The invention relates to methods and apparatuses for actuating and/or pumping liquids within microfluidic and nanofluidic devices.
The process of analyzing liquid samples containing chemical, biomolecular, and cellular species using micro total analysis systems (μTAS), “lab-on-a-chip,” or “microfluidic chips,” is a rapidly growing technology. These devices and systems incorporate micro- and nano-size channels, chambers, and fluid-related structures designed to manipulate and analyze biomolecules, cells, and nanoparticles, for example, that are present in a liquid-carrier medium. New methods are being developed for fabricating increasingly complex microfluidic chips having multiple layers, channels, and chambers. These complex microfluidic components require novel methods for precisely controlling liquid flow to enable full exploitation of new designs. In addition to the development of better micropumps, new designs and methods are needed for mixing of liquid flows within the microfluidic chip, and better “microvalves” are needed for controlling where and when flows can occur on the microfluidic chip.
Micropumps commonly used with micro-analysis chips include displacement pumps and dynamic pumps. Displacement pumps include reciprocating (diaphragm, piston), rotary, and aperiodic (pneumatic, phase-change, electrowetting, thermocapillary) pumps. Dynamic pumps, in which the driving force interacts directly with the liquid medium, include electro-osmotic, electrohydrodynamic, magnetohydrodynamic, and acoustic/ultrasonic pumps.
All of the above micropump technologies have their strengths and weaknesses. No single technology can be used in all situations. What is needed is a micropump technology that is useful in most common applications. The present invention results from the observation that none of the current micropump technologies involve the use of light energy, either directly or indirectly, to effect fluid pumping.
Liquid water has well-known absorption peaks that can be exploited to deliver energy into a water-based liquid medium in a highly localized or otherwise well-controlled fashion. As shown in
Compact and low-cost lasers at many different wavelengths have become available in recent years, and can be utilized to deliver energy into a water-based liquid medium. These lasers include modulated continuous-wave and pulsed solid-state lasers (e.g., semiconductor diode lasers) operating at 980 nm, 1320 nm, 1440 nm, and at telecom wavelengths in the 1500-1600 nm range, as well as quantum cascade lasers, inter-band, and inter-sub-band lasers operating at 3000 to 10,000 nm wavelengths.
If the liquid medium includes atoms or molecules that absorb strongly at visible or UV wavelengths, then semiconductor laser diodes or LEDs that emit visible or UV wavelengths may be used. One- or two-dimensional arrays of semiconductor laser diodes or LEDs may be used if emitter spacing in the array is small enough to provide a desired level of microfluidic pumping control.
One object of the present invention is to provide a novel method of pumping liquids in microfluidic chips, and, in particular, a method that enables pumping to and from chambers, such as may be embedded in a multi-layer 3-D chip structure. Flow direction and volumetric flow rate may be controlled, for example, by controlling pulse energy, pulse rate, and where on the chip light energy is applied. Laser or light energy may be focused into a chamber embedded within a 3-D structure in such a way that liquid is pumped out of the embedded chamber, but without affecting liquid or material in layers above, below, or adjacent the embedded chamber.
Another object of the present invention is to provide a novel pumping method that enables a liquid droplet, a liquid sample, or a liquid “plug,” being manipulated in the chip to be followed as it moves through the chip. The laser or light beam may be moved in real time as needed to keep the liquid plug moving to where it is intended to be. As an example, the simultaneous applications of two appropriately positioned beam spots may force the liquid plug to enter one channel at a channel branch point, rather than an alternative channel, thereby eliminating the need for microvalves at the branch point. Alternatively, a one-dimensional or two-dimensional array of semiconductor laser diode or LED emitters may be selectively energized in space and time, as needed, to follow the liquid droplet or plug through the chip. This is achieved by placing the one-dimensional or two-dimensional array in near contact with the microfluidic array so that the radiation emitted from the semiconductor laser diode or LED emitters is accurately imaged onto, or otherwise projected onto, the microfluidic chip.
