U.S. patent application number 12/424266 was filed with the patent office on 2009-10-15 for method and apparatus for controlling microfluidic flow.
Invention is credited to Jacob Rosenstein, Anubhav Tripathi.
Application Number | 20090257886 12/424266 |
Document ID | / |
Family ID | 36932083 |
Filed Date | 2009-10-15 |
United States Patent
Application |
20090257886 |
Kind Code |
A1 |
Rosenstein; Jacob ; et
al. |
October 15, 2009 |
Method And Apparatus For Controlling Microfluidic Flow
Abstract
An apparatus includes a pump; a gas pressure sensor; a
microfluidic chip defining a microfluidic conduit; and a gas
conduit providing fluid communication between the pump, the gas
sensor and the microfluidic conduit; and a controller coupled to
the pump and the gas pressure sensor, whereby the controller
controls the pump, thereby controlling the gas pressure at the
microfluidic conduit. An apparatus includes a microfluidic chip
defining a microfluidic conduit extending from a microfluidic
source electrode to a microfluidic ground electrode; a first
resistor coupled to the microfluidic source electrode; a first and
a second voltage divider, the first divider coupling a first power
ground to a side of the first resistor opposite the microfluidic
chip, the second divider coupling a second power ground to the lead
between the first resistor and the microfluidic source electrode,
and a first voltage sensor; and a second voltage sensor. Also
included are methods of operating the apparatus.
Inventors: |
Rosenstein; Jacob;
(Somerville, MA) ; Tripathi; Anubhav;
(Northborough, MA) |
Correspondence
Address: |
HAMILTON, BROOK, SMITH & REYNOLDS, P.C.
530 VIRGINIA ROAD, P.O. BOX 9133
CONCORD
MA
01742-9133
US
|
Family ID: |
36932083 |
Appl. No.: |
12/424266 |
Filed: |
April 15, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11184533 |
Jul 19, 2005 |
|
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12424266 |
|
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60656237 |
Feb 25, 2005 |
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Current U.S.
Class: |
417/2 ;
417/44.11; 417/53; 417/54; 417/86 |
Current CPC
Class: |
B01L 2200/143 20130101;
G01N 35/1016 20130101; B01L 3/0293 20130101; G01N 2035/1039
20130101; B01L 2400/0487 20130101; B01L 2200/146 20130101; B01L
2400/0415 20130101; B01L 3/5027 20130101; B01L 2300/14 20130101;
B01L 2400/0481 20130101 |
Class at
Publication: |
417/2 ; 417/54;
417/86; 417/44.11; 417/53 |
International
Class: |
F04B 41/06 20060101
F04B041/06; F04B 23/14 20060101 F04B023/14; F04B 49/06 20060101
F04B049/06 |
Claims
1. An apparatus, comprising: a) a pump; b) a gas pressure sensor;
c) a microfluidic chip defining a microfluidic conduit; and d) a
gas conduit providing fluid communication between the pump, the gas
sensor and the microfluidic conduit; and e) a controller coupled to
the pump and the gas pressure sensor, whereby the controller
controls the pump, thereby controlling the gas pressure at the
microfluidic conduit.
2. The apparatus of claim 1, wherein the pump is a peristaltic
pump.
3. The apparatus of claim 2, wherein the gas pressure sensor is
located off-chip.
4. The apparatus of claim 3, wherein the gas pressure sensor is a
macroscopic gas pressure sensor.
5. The apparatus of claim 3, further including a second pump
coupled to the controller, a second gas sensor, and a second gas
conduit coupled to the second gas sensor, the second pump, and the
microfluidic conduit, whereby a gas pressure differential across
the microfluidic conduit is determined at the controller.
6. The apparatus of claim 3, wherein the pump, the gas conduit, and
the gas sensor define a pressure channel, further including at
least one additional pressure channel, wherein each channel is
coupled to the controller.
7. The apparatus of claim 6, wherein the controller independently
controls the gas pressure at each intersection of the gas conduits
and the microfluidic conduits.
8. The apparatus of claim 3, further including a manifold at the
gas conduit that directs gas pressure to at least one of at least
two microfluidic conduits defined by at least one microfluidic
chip.
9. The apparatus of claim 8, wherein the manifold is a switchable
manifold, and the controller is coupled to the manifold to switch
the pump and the gas pressure sensor between at least two
microfluidic conduits.
10. The apparatus of claim 9, wherein the controller independently
controls the pressure through the manifold to the microfluidic
conduits.
11. An apparatus, comprising: a) a plurality of pressure channels,
each pressure channel including a pump; a gas pressure sensor; and
a gas conduit providing fluid communication between the pump, the
gas sensor and a microfluidic conduit defined by a microfluidic
chip; and b) a controller coupled to each pump and each sensor,
whereby the controller independently controls gas pressure at an
intersection of the gas conduit and the microfluidic channel.
12. The apparatus of claim 11, further comprising the microfluidics
chip, wherein each gas conduit is coupled to a corresponding
microfluidics conduit of the microfluidics chip.
13. The apparatus of claim 12, wherein at least one pump is a
peristaltic pump.
14. The apparatus of claim 13, wherein the gas pressure sensor is
located off-chip.
15. The apparatus of claim 14, wherein at least one gas pressure
sensor is a macroscopic gas pressure sensor.
16. The apparatus of claim 15, further including a junction in the
microfluidic chip between at least three said microfluidic
conduits, wherein the controller independently controls fluid flow
from two of the three conduits to thereby combine fluid from the
two microfluidic conduits at a junction with at least one other
microfluidic conduit.
17. The apparatus of claim 15, further including a switchable
manifold coupling the pump and the gas pressure sensor to at least
two said microfluidics conduits defined by at least one
microfluidic chip.
