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  Use of liquid junction potentials for electrophoresis without applied voltage in a microfluidic channelUSPTO Application #: 20060196771Title: Use of liquid junction potentials for electrophoresis without applied voltage in a microfluidic channel Abstract: This invention provides methods for using liquid junction potentials to control the transport of charged particles in fluid streams that are in laminar flow within microfluidic channels. Applications of the methods of this invention include sample preconditioning (removal of interfering substances), electrophoretic separation (fractionation) of charged particles, enhanced or delayed mixing of charged particles across a fluid interface relative to diffusion only, focusing charged particles in a fluid stream in one or two dimensions, and concentration of charged reactants at a fluid interface. (end of abstract) Agent: Townsend And Townsend And Crew, LLP - San Francisco, CA, US Inventors: Matthew S. Munson, Catherine R. Cabrera, Paul Yager, Anson Hatch, Andrew Kamholz USPTO Applicaton #: 20060196771 - Class: 204451000 (USPTO) Related Patent Categories: Chemistry: Electrical And Wave Energy, Non-distilling Bottoms Treatment, Electrophoresis Or Electro-osmosis Processes And Electrolyte Compositions Therefor When Not Provided For Elsewhere, Capillary Electrophoresis The Patent Description & Claims data below is from USPTO Patent Application 20060196771. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 10/268,620, filed on Oct. 9, 2002, which claims priority to U.S. Provisional Application No. 60/328,328 filed Oct. 9, 2001, which is hereby incorporated by reference in its entirety to the extent not inconsistent with the disclosure herewith. SOURCES OF GOVERNMENT FUNDING [0002] This work was funded, in part, by the U.S. Government. The U.S. Government may have some rights to certain aspects of the invention disclosed herein. BACKGROUND OF THE INVENTION [0003] Control and manipulation of charged particles in microfluidic systems is very useful for such applications as sample preconditioning (removal of interfering substances), electrophoretic separation (fractionation) of charged particles, enhanced or delayed mixing across a fluid interface, focusing particles in a fluid stream in one or two dimensions, and concentration of charged reactants at a fluid interface. [0004] Microfluidic systems and methods of use have been described in detail (Verpoorte, E., Electrophoresis, 2002 23(5), 677-712; Lichtenberg, J., et al., Talanta, 2002. 56(2), 233-266; Beebe, D. J., et al., Annual Review of Biomedical Engineering, 2002,4, 261-286; Wang, J., Electrophoresis, 2002, 23(5), 713-718; Becker, H. and L. E. Locascio, Talanta, 2002, 56(2), 267-287; Chovan, T. and A. Guttman, Trends in Biotechnology, 2002. 20(3), 116-122; Becker, H. and C. Gartner, Electrophoresis, 2000, 21(1), 12-26; McDonald, J. C., et al., Electrophoresis, 2000, 21(1), 27-40; Weigl, B. H. and P. Yager, Science, 1999, 283(5400), 346-347; and Shoji, S., Microsystem Technology in Chemistry and Life Science, 1998, 163-188.) The behavior of fluids under laminar flow, a hallmark of microfluidic technologies, allows contacting of two miscible fluids in a microchannel such that mixing only occurs through diffusive transport, which may be augmented by an imposed field, as in the H-filter (Brody, J. P., et al., Biophys J 1996, 71, 3430-3441; Weigl, B. H., et al., Science 1999, 283, 346-347) and T-sensor (Kamholz, A. E., et al., Anal Chem 1999, 71, 5340-5347; Kamholz, A. E., et al., Biophys J 2001, 80, 155-160; Kamholz, A. E., et al., Biophys J 2001, 80, 1967-1972). [0005] Methods for controlling the flow (transport) of particles in microfluidic systems have also been described, and include the use of electrophoresis, transverse electrophoresis, and hydrodynamic focusing, among others. [0006] Flow cytometry, or the analysis of individual particles in a fluid, requires the single-file alignment of the particles in an analysis region. Flow cytometers in microfluidic systems rely on the use of sheath fluids to hydrodynamically focus particles in a stream. [0007] Transverse electrophoresis requires the application of an external electric field across a microchannel to drive electrophoretic transport across the microchannel, and effectively separate charged species contained in the fluids in the microchannel. While effective, microfluidic electrophoresis adds complexity to the design of a microfluidic device by requiring additional fabrication techniques and steps for the incorporation of metal electrodes into the microfluidic channel. In addition, a microfluidic device incorporating traditional techniques of transverse electrophoresis requires an external voltage source. [0008] The formation of an electrical potential at the interface of two fluids that have different ionic compositions, the liquid junction potential (LJP), is a phenomenon that has been well studied experimentally and theoretically since the late 1800's (Maclnnes, D. A., The Principles of Electrochemistry, Reinhold Publishing, New York 1939; Planck, M., Ann. Phys. Chem. 1890, 40, 561-576; Jahn, H., Z. Phys. Chem. 1900, 33, 545-576; Henderson, P., Z. Phys. Chem. 1907, 59, 118-127; Henderson, P., Z. Phys. Chem. 1908, 63, 325-345; Lewis, G. N., Sargent, L. W., J. Am. Chem. Soc. 