Another object of the present invention is to provide a pumping method that enables precise metering of liquid flows in microfluidic chips where required flow rates may typically be in the picoliter/sec, nanoliter/sec, or microliter/sec range. For a given light wavelength, pulse duration, and applied spot diameter, pulse energy may adjusted over a very wide range, e.g., six orders of magnitude or more, as needed to precisely control volumetric flow rates and total transferred liquid volumes.
Another object of the present invention is to provide a novel means for mixing liquids in microfluidic devices, and, in particular, to enable mixing in chambers that may be embedded in a multi-layer 3-D chip structure. Mixing may be controlled, for example, by controlling pulse energy, pulse rate, and focused spot location of the incident light energy. One possible mixing method may involve the use of high-peak-power pulsed laser energy to create micro-bubbles in the liquid, in addition to creating a pressure wave, as a way to enhance or accelerate mixing.
Another object of the present invention is to provide a pumping method that may work into high pressure gradients as are typical in microfluidic chips. This may be achieved by controlling laser emission parameters such as wavelength, pulse energy, pulse duration, pulse rate, and beam/exposure-spot diameter, for example.
Another object of the present invention is to provide increased flexibility for tailoring pumping and mixing methods to the specific liquids being manipulated. In particular, laser wavelength may be adjusted to control the strength of light absorption by the liquid, which, in turn, may affect the amount of pulse energy and peak power needed to produce the desired light-induced effect in the liquid, such as, for example, pressure wave, speed of the liquid plug through the channel, and bubble production.
Another object of the present invention is to reduce or eliminate “dead volume” at the chip-to-world interface and elsewhere on the chip, as dead volumes are often relatively large with existing microfluidic pumping methods.
Another object of the present invention is to provide a method for multipoint actuation as may be used to drive multiple flow channels simultaneously, for example, or to control flow direction at branching points, for example. Light energy may be divided into multiple beamlets to drive multiple channels. Alternatively, the laser beam may be configured as a line focus to drive multiple channels at the same time. Alternatively, a one- or two-dimensional array of semiconductor laser diodes or LEDs that is placed in near-contact with the microfluidic chip may be used to effect multipoint actuation by selectively actuating individually addressable light emitters. The selective actuation may be a function of coordinate position and/or time for each of the addressable light emitters.
Another object of the present invention is to provide new means for pumping and mixing that improve the design and fabrication flexibility of microfluidic devices, and that, in particular, are compatible with relatively common chip designs.
Other advantages and benefits of the present invention will become apparent in the discussion below. The foregoing general description and detailed descriptions below are intended only to be exemplary and explanatory and are not intended to be restrictive of the invention. The detailed descriptions of embodiments provided below are intended only to be exemplary and explanatory and are not intended to restrict the scope of the invention.
The foregoing aspects, uses, and advantages of the present invention will be more fully appreciated as the same becomes better understood from the following detailed description of the present invention when viewed in conjunction with the accompanying figures, in which:
The following detailed description is of the best currently contemplated modes of carrying out the invention. The description is not to be taken in a limiting sense, but is made merely for the purpose of illustrating the general principles of the invention. Moreover, the detailed descriptions of embodiments provided below are intended only to be exemplary and explanatory and are not intended to be restrictive of the invention.
The present invention incorporates pulsed laser light, time-modulated continuous-wave laser light, or non-laser light having a wavelength that is strongly absorbed by a liquid medium itself or by molecular constituents dissolved in the liquid medium. Absorption of pulsed light energy beams creates a pressure wave in the liquid medium that forces the liquid to move through a microfluidic device. The timing and location of the applied light energy beams, producing exposure spots, controls how and when the liquid medium moves through various sections of a microfluidic device.
In addition to using direct absorption of light, the present invention may also employ the generation of a laser-induced plasma (LIP) in the liquid medium as a means to create a useful pressure wave. In general, generation of an LIP requires the use of a high-peak-power laser that can be focused to a beam diameter small enough that the electric field in the focused laser beam can “break down” the liquid medium as needed to create a plasma. Once created, the plasma strongly absorbs laser energy to create a pressure wave or shock wave in the liquid medium.