18. A method of controlling microfluidic flow, comprising the steps
of: a) applying gas pressure to at least one fluid at a
microfluidic conduit defined by a microfluidic chip; b) sensing the
gas pressure; and c) controlling the gas pressure in response to
the gas pressure sensed to control microfluidic flow of the fluid
in the microfluidic conduit.
19. The method of claim 18, wherein the microfluidics chip includes
a plurality of microfluidic conduits, further including
independently controlling the microfluidic flow in two or more
microfluidic conduits defined by the microfluidic chips.
20. The method of claim 19, wherein at least three microfluidic
conduits meet in a junction, further including independently
controlling fluid flow from two of the three conduits to thereby
combine fluid from the two microfluidic conduits at the
junction.
21. The method of claim 20, further including employing a negative
feedback loop from an intersection defined by the gas conduit and
the microfluidic conduit to the controller to thereby control gas
pressure at the intersection.
22. The method of claim 18, wherein the gas pressure is applied
with a peristaltic pump.
23. The method of claim 18, wherein the gas pressure is sensed
off-chip.
24. The method of claim 18, wherein the gas pressure is sensed with
a macroscopic gas sensor.
25. An apparatus, comprising: a microfluidic chip defining a
microfluidic conduit extending from a microfluidic source electrode
to a microfluidic ground electrode; a first resistor coupled by an
electrical lead to the microfluidic source electrode; a first and a
second voltage divider each including a pair of resistors in
series, the first divider coupling a first power ground to a side
of the first resistor opposite the microfluidic chip, and the
second divider coupling a second power ground to the lead between
the first resistor and the microfluidic source electrode, and a
first voltage sensor coupled between the voltage dividers at a
point in each voltage divider between the resistors in series; and
a second voltage sensor coupled across at least one said resistor
in series in the first voltage divider.
26. The apparatus of claim 25, further including within at least
one said voltage divider a variable resistor is coupled to adjust
the resistance of that voltage divider to about the resistance of
the other voltage divider.
27. The apparatus of claim 26, wherein the variable resistor is
adjusted to place the resistance of the voltage dividers within
about 0.02% of each other.
28. The apparatus of claim 27 further comprising a power supply
coupled to the first resistor and the first voltage divider.
29. The apparatus of claim 28, further comprising a controller
coupled to the power supply and the voltage sensors, wherein the
controller compares the voltages at the voltage sensors to identify
a microfluidic current between the microfluidic source electrode
and the microfluidic ground electrode, and controls the power
supply to control the microfluidic current, thereby controlling
microfluidic flow of a fluid in the microfluidic conduit via
electromotive force.
30. The apparatus of claim 29, wherein the apparatus is operated in
a constant current mode.
31. The apparatus of claim 29, wherein the apparatus is operated in
a constant voltage mode.
32. The apparatus of claim 25, wherein the first resistor, the
voltage dividers, the voltage sensors, the microfluidic conduit,
the microfluidic source electrode, and the microfluidic ground
electrode together define an electrical channel, further including
at least one additional electrical channel.
33. The apparatus of claim 32, further including a plurality of
pressure channels, each pressure channel including: a pump; a gas
pressure sensor; and a gas conduit providing fluid communication
between the pump, the gas sensor and the microfluidic conduit.
34. The apparatus of claim 33, wherein for each pressure channel,
the controller is coupled to the gas pressure sensor and the pump
to thereby sense and control gas pressure in each pressure channel,
thereby controlling microfluidic flow via pressure in each
microfluidic conduit that is coupled to each said pressure
channel.
35. The apparatus of claim 33, wherein at least one microfluidic
conduit is coupled to at least one said pressure channel and at
least one said electrical channel, whereby the controller
independently controls pressure and electrical current to thereby
control microfluidic flow in the microfluidic conduit.
36. A method of determining microfluidic current in a microfluidic
chip, comprising the steps of: a) applying an electrical current to
a fluid in a microfluidic conduit extending from a microfluidic
source electrode to a microfluidic ground electrode in a
microfluidic chip, thereby causing microfluidic fluid flow, b)
determining a value of the electrical current in the fluid between
the electrodes.
37. The method of claim 36, further including controlling the
microfluidic fluid flow by controlling the value of the electrical
current in the fluid between the electrodes.
38. The method of claim 37, wherein the electrical current is
controlled by: a) applying the electrical current from a power
supply coupled through a first resistor coupled by a lead to the
microfluidic source electrode; and b) determining the value of the
electrical current by measuring a first and second voltage
corresponding to the value of the electrical current, wherein the
first voltage is measured at a first voltage sensor coupled between
a first and second voltage divider, each divider including a pair
of resistors in series and the voltage measured at a point in each
voltage divider between the resistors in series, the first divider
coupling a side of the first resistor opposite the microfluidic
source electrode to a first power ground, and the second divider
coupling the lead between the first resistor and the microfluidic
source electrode to a second power ground; and the second voltage
is measured at a second voltage sensor coupled across at least one
said resistor in series in the second voltage divider.
39. The method of claim 38, further including within at least one
said voltage divider a variable resistor is coupled to adjust the
resistance of that voltage divider to about the resistance of the
other voltage divider.
40. The method of claim 39, wherein the variable resistor is
adjusted to place the resistance of the voltage dividers within
about 0.02% of each other.
41. The method of claim 40, wherein the first resistor, the voltage
dividers, the voltage sensors, the microfluidic conduit, the
microfluidic source electrode, and the microfluidic ground
electrode together define an electrical channel, and the further
including independently controlling at least two electrical
channels.
42. An apparatus, comprising: means to flow fluid in a microfluidic
chip; and means to control fluid flow by an analog signal
corresponding to a force that causes fluid flow in the microfluidic
chip.
