Title:
Method And Apparatus For Controlling Microfluidic Flow
Kind Code:
A1


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, US)
Tripathi, Anubhav (Northborough, MA, US)
Application Number:
12/424266
Publication Date:
10/15/2009
Filing Date:
04/15/2009
Primary Class:
Other Classes:
417/44.11, 417/53, 417/54, 417/86
International Classes:
F04B41/06; F04B23/14; F04B49/06
View Patent Images:



Primary Examiner:
KASTURE, DNYANESH G
Attorney, Agent or Firm:
HAMILTON, BROOK, SMITH & REYNOLDS, P.C. (CONCORD, MA, US)
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

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

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.

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.

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.

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.

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.

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.

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.

Therefore, there is a need in the field of microfluidics for improved methods and apparatus for controlling fluid transport.

SUMMARY OF THE INVENTION

Disclosed herein are improved methods and apparatus for pressure and electrical control of fluid transport for microfluidics applications.

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.

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.

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.

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.

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.

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%.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

FIG. 5 is a block diagram of the signals employed to control each pressure channel.

FIG. 6 is a graph of pressure versus time for a single pressure channel for the pressure controller example.

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.

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.

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).

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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).

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.

Electrical Control

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.

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.

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.

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%.

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.

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%.

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 2nd 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.

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

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.