1909, 31, 363-367.; MacInnes, D. A., J. Am. Chem. Soc. 1915, 37, 2301-2307; Lamb, A. B., et al., J. Am. Chem. Soc. 1920, 42, 229-237; MacInnes, D. A., et al., J. Am. Chem. Soc. 1921, 43, 2563-2573; Harned, H. S., J. Phys. Chem. 1926, 30, 433-456; Roberts, E. J., et al., J. Am. Chem. Soc. 1927, 49, 2787-2791; Taylor, P. B., J. Phys. Chem. 1927, 31, 1478-1500; Guggenheim, E. A., J. Phys. Chem. 1929, 33, 842-849; Guggenheim, E. A., J. Am. Chem. Soc. 1930, 52, 1315-1337; Christiansen, T. F., IEEE Trans. Biomed. Eng. 1986, 33,79-82; Forland, K. S., et al., J. Stat. Phys. 1995, 78, 513-529.) Methods of predicting the magnitude of the liquid junction potential as well as ways to compensate for it have been developed (Maclnnes, 1939; MacInnes, 1921; Guggenheim, 1929; Guggenheim, 1930; Cobben, P. L. et al., Anal Chim Acta 1993, 276, 347-352; Lvov, S. N., et al., J Electroanal Chem 1996, 403, 25-30; Borge, G., et al., J Electroanal Chem 1997, 440, 183-192). Detailed mathematical analysis and modeling of the underlying phenomena have also been pursued (Henry, J., et al., Asymptotic Anal 1995, 10, 279-302; Skryll, Yu., PCCP Phys Chem Chem Phys 2000, 2, 2969-2976; Samson, E., et al., J Colloid Interface Sci 1999, 215, 1-8). When an electrolyte, or ion concentration gradient exists between fluids flowing in adjacent laminar flow in a microfluidic channel, differential rates of diffusion of the ionic species can lead to a microscopic separation of charge, generating an electric potential. This potential is referred to as the liquid junction potential. This effect has been studied extensively in the presence of a selective barrier between two fluid phases, which often serves to accentuate the differences in transport of the chemical species. Although its effects often go overlooked (Demas, J. N., et al., Appl Spectrosc 1998, 52, 755-762; Greenlee, R. D., et al., Biotechnol Prog 1998, 14, 300-309), the LJP could cause significant problems in many microfluidic systems by inducing spurious electrophoretic transport of analytes. [0009] Borge (Borge, G., et al., J Electroanal Chem 1997, 440, 183-192) discloses the use of LJP for the potentiometric measurement of equilibrium constants of systems displaying acid/base equilibrium. Beyond this application, the LJP has not to date been exploited as a tool due to its relatively low magnitude and the short distances over which it acts. [0010] All references cited herein are incorporated in their entirety to the extent not inconsistent herewith. BRIEF SUMMARY OF THE INVENTION [0011] The present invention provides for a liquid junction potential (LJP) device useful in microfluidic devices for particle transport control to effect electrophoretic separation (fractionation), particle focusing, acceleration and deceleration of mixing, and concentration of reactants, without the application of an external electrical potential. Methods for the use of such a device are also provided. [0012] The LJP will almost always exist at the interface of two fluids in adjacent laminar flow if the two fluids have different ionic compositions. The potential can be generated at the interface between two solutions having different ionic concentrations, for example, or at the interface between solutions containing equivalent electrolyte concentrations of different ionic species. The junction potential is generated by the differences in mobility between the ionic species when the fluids have different ionic concentrations. For almost any electrolyte there will be a difference in the mobilities of the positive and negative ions. As the ions diffuse down their concentration gradients, a microscopic separation of charge is formed, which creates the LJP. [0013] For solutions having gradient forming species (e.g. electrolytes) that are different, but having a single ion in common, if the differing ions have different mobilities, these differences may be exploited to create a LJP, even if the ionic concentrations of each fluid are the same. [0014] LJPs, applied to microfluidic technologies, result in novel methods and devices for controlling (accelerating or decelerating) the movement (transport) of charged particles in microfluidic systems. This transport control via the LJP is also referred to as "passive electrophoresis" (PE). Specifically, this invention is directed to microfluidic PE methods for one-dimensional (1D) (a core fluid stream situated between two sheath fluid streams) and two-dimensional (2D) (core fluid surrounded on all sides by sheath fluid) focusing of charged particles in a fluid, extraction of particles from a fluid, electrophoretic separation (fractionation), of charged particles in a fluid, the concentration of reactive particles from two fluid streams at or near the fluid interface, and the acceleration or deceleration of mixing between two or more fluids in a microfluidic device. The invention also provides microfluidic devices incorporating LJP, methods of making such LJP microfluidic devices, and methods of utilizing such devices for the determination of the concentration of charged particles in a fluid. [0015] In one embodiment of this invention, a method is provided for controlling the transport of a charged particle in a first fluid stream with respect to an interface between said first fluid stream and a second fluid stream in adjacent laminar flow