Description
RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 11/184,533, filed Jul. 19, 2005, which claims the benefit of
U.S. Provisional Application No. 60/656,237, filed on Feb. 25,
2005, the entire teachings of which are incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] One goal of microfluidics is to provide precise, automated
fluid processing on minimally sized samples. A key part of a
microfluidic platform is the control instrumentation which
manipulates the fluid samples in the microfluidic features (e.g.,
conduits and wells) of the microfluidic chip. Typically, fluid can
be transported through the microfluidic features by an electrical
or pressure gradient.
[0003] Pressure-controlled fluid transport has been typically
achieved with programmable syringe pumps, usually driven by stepper
motors. Sample fluid can be loaded into a syringe pump and the
output routed directly into a microfluidics chip. The syringe can
be operated to create a pressure differential on the fluid,
transporting it through the microfluidic chip.
[0004] However, such programmable syringe pumps typically offer
only open loop control without means to readily measure pressure
differentials across the microfluidic features of the chip. Efforts
have been made to offer closed loop control by embedding miniature
pressure sensors into the microfluidic chips themselves. However,
compared to the wide range of macroscopic pressure sensors
available, such miniature pressure sensors can be expensive,
limited in precision/range and difficult to integrate into
microfluidic chips. In addition, the volume requirements of syringe
pump platforms can minimize the sample size advantage of
microfluidics, as a comparatively large reservoir of fluid can be
required to fill a syringe. Moreover, syringe pump platforms can be
difficult to adapt to multi-channel arrangements. Equipping a
multi-channel system with a syringe pump for each channel, for
example a 16-channel system, can require a bulky system containing
16 syringe pumps, each with its own motor and controller. Also,
operation and maintenance of a multiple syringe pump system can be
labor intensive.
[0005] Electrically controlled fluid transport has been achieved by
applying high voltages across electrodes that span a microfeature
of the chip, e.g., an electrode can be placed in a well at each end
of a conduit, the wells supplying fluid to the conduit. When a high
voltage is applied across the electrodes, charged particles can be
drawn through the conduits between wells. The electrical resistance
of fluids typically employed can be high enough to require voltages
of up to several thousand volts (kV) to induce direct currents of
several microamperes sufficient to lead to the desired fluid flow.
In microfluidics applications, current control requirements can be
demanding; although the supplies typically rarely need to supply
more than about 40 microamperes, it can be important to know the
actual current to within less than 1 microampere.
[0006] Moreover, dealing with several such high voltage electrical
channels can present a challenge to measurement of an electrical
channel's output current. A conventional low-side current
measurement can be impossible because a microfluidic chip typically
has no common drain. A high-side current measurement could be
employed on each electrical channel, but a conventional approach to
such measurements would use a differential amplifier or isolation
amplifier capable of handling extremely high voltages (e.g., 5,000
V of common mode voltage, a capability not possessed by typical
differential and isolation amplifiers). Also, non-contact "clamp"
style current measurements typically would not be effective with
direct currents in the microampere range.
[0007] Moreover, precise control of current and fluid transport can
be difficult when employing high voltage supplies. Although many
basic regulated programmable high voltage power supplies are
available, they are not typically useable in a microfluidics
application without modifications or external measurement setups.
One reason for this is that many high voltage supplies are unable
to sink current, which is generally not acceptable in a
microfluidics chip where electrical channels can be directly
interacting through the chip. Another reason is that available high
voltage supplies typically either have relatively coarse current
monitoring or lack current monitoring altogether.
[0008] Commercially available electrical microfluidic controllers
can be effective in some respects, but typically can be difficult
or impossible to integrate with pressure control, which can be
desirable for many experimental reasons (for example, for easily
switching between fluids of widely different conductivities).
Moreover, many otherwise capable commercial controllers are not
equipped to easily integrate with other typical lab instrumentation
such as pressure controllers, heaters, spectroscopic detectors,
microscopes, or the like.
[0009] Therefore, there is a need in the field of microfluidics for
improved methods and apparatus for controlling fluid transport.
SUMMARY OF THE INVENTION
[0010] Disclosed herein are improved methods and apparatus for
pressure and electrical control of fluid transport for
microfluidics applications.
[0011] In various embodiments of the invention, an apparatus
includes a pump; a gas pressure sensor; a microfluidic chip
defining a microfluidic conduit; a gas conduit providing fluid
communication between the pump, the gas sensor and the microfluidic
conduit; and a controller coupled to the pump and the gas pressure
sensor. The controller controls the pump, thereby controlling the
gas pressure at the microfluidic conduit.
[0012] In various embodiments, a second pump can be coupled to the
controller, a second gas sensor. Also, a second gas conduit can be
coupled to the second gas sensor, the second pump, and the
microfluidic conduit. A gas pressure differential across the
microfluidic conduit can be determined at the controller. In
various embodiments, the pump, the gas conduit, and the gas sensor
define a pressure channel, and the apparatus includes at least one
additional pressure channel. Each channel is coupled to the
controller. Typically, the controller independently controls the
gas pressure at each intersection of the gas conduits and the
microfluidic conduits. In various embodiments, the apparatus
includes a manifold at the gas conduit that directs gas pressure to
at least one of at least two microfluidic conduits defined by at
least one microfluidic chip. The manifold can be a switchable
manifold, and the controller can be coupled to the manifold to
switch the pump and the gas pressure sensor between at least two
microfluidic conduits. Typically, the controller independently
controls the pressure through the manifold to the microfluidic
conduits.
[0013] In various embodiments, an apparatus includes a plurality of
pressure channels, each pressure channel including a pump; a gas
pressure sensor; and a gas conduit providing fluid communication
between the pump, the gas sensor and a microfluidic conduit defined
by a microfluidic chip. Also included is a controller coupled to
each pump and each sensor, whereby the controller independently
controls gas pressure at an intersection of the gas conduit and the
microfluidic channel. Typically, the apparatus includes the
microfluidics chip, wherein each gas conduit is coupled to a
corresponding microfluidics conduit of the microfluidics chip. In
various embodiments, a junction is included in the microfluidic
chip between at least three said microfluidic conduits. The
controller independently controls fluid flow from two of the three
conduits to combine fluid from the two microfluidic conduits at a
junction with at least one other microfluidic conduit.