As understood in the present specification, the term “microfluidic” is used to indicate devices having sub-mm, micron, sub-micron, and nanometer-size channels, chambers, and other physical features. As described above, the main liquid-water absorption peaks occur at 2940 nm, 1920-1940 nm, 1440 nm, 1320-1340 nm, and 980 nm. However virtually any wavelength in the 2940 nm to 11000 nm range has strong enough absorption in liquid water to be useful in the present invention. This also applies to wavelengths in the 980 to 2940 nm range, and to UV wavelengths shorter than about 300 nm.
The phrase “strongly absorbed” is used herein to mean that, considering the applied wavelength, pulse energy, pulse duration, and beam spot diameter, absorption of laser or light energy is strong enough to create a pressure wave in the liquid medium that can be used to do something useful, such as, for example, induce fluid movement through a channel or into a chamber, or to mix liquids, and is not intended to be restrictive on the invention.
Regarding the use of the term “pulsed,” a laser or light pulse has an appropriate pulse duration and pulse energy (enough peak power), that is modulated in time by some means as needed, considering the laser wavelength and how strongly it is absorbed in the liquid medium, to create a useful pressure wave in the liquid, and is not intended to be restrictive on the invention. Accordingly, the term “pulsed laser” as used herein means a continuous-wave laser, or a light-emitting diode (LED), that has its emitted power modulated in time in a way that is useful for creating pressure waves in microfluidic devices.
The present invention employs pulsed or time-modulated light or laser emission having a wavelength that is strongly absorbed by the liquid medium itself, or by molecular constituents dissolved in the liquid medium. Direct absorption of pulsed/modulated light energy in the liquid creates a pressure wave in the liquid medium that forces a liquid to move through (i.e., pumped through) the microfluidic device. The timing and location of applied pulsed light energy controls how, when, and where liquids are moved through various sections of the microfluidic device. The invention is expected to be especially useful for manipulation of flows in three-dimensional (3-D) microfluidic devices since laser or light energy may be focused within specific layers of the device in a controlled fashion.
The invention relates to the use of light energy to optically actuate and control the flow of liquid in a microfluidic chip device, as are typically used for micro-analysis or micro-synthesis of chemical or biochemical species in a liquid medium. The invention employs direct absorption or other direct interaction of light with the liquid medium, or a species dissolved in the liquid medium, as a means to create pressure waves in the liquid and implement specific microfluidic tasks such as volumetric flow control, flow branching and direction, and fluid mixing. Various exemplary embodiments of the present invention are described in the specification below, each with reference to the appropriate Figure(s). It should be understood that, for clarity of illustration, not all disclosed microfluidic features are shown to the same scale, or in correct proportion to one another, and should not be taken as literal illustrations of actual microfluidic and nanofluidic devices. In addition, although some devices are presented with straight edges, angular corners, and flat surfaces, present-day manufacturing methods can produce these components having, rounded edges, corner fillets, and curved surfaces.
In accordance with an aspect of the present invention, there is shown in
A lens 112 is used to converge the light beam 110 to a light beam focal spot 114, or focal region, in the microfluidic chamber 102 or in another specified fluid volume (not shown) in the microfluidic chip 100. The thermal energy in the light beam 110, which may be a coherent light laser beam, causes the liquid medium 104 to flow out of the microfluidic chamber 102, as indicated by an arrow 116, and through the fluid flow channel 106. In accordance with the liquid-water absorption parameters described above, if water is a significant or substantial component of the liquid medium 104, the emission frequency of the light beam 110 is specified to be a wavelength of from 980 nm to 11000 nm and, preferably, a wavelength at or near one or more of peak wavelengths of: 980 nm, 1320-1340 nm, 1440 nm, 1920-1940 nm, and 2940 nm.
