
longer and narrower to prevent the sample from filling the gas
chamber (103). After heating, firstly the gas is performing pure
thermal expansion, then a part of sample (201) will gradually
evaporate into gas (202), which raises the saturation vapor
pressure. Finally these two factors contribute to the gas volume
increase, a bubble is generated to isolate the reaction chamber
(302). It is should be noted that the chip is not sealed in the
progress.
EXAMPLE 6
High-Humidity Environment, Closed System (Outlet is Sealed after
Injection), the Microvalve is Actuated through Cooling the Gas
Chamber
[0098] As shown in FIG. 9, the microfluidic chip is similar to the
one in Example 5, but it is composed of three layers, a 4 mm thick
PDMS cover layer, a 0.2 mm thick glass middle layer and a 2 mm
thick glass bottom layer (the dashed line in the bottom layer
represents the projection of cover layer). The cover layer is
embedded with a micro-reactor array, in which a channel (101) and
42 reaction chambers (302) (diameter=3 mm, depth=1 mm) are arranged
serially in a snake pattern and the distance between each reaction
chamber (diameter=4 mm, depth=1 mm) is uniform. It further contains
the bubble-based microvalve (301), in which each gas chamber (103)
(l.times.w.times.h=3 mm.times.3 mm.times.1.5 mm) between reaction
chambers (302) is connected to the channel (101) through a
connecting channel (102) (l=1 mm). The bottom layer contains a
cooling channel (901) (w.times.h=1 mm.times.0.2 mm), which is
aligned with gas chambers (103). All channels are 0.2 mm deep, 0.2
mm wide.
[0099] The cover layer of the microfluidic chip is fabricated in
polydimethylsiloxane (PDMS) using a rapid prototyping technique and
the cooling channel (901) in the bottom layer are patterned onto a
glass slide using a wet etching method. The cooling channel (901)
is filled with cooling solution by a peristaltic pump, that can
only cool gas chambers (103) and not affect reaction chambers
(302).
[0100] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 75%. When injecting SDS solution
(201) (10% W/V) to channel (101) at 360 .mu.L/min, this sample
serially enters into each reaction chamber (302), then the inlet
and outlet are sealed. Saline solution at 0.degree. C. is injected
to the cooling channel (901) at 1 mL/min. One minute later, a
bubble is induced into the channel (101), thus blocking the channel
(101) and isolating the reaction chamber (302) (FIG. 2).
[0101] The working principle is: after cooling, gas chambers will
change to near 0.degree. C., and vapor from the relatively warmer
region will condensate in the walls of cooler gas chambers, i.e.,
mass transfer between the liquid in the channel (101) and the gas
in the gas chamber (103) is happening, a part of gas is displaced
into the channel (101), and a bubble is generated to isolate the
reaction chamber (302). It should be noted that the chip is sealed
in the process, thermal contraction of the gas does not reduce the
gas volume, but reduces the pressure.
EXAMPLE 7
High-Humidity Environment, Closed System (Outlet is Sealed after
Injection), the Microvalve is Actuated through Adding Substances
into the Gas Chamber
[0102] As shown in FIG. 10, the microfluidic chip is similar to the
one in Example 6, it is composed of three layers, a 4 mm thick PDMS
cover layer, a 0.05 mm thick PDMS middle layer and a 2 mm thick
glass bottom layer (the dashed line in the bottom layer represents
the projection of cover layer). The cover layer is embedded with a
micro-reactor array, in which a channel (101) and 42 reaction
chambers (302) (diameter=3 mm, depth=1 mm) are arranged serially in
a snake pattern and the distance between each reaction chamber
(diameter =4 mm, depth=1 mm) is uniform. The bottom layer contains
interconnecting channels (1001) (w.times.h=1 mm.times.0.2 mm) and
gas chambers (103) (w.times.h=1 mm.times.0.2 mm), which is aligned
with the channel (101) of the cover layer.
[0103] Gas chambers (103) are interconnected by a few
interconnecting channels (1001), and share a unique gas outlet
(1002), i.e., all the bubble-based microvalves (301) are connected
as a complete gas network. The cover layer of the microfluidic chip
is fabricated in polydimethylsiloxane (PDMS) using a rapid
prototyping technique and bubble-based microvalves (301) in the
bottom layer are patterned onto a glass slide using a wet etching
method.
[0104] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 75%. When injecting SDS solution
(201) (10% W/V) to channel (101) at 360 .mu.L/min, this sample
serially enters into each reaction chamber (302), then the inlet
and outlet are not sealed. Nitrogen is injected to the gas outlet
(1002) at 1.2 MPa. Ten minute later, the volume increase of gas
(202) in gas chamber (103) induces a bubble into the channel (101),
thus blocking the channel (101) and isolating the reaction chamber
(302). After that, the gas outlet (1002) is closed and bubbles keep
stable.
[0105] The working principle is: a gas-permeable membrane, the PDMS
middle layer is placed between the channel (101) and the gas
chambers (103) to prevent sample from filling the gas chambers
(103), so connecting channels in Examples 5-6 are no longer needed.
When nitrogen is injected, it will enter into each gas chamber
(103) along the gas network, then gradually permeate into the
channel (101) through PDMS middle layer. After a period of time, a
bubble is generated to isolate the reaction chamber (302). Because
the equilibrium of gas solubility has been set up, outside gas
pressure is not required to continue.