[0014] In typical embodiments of the apparatus described in the
preceding two paragraphs, the gas pressure sensor is physically
separate from the chip. For example, the gas pressure sensor can
measure a pressure at the microfluidic conduit on the chip by
measuring the gas pressure in the gas conduit, which provides the
fluid (e.g., gas) communication between the gas pressure sensor and
the chip. In some embodiments, the gas pressure sensor can be a
macroscopic gas pressure sensor. Also, the pump is typically a
peristaltic pump.
[0015] In various embodiments of the invention, a method of
controlling microfluidic flow includes the steps of applying gas
pressure to at least one fluid at a microfluidic conduit defined by
a microfluidic chip; sensing the gas pressure; and controlling the
gas pressure in response to the gas pressure sensed to control
microfluidic flow of the fluid in the microfluidic conduit.
Typically, the microfluidics chip can include a plurality of
microfluidic conduits, and the method further includes
independently controlling the microfluidic flow in two or more
microfluidic conduits defined by the microfluidic chips. In some
embodiments, at least three microfluidic conduits meet in a
junction, and the method also includes independently controlling
fluid flow from two of the three conduits to thereby combine fluid
from the two microfluidic conduits at the junction. In some
embodiments, the method can employ a negative feedback loop from an
intersection defined by the gas conduit and the microfluidic
conduit to the controller to control gas pressure at the
intersection. In various embodiments, the gas pressure can be
applied with a peristaltic pump. In some embodiments, the gas
pressure can be sensed by a gas pressure sensor that is off-chip,
in other words physically separate from the microfluidic chip and
the microfluidic conduit; and/or the gas pressure can be sensed
with a macroscopic gas sensor.
[0016] In various embodiments of the invention, an apparatus
includes a microfluidic chip defining a microfluidic conduit
extending from a microfluidic source electrode to a microfluidic
ground electrode. Also included is a first resistor coupled by an
electrical lead to the microfluidic source electrode; and a first
and a second voltage divider each including a pair of resistors in
series. The first divider couples a first power ground to a side of
the first resistor opposite the microfluidic chip, and the second
divider couples a second power ground to the lead between the first
resistor and the microfluidic source electrode. Also included is a
first voltage sensor coupled between the voltage dividers at a
point in each voltage divider between the resistors in series; and
a second voltage sensor coupled across at least one said resistor
in series in the first voltage divider. Typically, a power supply
can be coupled to the first resistor and the first voltage divider.
More typically, at least one voltage divider includes a variable
resistor coupled to adjust the resistance of that voltage divider
to about the resistance of the other voltage divider. The variable
resistor can be adjusted to place the resistance of the voltage
dividers well within about 1% of each other, typically within
0.02%.
[0017] Generally, a controller can be coupled to the power supply
and the voltage sensors. The controller compares the voltages at
the voltage sensors to identify a microfluidic current between the
microfluidic source electrode and the microfluidic ground
electrode. The controller also controls the power supply to control
the microfluidic current, thereby controlling microfluidic flow of
a fluid in the microfluidic conduit via electromotive force. In
some embodiments, the apparatus can be operated in a constant
current mode, and in some embodiments, the apparatus can be
operated in a constant voltage mode.
[0018] In various embodiments, the first resistor, the voltage
dividers, the voltage sensors, the microfluidic conduit, the
microfluidic source electrode, and the microfluidic ground
electrode together define an electrical channel, and the apparatus
further includes at least one additional electrical channel.
[0019] In some embodiments, the apparatus further includes a
plurality of pressure channels, each pressure channel including a
pump; a gas pressure sensor; and a gas conduit providing fluid
communication between the pump, the gas sensor and the microfluidic
conduit. Typically, for each pressure channel, the controller can
be coupled to the gas pressure sensor and the pump to sense and
control gas pressure in each pressure channel, thereby controlling
microfluidic flow via pressure in each microfluidic conduit that is
coupled to each pressure channel. In particular embodiments, at
least one microfluidic conduit is coupled to at least one pressure
channel and at least one electrical channel. The controller can
independently control pressure and electrical current to control
microfluidic flow in the microfluidic conduit.
[0020] A method of determining microfluidic current in a
microfluidic chip, includes the step of applying an electrical
current to a fluid in a microfluidic conduit extending from a
microfluidic source electrode to a microfluidic ground electrode in
a microfluidic chip, thereby causing microfluidic fluid flow. Also
included is determining a value of the electrical current in the
fluid between the electrodes. Generally, the method includes a step
of controlling the microfluidic fluid flow by controlling the value
of the electrical current in the fluid between the electrodes.
[0021] Typically, the electrical current can be controlled by
applying the electrical current from a power supply coupled through
a first resistor coupled by a lead to the microfluidic source
electrode; and determining the value of the electrical current by
measuring a first and second voltage corresponding to the value of
the electrical current. The first voltage can be measured at a
first voltage sensor coupled between a first and second voltage
divider, each divider including a pair of resistors in series and
the voltage measured at a point in each voltage divider between the
resistors in series, the first divider coupling a side of the first
resistor opposite the microfluidic source electrode to a first
power ground, and the second divider coupling the lead between the
first resistor and the microfluidic source electrode to a second
power ground. The second voltage can be measured at a second
voltage sensor coupled across at least one resistor in series in
the second voltage divider.
[0022] Also included is a step of adjusting a variable resistor
coupled to adjust the resistance of that voltage divider to about
the resistance of the other voltage divider, wherein the variable
resistor is included within at least one voltage divider.