The lens 112 may not be required for producing the light beam focal spot 114 if the size of the light beam 110 is small enough to spatially overlap a desired portion of the microfluidic chamber 102, without affecting other regions of the microfluidic chip 100, or if the desired pressure wave can be induced without focusing the light beam 110. The volumetric flow rate of the liquid medium 104 may be controlled by adjusting applied energy, peak power, pulse rate, and/or other parameters, of the light beam 110. The total flow volume may be controlled by controlling the total thermal energy applied via the light beam focal spot 114.
There is shown in
Another method of controlling the flow of fluid samples alternative is to place a 1-D emitter array or a 2-D emitter array of individually-addressable light emitters in near-contact with a microfluidic chip, and to selectively activate, in space and time, exposure characteristics of the emitter array of individually-addressable light emitters such that a pressure wave is created in a specified region of the fluid to effect fluid motion relative to the microfluidic chip. The light emitters in the emitter array may be edge-emitting semiconductor diode lasers, vertical-cavity semiconductor diode lasers, light-emitting diodes (LEDs), or similar light-emitting sources that lend themselves to packaging in a reasonably dense array format. Depending on the light-emitter design, and on application needs, micro-optic arrays may or may not be included in order to spatially collimate the emissions of corresponding individual light emitters. Arrays of semiconductor-based light emitters are available in the present state of the art, and design improvements will be available in the foreseeable future, at many different wavelengths that may be advantageous for use in the present invention.
Continuing the process of controlling fluid sample flow, the constantly moving laser or light beam focal spot would follow the pressure wave, and the pressure wave would force the fluid sample through a desired fluid flow channel. Advantageously, the light emitter array is positioned proximate the microfluidic array so that the radiation emitted from the individually-addressable light emitters is accurately imaged onto, or otherwise projected onto, selected fluid flow channels in the microfluidic chip.
In an exemplary embodiment, shown in
The transport focus regions 193, 195, 197 are produced by a 1-D array 200 of individually-addressable semiconductor diode or LED emitters 212, 214, 216, that are moved and positioned relative to the microfluidic chip 180 by a scanning table 208. In response to movement of the scanning table 208, the fluid samples 202, 204, 206 are transported in the respective fluid flow channels 182, 184, 186, either simultaneously or sequentially in time. A scanning controller 198 controls movement of the scanning table 208 and selectively activates individual emitters 212, 214, 216 that are positioned in near contact with the respective fluid flow channels 182, 184, 186.
An exemplary embodiment incorporating a 2-D array of semiconductor emitters is shown in
In the particular configuration shown, a first fluid sample 232 is transported through a first fluid flow channel 222 by a first transport light beam focal spot 238. Similarly, a second fluid sample 242 is transported through a second fluid flow channel 224 by a second transport light beam focal spot 248, and a third fluid sample 252 is transported through a third fluid flow channel 226 by a third transport light beam focal spot 258. The transport focus regions 238, 248, 258 are produced by respective semiconductor emitters 262, 264, 266, that are individually, selectively activated in space and time as needed to move, direct, or mix the transport light beam focus spots 238, 248, 258. The microfluidic chip 220 is moved and positioned relative to the semiconductor emitter array 260 by a scanning table 250 to precisely position the transport focus regions 238, 248, 258 on the microfluidic chip 220. A scanning controller 240 selectively activates individual emitters 262, 264, 266 and determines the position of the scanning table 250 in coordination with the activation of selective emitters such that the fluid samples 232, 242, 252 are transported in the respective fluid flow channels 222, 224, 226, either simultaneously or sequentially in time.
There is shown in
In an exemplary embodiment, one or more laser or light beams may be used to effect fluid mixing in a chamber or in a fluid flow channel. In the example of
In another method of mixing a fluid sample, shown in
It is to be understood that the description herein is only exemplary of the invention, and is intended to provide an overview for the understanding of the nature and character of the disclosed methods and apparatuses for moving and mixing liquids within microfluidic and nanofluidic devices. The accompanying drawings are included to provide a further understanding of various aspects and embodiments of the devices of the invention which, together with their description and claims, serve to explain the principles and operation of the invention.
Number | Date | Country | |
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63045080 | Jun 2020 | US |