EXAMPLE 8
High-Humidity Environment, Closed System (Outlet is Sealed after
Injection), the Microvalve is Actuated through Exerting Forces onto
Gas Chambers
[0106] The microfluidic chip is the same as the one in Example 2,
except that the 1 mm thick PMMA cover layer is instead of 0.2 mm
thick PMMA membrane. A supplementary tool, the pyramid ring (FIG.
11), is used for pressing the gas chamber. It is composed of a
metal ring and 23 pyramids (1101), each pyramid is aligned with the
gas chamber (103) of the cover layer.
[0107] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 75%. When injecting SDS solution
(201) (10% W/V) to channel (101) at 360 .mu.L/min, this sample
serially enters into each reaction chamber (302), then the inlet
and outlet are sealed. When exerting forces on the pyramid ring,
which is placed on the chip, a part of the gas (202) in the gas
chamber (103) is pushed out. A bubble is generated to block the
channel (101) and isolate the reaction chamber (302). If removing
forces at this time, the bubble will retract into the gas chamber
(103), and reaction chambers (302) will not be independent.
[0108] The working principle is: the PM MA membrane will deform
under the external force, which changes the location of gas and
induces a bubble.
EXAMPLE 9
High-Humidity Environment, Open System (Outlet is Not Sealed after
Injection), the Microvalve is Actuated through Adding Substances
into the Gas Chamber
[0109] As shown in FIG. 12, the microfluidic chip is the same as
the one in Example 1, except the gas chamber (103) instead of the
gas channel (1202), so the microvalve can be regard as
channel-bubble-based microvalve (1201). The gas channel (1202) is a
PVC tube (diameter=0.1 mm), one end is bonded to the channel (101)
by epoxy resin and the other is connected to a syringe.
[0110] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 75%. When injecting water sample
to channel (101) in 5 .mu.L/min, most of the sample is entering
into the wide branch channel (402) because of the bigger fluid
resistance of narrow branch channel (401). Air is injected into the
gas channel (1202) for 2 s, which induces a bubble into the channel
(101). The bubble is thus held by the necked channel (403), so the
wide branch channel (402) is blocked while sample can only enter
into narrow branch channel (401) (FIG. 12).
[0111] The working principle is: since the gas channel (1202) is
closed by syringe in the beginning, water does not fill the gas
chamber (103). Once a little air is injected, a bubble is generated
to block the downstream flow.
EXAMPLE 10
High-Humidity Environment, Closed System (Outlet is Sealed after
Injection), the Microvalve is Actuated through Removing
Substances
[0112] As shown in FIG. 13, the microfluidic chip is the same as
the one in Example 1, except that the bubble-based microvalve (301)
is replaced by the combined bubble-based microvalve (1301), which
contains a gas chamber (103) and a gas channel (1202). The gas
channel (1202) is a PVC tube (diameter=0.1 mm), one end is bonded
to the channel (101) by epoxy resin and the other is connected to a
syringe.
[0113] The device is positioned in the lab with room temperature
20.degree. C., relative humidity 75%. When injecting water sample
to channel (101) in 5 .mu.L/min, most of the sample is entering
into the wide branch channel (402) because of the bigger fluid
resistance of narrow branch channel (401). Using the syringe,
sample is extracted into the gas channel (1202) for 2 s, which
reduces the pressure of the channel (101). Accordingly, the gas in
gas chamber (103) expands and induces a bubble into the channel
(101). The bubble is held by the necked channel (403), so the wide
branch channel (402) is blocked, thus sample can only enter into
narrow branch channel (401) (FIG. 14) and the gas chamber (103) is
partly filled by sample.
[0114] Sample is once again extracted into the gas channel (1202)
for 10 s, the bubble disappears and the wide branch channel (402)
is again open.
[0115] The working principle is: if removing substances outside gas
chamber, a low pressure will be generated, then the gas volume will
be increasing under the low pressure, finally that induces a bubble
to block the downstream flow. If extracting bubble with syringe,
the microvalve will remain open. In this embodiment, the
bubble-based microvalve can control the flow stage shift between
open-closed.
EXAMPLE 11
Structure of Bubble-Based Microvalve and an Actuation Means
[0116] This structure utilizes gas chamber (103), which is not
connected to outside, rather than gas channel (1202).
[0117] In low-humidity environment (ambient relative humidity is
5-50%), during sample (201) priming of the channel (101), geometry
character of gas chamber (103) ensures that the liquid-air phase
line remains in the interface between the gas chamber (103) and the
channel (101), the sample (201) does not fill (or fill partly) the
gas chamber (103), meanwhile, air trapped in the gas chamber (103)
keeps its original property of low-humidity. At this time the
microvalve is not actuated. After sample (201) priming, a part of
sample (201) will spontaneously evaporate into gas (202) until gas
(202) reaches saturation, which increases the pressure of the gas
(202), and finally induces a bubble into the channel (101). At this
time the microvalve is actuated, the channel (101) is closed by the
bubble.
[0118] In the microfluidic chip, microvalves and reaction chambers
are connected to each other in series. After a sample is injected
into this chip, sample volume of each chamber is uniform, and each
reaction chamber can soon be independent in the action of
microvalve.
[0119] The above examples are included for illustrative purposes
only and are not intended to limit the scope of the invention. Many
variations to those described above are possible. Since
modifications and variations to the examples described above will
be apparent to those of skill in this art, it is intended that this
invention be limited only by the scope of the appended claims.
[0120] The advantage of the microvalve described herein includes
simple design, controllable operation, broad application range
especially for the case that heat effect should not be introduced
and the case that closed system should be ensured.
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