Typically, the variable resistor can be adjusted to place the
resistance of the voltage dividers well within about 1% of each
other, typically within 0.02%. Also, the method includes
independently controlling at least two electrical channels, wherein
the first resistor, the voltage dividers, the voltage sensors, the
microfluidic conduit, the microfluidic source electrode, and the
microfluidic ground electrode together define an electrical
channel, and the further apparatus includes at least two electrical
channels.
[0023] The disclosed pressure control method and apparatus has
several advantages. For example, in the disclosed pressure control
method and apparatus, the pressures can be set by an analog control
signal, allowing a number of pressure channels to be arranged in
parallel. Also, the disclosed pressure control by nature can
determine precise pressure at each channel, without the need for
further equipment. The disclosed pressure control method and
apparatus, being adaptable to analog control, can be adapted
without any inherent pressure resolution limit by adjusting the
feedback gain and choosing an appropriate gearing for the pump
motor, in contrast to the inherent step size limit in syringe
systems built with stepper motors. Thus, the resolution of the
system is typically finer than the accuracy of the sensor, and thus
pressure resolution typically is constrained only by the resolution
and stability of the gas pressure sensor employed. Because the gas
pressure sensor can be a macroscopic gas pressure sensor, many more
options in price, range and precision can be available compared to
special purpose miniature sensors. Also, it can be much easier to
integrate off-chip pressure sensors, e.g., macroscopic gas pressure
sensors into the disclosed pressure control than to embed a
miniature gas pressure sensor in a microfluidics chip. Moreover, as
shown in Example 1, pressure control can be achieved to better than
the rated resolution of the pressure sensor. Further, the disclosed
pressure control method and apparatus can also be employed with a
passive channel for monitoring pressure. The disclosed pressure
controller can be assembled from components that are generally
simpler and cheaper than typical syringe pumps and their control
systems. The disclosed pressure control method and apparatus can
also be more compact and more easily networked than a comparable
syringe pump system, especially for multi-channel systems.
[0024] The disclosed electrical control method and apparatus can
provide closed loop control that can lead to more precise control
in constant-current and constant-voltage modes, which can be chosen
independently for each electrical channel. In either mode,
continuous measurements of voltage and current can be made. Another
feature is that the disclosed electrical control can be employed in
combination with available programmable high voltage supplies,
whereas previously such supplies were generally inadequate for
microfluidics, for example because of the lack of precise current
measurement capability.
[0025] Moreover, the disclosed pressure and electrical methods and
apparatus can be employed together to provide independent pressure
and electrical control of microfluidic flow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1A is a schematic representing an exemplary apparatus
100, an embodiment of the invention, for pressure control of fluid
flow in a microfluidic chip.
[0027] FIG. 1B is a schematic representing a pressure controller
apparatus 100B, an embodiment of the invention, for controlling
fluid flow by applying pressure at more than one location in a
microfluidic chip.
[0028] FIG. 1C is a schematic representing an exemplary apparatus
100C of the invention, which is the apparatus of FIG. 1B wherein
the microfluidics chip 116 has a "T" shaped junction between
conduits.
[0029] FIG. 2 is a schematic of an embodiment of the invention,
representing a microfluidics chip having two pressure channels,
where each pressure channel can have the pumps, sensors, and
conduits shown in FIG. 1A or 1B, controlled by a single controller
120 at a single microfluidics chip 116.
[0030] FIG. 3 is a schematic of an embodiment of the invention,
representing a single pressure channel controller 300 similar to
that of FIG. 1A wherein one pump 102 is coupled through a gas
conduit 104 to a manifold 302, e.g., a controllable switch or
valve.
[0031] FIG. 4 is a schematic of an embodiment of the invention,
representing a dual pressure channel controller 400 similar to 300
except that manifold 402 can switch between each location 112 and
118 on chip 116, corresponding to microfluidics conduit 114, and
also between each location 112B and 118B, corresponding to
microfluidics conduit 114B.
[0032] FIG. 5 is a block diagram of the signals employed to control
each pressure channel.
[0033] FIG. 6 is a graph of pressure versus time for a single
pressure channel for the pressure controller example.
[0034] FIG. 7 is a schematic of an exemplary apparatus 700, an
embodiment of the invention, for electrical control of fluid flow
in a microfluidic chip.
[0035] FIG. 8 is a graph of constant output current lines in a
plane that can be formed from the ideal values of Vchip and
Vsense.
[0036] FIG. 9A shows the Vchip values measured for two electrical
channels in constant voltage control mode (about 5 to 30 seconds)
and constant current mode (about 30 to 55 seconds).
[0037] FIG. 9B shows calculated output currents 902 and 904
calculated for the two electrical channels of FIG. 9A in constant
voltage control mode (about 5 to 30 seconds) and constant current
mode (about 30 to 55 seconds).
DETAILED DESCRIPTION OF THE INVENTION
[0038] The foregoing and other objects, features and advantages of
the invention will be apparent from the following more particular
description of preferred embodiments of the invention, as
illustrated in the accompanying drawings in which like reference
characters refer to the same parts throughout the different views.
The drawings are not necessarily to scale, emphasis instead being
placed upon illustrating the principles of the invention.
