Method and apparatus for controlling microfluidic flow

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.

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.

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.