Fluid handling – Processes – Cleaning – repairing – or assembling
Reexamination Certificate
2002-06-27
2002-11-19
Chambers, A. Michael (Department: 3753)
Fluid handling
Processes
Cleaning, repairing, or assembling
C137S240000, C137S56100R, C137S833000
Reexamination Certificate
active
06481453
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to microfluidic devices and the control and metering of fluid within those devices. These devices are useful in various biological and chemical systems, particularly in systems where fluid metering is important, as well as in combination with other liquid-distribution devices.
BACKGROUND OF THE INVENTION
There has been a growing interest in the manufacture and use of microfluidic systems for the acquisition of chemical and biological information. In particular, when conducted in microfluidic volumes, complicated biochemical reactions may be carried out using very small volumes of liquid. Among other benefits, microfluidic systems improve the response time of reactions, minimize sample volume, and lower reagent consumption. When volatile or hazardous materials are used or generated, performing reactions in microfluidic volumes also enhances safety and reduces disposal quantities.
Traditionally, microfluidic devices have been constructed in a planar fashion using techniques that are borrowed from the silicon fabrication industry. Representative systems are described, for example, in some early work by Manz et al. (Trends in Anal. Chem. (1990) 10(5): 144-149; Advances in Chromatography (1993) 33: 1-66). In these publications, microfluidic devices are constructed by using photolithography to define channels on silicon or glass substrates and etching techniques to remove material from the substrate to form the channels. A cover plate is bonded to the top of the device to provide closure. Miniature pumps and valves can also be constructed to be integral (e.g., within) such devices. Alternatively, separate or off-line pumping mechanisms are contemplated.
More recently, a number of methods have been developed that allow microfluidic devices to be constructed from plastic, silicone or other polymeric materials. In one such method, a negative mold is first constructed, and plastic or silicone is then poured into or over the mold. The mold can be constructed using a silicon wafer (see, e.g., Duffy et al., Analytical Chemistry (1998) 70: 4974-4984; McCormick et. al., Analytical Chemistry (1997) 69: 2626-2630), or by building a traditional injection molding cavity for plastic devices. Some molding facilities have developed techniques to construct extremely small molds. Components constructed using a LIGA technique have been developed at the Karolsruhe Nuclear Research center in Germany (see, e.g., Schomburg et al., Journal of Micromechanical Microengineering (1994) 4:186-191), and commercialized by MicroParts (Dortmund, Germany). Jenoptik (Jena, Germany) also uses LIGA and a hot-embossing technique. Imprinting methods in PMMA have also been demonstrated (see, Martynova et.al., Analytical Chemistry (1997) 69: 4783-4789) However, these techniques do not lend themselves to rapid prototyping and manufacturing flexibility. Additionally, the foregoing references teach only the preparation of planar microfluidic structures. Moreover, the tool-up costs for both of these techniques are quite high and can be cost-prohibitive.
A more recent method for constructing microfluidic devices uses a KrF laser to perform bulk laser ablation in fluorocarbons that have been compounded with carbon black to cause the fluorocarbon to be absorptive of the KrF laser (see, e.g., McNeely et aL, “Hydrophobic Microfluidics,” SPIE Microfluidic Devices & Systems IV, Vol. 3877 (1999)). This method is reported to reduce prototyping time; however, the addition of carbon black renders the material optically impure and presents potential chemical compatibility issues. Additionally, the reference is directed only to planar structures.
Various conventional tools and combinations of tools are used when analyzing or synthesizing chemical or biological products in conventional macroscopic volumes. Such tools include, for example: metering devices, reactors, valves, heaters, coolers, mixers, splitters, diverters, cannulas, filters, condensers, incubators, separation devices, and catalyst devices. Attempts to perform chemical or biological synthesis and/or analysis in microfluidic volumes have been stifled by difficulties in making tools for analysis and/or synthesis at microfluidic scale and then integrating such tools into microfluidic devices. Another difficulty is accurately measuring stoichiometric microfluidic volumes of reagents and solvents to perform synthesis on a microfluidic scale. Additionally, difficulties in rapidly prototypic microfluidic devices are compounded by attempts to incorporate multiple analysis and/or synthesis tools for multi-step analysis and/or synthesis.
When working with fluids in conventional macroscopic volumes, fluid metering is relatively straightforward. In microfluidic volumes, however, fluid metering is considerably more difficult. Most, if not all, microfluidic systems require some interface to the conventional macrofluidic world. Using conventional macrofluidic techniques, the smallest volume of liquid that can be generated is a droplet, typically ranging in volume between approximately 1-100 microliters. At the low end of this volumetric range it is extremely difficult to consistently create droplets having a reasonably low volumetric standard deviation. Applications in which fluidic metering accuracy is important include microfluidic synthesis, wherein it would be desirable to measure stoichiometric microfluidic volumes of reagents and solvents.
A known method of obtaining small droplets is to combine fluids to be metered with surfactants before dispensing the liquid through a pipet tip. But this method is unacceptable for many applications, since adding surfactants may detrimentally compromise the purity of the fluid to be metered, and it may be very challenging to remove the surfactants and purify the fluid for further processing or use.
It is further difficult to segregate a small fluid volume from a larger bulk volume within a microfluidic device. Such segregation requires the forces of cohesion (interaction between like fluid molecules) and adhesion (interaction between fluid molecules and the surrounding conduit) to be overcome. It is believed that the general dominance of surface effects over momentum effects in microfluidic systems contributes to the challenge of performing fluid metering within such systems.
Another known method for metering small volumes of fluids is to cause the fluid to flow into a receptacle at a particular flow rate for a particular period of time and integrate the flow rate over the time to determine the volume deposited in the receptacle. For example, a fluid flowing into a receptacle at a rate of one microliter per second for one second will yield a one microliter sample in the receptacle. PCT Patent Application Number WO-01/04909 A1, entitled “Fluid Delivery Systems for a Microfluidic Device Using a Pressure Pulse,” by Orchid Biosciences, Inc. (the “Orchid Application”), discloses a system where a plurality of branches are filled with a fluid up to a capillary break. The capillary break prevents the fluid from flowing into the test cell until the fluid pressure exceeds the pressure required to overcome the impedance of the capillary break (the “break pressure”). A pressure pulse of predetermined duration and amplitude is provided to overcome the break pressure. The duration of the pressure pulse is selected so that the desired amount of fluid flows into the test cell. In other words, the pressure pulse causes the fluid to flow into the test cell at a given rate for a given period of time to provide the desired sample volume.
This approach may not achieve the desired accuracy because of hysteresis in the system resulting from the fluid compression and variations in fluidic impedance throughout the system. Moreover, inaccuracies may be amplified in larger systems where large numbers of receptacles, many at some distance from the pressure source, are served by a complex system of fluid conduits. Also, the behavior of the system may vary depending on the materials with which the device is constructed. It is
Dantsker Eugene
Karp Christoph D.
O'Connor Stephen D.
Pezzuto Marci
Chambers A. Michael
Gustafson Vincent K.
Labbee Michael F.
Nanostream, Inc.
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