[0039] FIG. 1A is a schematic representing an exemplary apparatus
100, an embodiment of the invention, for pressure control of fluid
flow in a microfluidic chip. Pump 102, typically a simple
peristaltic pump that can be driven by an electrical motor, e.g., a
direct current motor, can be coupled via conduit 104 to gas
pressure sensor 106. Conduit 104 can have a flexible portion to
facilitate operation of the peristaltic pump. Gas input end 108 of
gas conduit 104/pump 102 can be coupled to a gas supply (e.g., a
pressurized gas supply, a particular gas desirable for experimental
conditions such as an inert gas, or the like), or can be open to
the atmosphere. Gas pressure output end 110 of conduit 104 can be
coupled to a microfluidic conduit 114 defined by microfluidic chip
116, providing fluid communication among pump 102, microfluidic
conduit 114, and gas pressure sensor 106. The microfluidic flow in
microfluidics chip 116 can be controlled by pressurizing gas in
contact with a fluid in microfluidic conduit 114. Gas conduit 104
can be coupled to microfluidic conduit 114 at any location, but
typically can be coupled a microfluidic feature located on conduit
114 such as a fluid reservoir, reaction chamber, analysis chamber,
waste chamber, or the like, e.g., fluid reservoir 112. Application
of positive pressure can drive the fluid from fluid reservoir 112
through microfluidic conduit 114 to fluid reservoir 118. The air
pressure can be monitored by a gas sensor located off-chip, or
physically separate from the chip as shown in FIG. 1A, which can
avoid the work involved in integrating microscopic gas sensors
on-chip. The gas pressure sensor can be a macroscopic gas pressure
sensor 106 of any suitable accuracy and range coupled to gas
conduit 104. Thus, the apparatus of FIG. 1 represents a single
pressure channel, including pump 102, conduit 104, gas pressure
sensor 106, and microfluidic conduit 114 on a microfluidic chip 116
as component parts.
[0040] An optional analog electronics controller 120 can accept an
external control voltage and implement a negative feedback pressure
regulator, whereby a precise air pressure can be calculated from an
analog voltage.
[0041] The peristaltic pump, e.g., pump 102 can be driven by a
direct current motor speed controller (speed card), and its speed
can be set to be proportional to the difference between the desired
and measured pressures. Consequently, the pump can be stationary
when the system is at a target pressure in a standard linear
feedback arrangement. Pressure controller apparatus 100 can also
implement feedback control by taking the difference between a
calibrated pressure output and a control voltage from an external
source. This difference can optionally be multiplied by a constant
and sent to the pump as the pump speed.
[0042] FIG. 1B is a schematic representing a pressure controller
apparatus 100B, an embodiment of the invention, for controlling
fluid flow by applying pressure at more than one location in a
microfluidic chip. As in FIG. 1A, pump 102 can be coupled via
conduit 104 to gas pressure sensor 106. Gas input end 108/pump 102
of conduit 104 can be coupled to a gas supply and gas pressure
output end 110 of conduit 104 can be coupled to fluid reservoir 112
of microfluidic conduit 114 on microfluidic chip 116. Also, pump
102B can be coupled via gas conduit 104B to gas pressure sensor
106B; gas input end 108B of conduit 104B can be coupled to a gas
supply; and gas pressure output end 110B of conduit 104B can be
coupled to fluid reservoir 118 in microfluidic conduit 114 on
microfluidic chip 116. Controller 120 can be coupled to pressure
sensors 106/106B and to pumps 102/102B. The controller can sense
the pressure in each conduit 104/104B, and thus the pressure at the
intersection between each fluid reservoir 112 and 118 and their
respective conduits, and thus the pressure differential between
each fluid reservoir 112 and 118. By operating pumps 102/102B, the
controller can control the pressure at each fluid reservoir 112 and
118. Pumps 102/102B can be operated independently, for example, in
a "push-pull" mode, pump 102 can apply pressure that is positive
compared to pressure applied by pump 102B. Consequently, by
applying and controlling gas pressure, the controller can control
fluid transport between fluid reservoirs in microfluidics conduit
114.
[0043] FIG. 1C is a schematic representing an exemplary apparatus
100C of the invention, which is the apparatus of FIG. 1B wherein
the microfluidics chip 116 has a "T" shaped junction between
conduits. For example, fluids can be directed from fluid reservoirs
112 and 118 into conduit 114, where the fluids begin to combine as
they enter conduit 114C (the "T" junction between conduit 114 and
conduit 114C), and can then be directed to reservoir 112C.
[0044] In various embodiments, multiple pressure channels can be
controlled simultaneously. For example, a system can be equipped to
control 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 20, 24, 32, or more
different pressure channels. FIG. 2 is a schematic of an embodiment
of the invention, representing a microfluidics chip having two
pressure channels, where each pressure channel can have the pumps,
sensors, and conduits shown in FIG. 1A or 1B, controlled by a
single controller 120 at a single microfluidics chip 116.
[0045] The microfluidic chips shown in the figures are simple
examples to demonstrate the principles of applying the disclosed
pressure control method and apparatus to a microfluidics chip. Many
other microfluidic chips exist in the art with various conduits,
reservoirs, junctions and the like, to which the disclosed pressure
and/or electronics control methods and apparatus can be applied by
one of ordinary skill in the art using the description herein.
[0046] In various embodiments, one or more components can be shared
to reduce cost or complexity. FIG. 3 is a schematic of an
embodiment of the invention, representing a single pressure channel
controller 300 similar to that of FIG. 1A wherein one pump 102 is
coupled through a gas conduit 104 to a manifold 302, e.g., a
controllable switch or valve. The controller 120 can switch gas
pressure from pump 102 through manifold 302, in this case between
each fluid reservoir 112 and 118 on microfluidics chip 116. Thus,
by employing manifold 302, the controller can control a gas
pressure differential between location 112 and 118 on chip 116 by
sharing a single pump, a single sensor, a single pump and a single
sensor, or the like.
[0047] FIG. 4 is a schematic of an embodiment of the invention,
representing a dual pressure channel controller 400 similar to 300
except that manifold 402 can switch between each location 112 and
118 on chip 116, corresponding to microfluidics conduit 114, and
also between each location 112B and 118B, corresponding to
microfluidics conduit 114B. Thus, one of ordinary skill in the art
will appreciate that with appropriate connections and switching,
pumps, gas supplies, sensors, or the like can be shared within the
same pressure channel (as in FIG. 1B) or across multiple pressure
channels in many different configurations limited only by the
capabilities of the available components and the ability of the
microfluidics system to tolerate intermittent control. In systems
where continuous, uninterrupted control is desirable, each location
at each pressure channel can have a dedicated pump and sensor as
shown in FIG. 2.