therewith in a microfluidic channel, the method comprising creating a liquid junction potential at said interface by providing ions in at least one of said fluids of charge, concentration, mobility, and/or charge magnitude selected to accelerate or decelerate movement of said charged particle with respect to said interface. [0016] A method is also provided wherein charged particles are focused in one dimension within a microfluidic channel, the method comprising the steps of: [0017] a) introducing a core fluid containing a charged particle into said microfluidic channel; and [0018] b) introducing sheath fluid into said microfluidic channel such that the sheath fluid surrounds the core fluid on two opposite sides of the core fluid and such that the core fluid and each sheath fluid form a fluid interface and flow in adjacent laminar flow in said microfluidic channel; [0019] said sheath fluid comprising a first set of gradient-forming species and said core fluid optionally comprising the same gradient-forming species, said gradient-forming species comprising at least a first ion and a second ion, wherein said first ion has a charge opposite the charge of said particle and has a higher mobility than said second ion and wherein said second ion has the same charge as said particle and wherein when said gradient-forming species are present in said core fluid, said first ion is present in higher concentration in said sheath fluid than in the core fluid; [0020] whereby a liquid junction potential is formed at each interface between said sheath fluids and said core fluid and charged particles are focused in said core fluid. [0021] Alternatively said core fluid comprises a second set of gradient-forming species wherein the ionic concentrations of the first and second sets of gradient-forming species are equal, the second ion in each set of gradient-forming species is the same, and the first ion in the second set of gradient-forming species has a lower mobility than the first ion in the first set of gradient-forming species. [0022] A method is also provided wherein charged particles are extracted from a fluid within a microfluidic channel, the method comprising the steps of: [0023] a) introducing a core fluid containing a first charged particle into said microfluidic channel; and [0024] b) introducing sheath fluid into said microfluidic channel such that the sheath fluid surrounds the core fluid on two opposite sides of the core fluid and a fluid interface is formed between the core fluid and each sheath fluid and said core and sheath fluids flow in adjacent laminar flow in said microfluidic channel; [0025] wherein said sheath fluid comprises a first set of gradient-forming species and said core fluid optionally comprises the same set of gradient-forming species, said set of gradient-forming species comprising at least a first ion and a second ion, wherein said first ion has the same charge of said particle and has a higher mobility than said second ion and wherein said second ion has the opposite charge of said particle and wherein when said gradient-forming species are present in said core fluid said first ion is present in higher concentration in the sheath fluid than in the core fluid; [0026] whereby a liquid junction potential is formed at each interface between said sheath fluids and said core fluid and said charged particles are extracted from said core fluid. [0027] Alternatively said core fluid comprises a second set of gradient-forming species wherein the ionic concentrations of the first and second sets of gradient-forming species are equal, the second ion in each set of gradient-forming species is the same, and the first ion in the second set of gradient-forming species has a lower mobility than the first ion in the first set of gradient-forming species. [0028] A method is also provided wherein charged particles are separated within a microfluidic channel, the method comprising the steps of: [0029] a) introducing a core fluid containing at least a first and a second charged particle into said microfluidic channel, wherein each of said charged particles has the same charge and each of said charged particles has a different mobility; and [0030] b) introducing sheath fluid into said microfluidic channel such that the sheath fluid surrounds the core fluid on two opposite sides of the core fluid and a fluid interface is formed between the core fluid and each sheath fluid and said core fluid and said sheath fluids flow in adjacent laminar flow in said microfluidic channel; [0031] wherein said sheath fluid comprises a first set of gradient-forming species and said core fluid optionally comprises the same set of gradient-forming species, said set of gradient-forming species comprising at least a first ion and a second ion, wherein said first ion has the same charge of said charged particles and has a higher mobility than said second ion and wherein said second ion has the opposite charge of said particle and wherein when said gradient-forming species are present in said core fluid said first ion is present in higher concentration in the sheath fluid than in the core fluid; [0032] whereby a liquid junction potential is formed at each interface between said sheath fluid and said core fluid and said charged particles are separated. 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