[0048] A plurality of pressure channels can be run in parallel.
Although the power sources can be shared, the pressure channels can
be entirely independent, each receiving its own control signal and
the pressure in each can be independently regulated.
[0049] The design of the microfluidic chips shown in FIGS. 1A-4 are
simple for the purpose of exemplification. Many other microfluidic
chips exist in the art with various conduits, reservoirs, junctions
and the like, to which the disclosed pressure and/or electronics
control methods and apparatus can be applied by one of ordinary
skill in the art using the description herein.
[0050] FIG. 5 is a block diagram of the signals employed to control
each pressure channel. An uncalibrated pressure measurement from
pump/sensor 102/106 is fed into a portion of the controller circuit
500. Gain 512 and offset 514 can be calibrated to scale the signal
and zero the signal, respectively. An external control signal 516
can be employed to modulate (increase or decrease) or maintain the
pressure. A feedback gain loop 518 determines the correct input to
pump 102 to achieve the desired pressure control.
EXEMPLIFICATION
Example 1
Pressure Controller
[0051] A pressure controller was built according to the disclosed
pressure controller. By appropriate selection of components, eight
pressure channels were combined with a 15 PSI differential gas
pressure sensor with an accuracy of +/-0.015 PSI. The accuracy and
range can depend on the gas pressure sensor chosen, but in this
example the pressure was found to be regulated to within better
than 0.067% of the gas pressure sensor output. In this system,
target pressures were reached well within one second.
[0052] A portion of the control electronics was dedicated to
getting an accurate pressure measurement. A silicon piezo-resistive
differential gas pressure sensor received constant current
excitation and its output was calibrated for gain and zero offset.
The output gain was set at 0.333 volts/pounds per square inch
(V/PSI, e.g., 0.9 PSI air pressure corresponds to 0.3 V signal and
-0.9 PSI air pressure corresponds to -0.3 V signal).
[0053] FIG. 6 is a graph of pressure versus time for a single
pressure channel for the pressure controller example. Starting at
zero relative pressure, the pressure was increased to about 0.5 PSI
and then stepped down in about 0.02 PSI increments over a time
period of about 250 seconds. The time period was selected for ease
of demonstration. The system can readily complete a similar
pressure change in much less than 250 seconds.
[0054] Electrical Control
[0055] The key feature of the disclosed electrical microfluidic
controller lies in its method of measuring the output current of
high voltage electrical channels. FIG. 7 is a schematic of an
exemplary apparatus 700, an embodiment of the invention, for
electrical control of fluid flow in a microfluidic chip. The basic
configuration of the current sensing network employs a high-side
series resistor 710 (in this example a 100 megaohm resistor) with a
first voltage divider including series resistors 711 and 712 and a
second voltage divider including series resistors 713 and 714
(e.g., 100 kilo ohm (711 and 713): 100 mega ohm (712 and 714)
resistors to result in 100K/(100 k=100M) 1/1001 voltage division),
coupling either side of the high-side resistor 710 to power ground
726. The network can be coupled to a microfluidics chip 716 at
location 718, programmable high voltage supply 724, and ground 726.
Also coupled to the network are voltage sensors 706 (measuring
Vchip 730, corresponding to the network output voltage) and 708
(measuring Vsense 728). The chip side voltage divider 713/714 can
cause some current to be drawn across high side series resistor 710
even in cases when no current can be measured entering the chip, so
in such cases Vsense 728 can be >0. The Vsense 728 value at zero
output current (zero chip current) can be directly related to the
value at voltage supply 724, so it can be measured and used to
compensate for the current leakage through high side resistor 710.
Thus, each electrical channel can have several measurements
associated with it, Vsense at 728, and Vchip at 730. The voltages
Vchip at 730 and Vsense at 728 together can be employed to
calculate the current entering the microfluidics chip because the
two values together can correspond to a distinct output
current.
[0056] In various embodiments, the voltage Vchip 730 is not
measured and voltage sensor 706 can be eliminated. To calculate the
current entering the microfluidics chip for a particular electrical
channel, the voltages Vsupply at 718 and Vsense at 728 together can
be employed to calculate the current entering the microfluidics
chip because the two values together can correspond to a distinct
output current. The calculation of the current is similar though
some constants associated with the resistors can be different.
[0057] Stated another way, for each Vchip at 730 (or Vsupply at
718) there can be a single value of Vsense at 728 that can
correspond to a particular output current.
[0058] For example, FIG. 8 shows constant output current lines in a
plane that can be formed from the ideal values of Vchip and Vsense,
which results in a clear pattern. The zero output current values
can fall on the line 800 that intersects the origin, and each other
constant current line can be plotted parallel to the zero output
current line. The slopes of the constant output current lines can
be sensitive to the relative proportionality of the two voltage
dividers 711/712 and 713/714, which can operate without calibration
but can typically be calibrated to be close to each other e.g.,
well within 1% of total resistance, or more typically within about
0.1%, or particularly within 0.02%.
[0059] Typically, there can be variations in resistors as well as
non-linear responses, and thus each electrical channel can be
calibrated independently. Typically, the network can be stable
within its operating range such that the system can be calibrated.
The components which can typically affect stability include the
voltage divider resistors. Because these resistors can typically
bear several thousand volts, and some desired measurements depend
on the difference between the voltage dividers, it can be desirable
that each voltage divider be stable. Stable voltage divider
resistance can be obtained by employing high-voltage, high wattage
resistors. The resistors can be selected for a high power tolerance
and/or high thermal mass to minimize changes or "drifting" in the
resistance with temperature, e.g., due to heating of the resistor.
Moreover, (referring again to FIG. 7) the lower resistor in each
voltage divider can comprise a simple calibration circuit 732.
[0060] The spacing between the constant current lines in the Vsense
versus Vchip plan in FIG. 8 can be proportional to the actual value
of high side series resistor 710; thus, in typical embodiments,
this value can be the same between different electrical channels
within the manufacturing tolerance of the resistors e.g., for
typical resistors, within 1%.
[0061] Calibration is desirable for the slope of this line,
including compensation for any small offsets introduced by other
portions of the electronics. The calibration can be achieved by
disconnecting an electrical channel 700 from the microfluidics chip
716, so that the output is floating at zero output current. A range
of voltages can be applied to the channel, and the Vchip and Vsense
recorded to generate the zero output current line 800. In practice,
this data can typically be fit with a 2.sup.nd order or higher
polynomial and can be considered the zero output current curve 800,
though typically the linear term can dominate and thus the zero
output current curve 800 can be referred to as the zero output
current line 800. Once the zero output current curve/line 800 can
be determined for a channel, the output currents can be calculated
for any value of Vchip and Vsense for that electrical channel. The
procedure can be repeated for each electrical channel so that the
output currents can be calculated independently for each electrical
channel.
[0062] Typically, when the current measurement is thus calibrated
the control system can be implemented in software. Exemplary
experiments can involve switching channels back and forth between
constant voltage mode and constant current mode. Constant voltage
can be typical for the system in embodiments which can employ
regulated, programmable high voltage supplies. Constant current
regulation can be achieved by employing feedback, e.g. linear
feedback within the software. A channel can start at user-defined
"guess" voltage, and the software can adjust it until a desired
output current can be reached.
Example 2
Electrical Controller
[0063] Example 2 demonstrates one electrical channel of a prototype
8 electrical channel 0-5000 V controller that can support constant
voltage or constant current modes to an accuracy of within 0.1
microamperes.
[0064] For each electrical channel, a commercially available
programmable voltage supply was employed that was capable of 0-5000
V at 200 microamperes. The output of each supply enters the
disclosed electrical control network which can calculate the output
voltage and current and which can be connected via an output to an
electrode contacting a conduit in a microfluidic chip.
[0065] In this example, two electrical channels were connected to
each other through a 100 megaohm resistor, so that, for example, a
500 V difference between the electrical channels can result in one
electrical channel sourcing 5 microamperes and the other electrical
channel sinking 5 microamperes.
[0066] One electrical channel was held at 2000 V while the other
electrical channel was varied employing constant voltage control
and separately employing constant current control. The values for
the constant current control and constant voltage control were
selected to mimic each other for purposes of comparing the two
control modes. The values were changed in 5 second steps.
[0067] FIG. 9A shows the Vchip values measured for the two
electrical channels in constant voltage control mode (about 5 to 30
seconds) and constant current mode (about 30 to 55 seconds). The
Vchip of one electrical channel (902) is held at about 2000 volts
while Vchip for the other electrical channel (904) steps about 250
V every 5 seconds.
[0068] FIG. 9B shows the calculated output currents 902 and 904
calculated for the two electrical channels of FIG. 9A in constant
voltage control mode (about 5 to 30 seconds) and constant current
mode (about 30 to 55 seconds). The calculated current values mirror
each other across the zero current axis as one electrical channel
sources current while the other electrical channel sinks current.
The calculated current values for each electrical channel step
about 2.5 microamperes in opposing directions about every 5
seconds.
[0069] As can be seen in FIGS. 9A and 9B, the current control
regime is slightly "sloppier" in that the step values are slightly
overshot at some steps (e.g. at 30, 35, 40, and 50 seconds)
compared to the typical behavior in the voltage control mode (about
5 to 30 seconds). Still, though some overshoot is observed at the
step transitions, the control during the step between transitions
was seen to be stable in both constant current mode and constant
voltage mode.
Example 3
Computer and Software Control
[0070] The pressure and electrical controllers can interact with
the microfluidic chip through analog voltage signals, producing
measurements and responding to input stimuli in terms of voltages.
Thus, a desirable computer control system can work with analog
voltages as well. An exemplary setup (employed in Examples 1 and 2)
can be driven by a single desktop computer which can be equipped
with appropriate analog inputs, outputs, and control software.
Using commercially available components (e.g., a 32 channel 13 bit
analog output card and two 16 channel 16 bit analog input cards,
controlled by LabView software from National Instruments, Austin
Tex.; In other embodiments, custom components can be employed,
e.g., dedicated analog inputs and outputs, custom software
programming), real-time graphical monitoring of all channels was
achieved. Moreover, these values were recorded, and could be
correlated with the output of other instruments or used to control
other instruments (e.g., spectrometric detectors such as a
fluorescence detector) or the like. Automated scripts and manual
control were employed.
[0071] The software can be employed to calibrate the pressure
controller 100, e.g., it can be employed to operate the calibration
network in FIG. 5, and can operate controller 120 to control the
pumps 102 and sensors 106.
[0072] The software can be employed to calibrate electrical
controller 700, e.g., it can be employed to conduct the calibration
experiments, collect the zero output current data, perform the
polynomial curve fit to the zero current data to get the zero
current curves for each channel (from which the output current for
each channel can be calculated from Vsense and Vchip), and the
like. A software based linear feedback loop can be employed when
operating in constant current mode. The software can be employed to
automatically calibrate the current sensing network. In such a
function, the user can be asked to disconnect the system from the
microfluidics chip, to achieve the zero-current output state.
Alternatively, a computer controlled switch could be employed to
float the channels at zero output current to allow for more
automated calibration.
[0073] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *