초록 ▼

An electrokinetic microfluidic flow cytometer apparatus can include a substrate, a pair of signal and noise detection channels, and a particle detection circuit. The substrate includes an input port, an output port, and a microchannel that fluidly connects the input port and the output port to allow

An electrokinetic microfluidic flow cytometer apparatus can include a substrate, a pair of signal and noise detection channels, and a particle detection circuit. The substrate includes an input port, an output port, and a microchannel that fluidly connects the input port and the output port to allow fluid to flow therebetween. The signal and noise detection channels are defined in the substrate and are fluidly connected to the microchannel from locations that are adjacent to each other. The signal and noise detection channels extend in opposite directions away from the microchannel to receive ambient electrical noise. The particle detection circuit generates a particle detection signal in response to a differential voltage across the signal and noise detection channels, which tracks changes in resistivity across an adjacent portion of the microchannel while at least substantially canceling a common component of the ambient electrical noise.

대표청구항 ▼

1. An electrokinetic microfluidic flow cytometer apparatus comprising: a substrate having defined therein an input port, an output port, and a microchannel that fluidly connects the input port and the output port to allow fluid to flow therebetween;a pair of signal and noise detection channels that

1. An electrokinetic microfluidic flow cytometer apparatus comprising: a substrate having defined therein an input port, an output port, and a microchannel that fluidly connects the input port and the output port to allow fluid to flow therebetween;a pair of signal and noise detection channels that are defined in the substrate and fluidly connected to the microchannel from locations adjacent to each other and which extend in opposite directions away from the microchannel to receive ambient electrical noise; anda particle detection circuit that is electrically connected to the signal and noise detection channels and generates a particle detection signal in response to a differential voltage across the signal and noise detection channels, which tracks changes in resistivity across an adjacent portion of the microchannel as particles within the fluid move responsive to an electric field along that portion of the microchannel, while at least substantially canceling a common component of the ambient electrical noise received by the signal and noise detection channels; anda sensing gate that reduces the cross sectional area of the microchannel through which fluid carrying particles can flow, wherein the signal and noise detection channels are fluidly connected to the microchannel adjacent to the sensing gate, and wherein the particle detection circuit generates the particle detection signal responsive to resistivity changes that occur across the sensing gate as particles flow through the sensing gate under electrokinetic force,wherein the sensing gate reduces the width of the microchannel through which fluid can flow to less than about ten times a width of individual particles that are to be sensed as they flow within fluid through the sensing gate. 2. The electrokinetic microfluidic flow cytometer apparatus of claim 1, further comprising: a particle counting circuit that counts a number of particles moving past the signal and noise detection channels in response to pulses in the particle detection signal. 3. The electrokinetic microfluidic flow cytometer apparatus of claim 1, wherein: the sensing gate has a length between about 5 μm to about 100 μm along which it reduces the width of the microchannel. 4. The electrokinetic microfluidic flow cytometer apparatus of claim 1, wherein: the signal and noise detection channels are fluidly connected to portions of the microchannel that are spaced apart and immediately adjacent to opposite sides of the sensing gate. 5. The electrokinetic microfluidic flow cytometer apparatus of claim 1, wherein: the signal and noise detection channels are fluidly connected to opposite facing sidewalls of a portion of the microchannel that are immediately adjacent to a same side of the sensing gate. 6. The electrokinetic microfluidic flow cytometer apparatus of claim 1, wherein: the sensing gate comprises a pair of members that extend toward each other from opposite facing sidewalls of a portion of the microchannel to reduce the cross sectional area of the microchannel through which the fluid flows and increase sensitivity of the particle detection circuit to resistivity changes that occur between the members as individual particles flow between the members within the microchannel. 7. The electrokinetic microfluidic flow cytometer apparatus of claim 1, wherein: the sensing gate comprises a member that extends from a central region of the microchannel toward opposite sidewalls of the microchannel to reduce the cross sectional area of the microchannel through which fluid can flow and increase sensitivity of the particle detection circuit to resistivity changes that occur between the member and sidewalls of the microchannel as individual particles flow therethrough. 8. The electrokinetic microfluidic flow cytometer apparatus of claim 7, wherein: a distance across each region between the member and the opposite sidewalls of the microchannel is in a range between about 1 μm to about 50 μm. 9. The electrokinetic microfluidic flow cytometer apparatus of claim 1, further comprising: at least two electrodes, one of which is positioned within the input port and the other of which is positioned within the output port;a control circuit that controls application of an electric voltage across the electrodes to create an electric field along the microchannel and electrokinetic force which transports fluid from the input port to the output port; anda sensing gate that reduces the cross sectional area of the microchannel through which fluid carrying particles can flow, wherein the signal and noise detection channels are fluidly connected to the microchannel adjacent to the sensing gate, and wherein the particle detection circuit generates the particle detection signal responsive to resistivity changes that occur across the sensing gate as particles flow through the sensing gate in the presence of the electric field along the microchannel. 10. The electrokinetic microfluidic flow cytometer apparatus of claim 1, further comprising a sensing gate that reduces the cross sectional area of the microchannel through which fluid carrying particles can flow, wherein: the signal and noise detection channels are fluidly connected to the microchannel adjacent to the sensing gate and extend a same distance away from the sensing gate and the microchannel to be configured to receive about equal amounts of ambient electrical noise, andthe particle detection circuit is configured to substantially cancel the ambient electrical noise received from the signal and noise detection channels while generating the particle detection signal responsive to resistivity changes that occur across the sensing gate as particles flow through the sensing gate. 11. The electrokinetic microfluidic flow cytometer apparatus of claim 10, wherein: the signal and noise detection channels extend in opposite directions that are substantially perpendicular to a flow direction of the adjacent microchannel to increase the electrical coupling of the signal and noise detection channels to ambient electrical noise. 12. The electrokinetic microfluidic flow cytometer apparatus of claim 1, wherein: the signal and noise detection channels each have a same volume extending away from the microchannel to be configured to receive about equal amounts of ambient electrical noise; andthe particle detection circuit is configured to substantially cancel the ambient electrical noise received from the signal and noise detection channels when generating the particle detection signal. 13. The electrokinetic microfluidic flow cytometer apparatus of claim 12, wherein: the signal and noise detection channels have substantially the same cross sectional areas and length to be configured to receive about equal amounts of ambient electrical noise. 14. The electrokinetic microfluidic flow cytometer apparatus of claim 1, further comprising: a first pair of electrodes, wherein each electrode is positioned in a space within a different one of the signal and noise detection channels that is fluidly connected to the microchannel, and wherein the particle detection circuit is electrically connected to the electrodes and generates the particle detection signal responsive to differential voltage across the first pair of electrodes. 15. The electrokinetic microfluidic flow cytometer apparatus of claim 14, wherein: the particle detection circuit comprises a differential amplifier having a pair of input terminals, one of the input terminals is connected to one of the electrodes within one of the signal and noise detection channels and the other one of the input terminals is connected to the other one of the electrodes within the other one of the signal and noise detection channels. 16. The electrokinetic microfluidic flow cytometer apparatus of claim 1, wherein the output port comprises a plurality of particle sorting output ports that are defined in the substrate and are fluidly connected to an optical detection region of the microchannel on an opposite side of the signal and noise detection channels from the input port, and further comprising: a particle optical characterization apparatus that detects an optical characteristic of at least one particle in a fluid within the optical detection region of the microchannel; anda particle sorting circuit that separately controls voltages that are applied between each of the particle sorting output ports and at least the optical detection region of the microchannel in response to the detected optical characteristic of the at least one particle to transport the at least one particle by electrokinetic flow of the fluid from the optical detection region to a selected one of the output ports. 17. An electrokinetic microfluidic flow cytometer apparatus comprising: a substrate having defined therein an input port, an output port, and a microchannel that fluidly connects the input port and the output port to allow fluid to flow therebetween;a pair of signal and noise detection channels that are defined in the substrate and fluidly connected to the microchannel from locations adjacent to each other and which extend in opposite directions away from the microchannel to receive ambient electrical noise; anda particle detection circuit that is electrically connected to the signal and noise detection channels and generates a particle detection signal in response to a differential voltage across the signal and noise detection channels, which tracks changes in resistivity across an adjacent portion of the microchannel as particles within the fluid move responsive to an electric field along that portion of the microchannel, while at least substantially canceling a common component of the ambient electrical noise received by the signal and noise detection channels; anda sensing gate that reduces the cross sectional area of the microchannel through which fluid carrying particles can flow, wherein the signal and noise detection channels are fluidly connected to the microchannel adjacent to the sensing gate, and wherein the particle detection circuit generates the particle detection signal responsive to resistivity changes that occur across the sensing gate as particles flow through the sensing gate under electrokinetic force,wherein the sensing gate comprises a pair of members that extend toward each other from opposite facing sidewalls of a portion of the microchannel to reduce the cross sectional area of the microchannel through which the fluid flows and increase sensitivity of the particle detection circuit to resistivity changes that occur between the members as individual particles flow between the members within the microchannel, and a distance across the fluid flow region between the members is in a range between about 1 μm to about 50 μm. 18. An electrokinetic microfluidic flow cytometer apparatus comprising: a substrate having defined therein an input port, an output port, and a microchannel that fluidly connects the input port and the output port to allow fluid to flow therebetween;a pair of signal and noise detection channels that are defined in the substrate and fluidly connected to the microchannel from locations adjacent to each other and which extend in opposite directions away from the microchannel to receive ambient electrical noise; anda particle detection circuit that is electrically connected to the signal and noise detection channels and generates a particle detection signal in response to a differential voltage across the signal and noise detection channels, which tracks changes in resistivity across an adjacent portion of the microchannel as particles within the fluid move responsive to an electric field along that portion of the microchannel, while at least substantially canceling a common component of the ambient electrical noise received by the signal and noise detection channels;a sensing gate that reduces the cross sectional area of the microchannel through which fluid carrying particles can flow, wherein the signal and noise detection channels are fluidly connected to the microchannel adjacent to the sensing gate, and wherein the particle detection circuit generates the particle detection signal responsive to resistivity changes that occur across the sensing gate as particles flow through the sensing gate under electrokinetic force; anda flow focusing guide having a converging cross sectional fluid flow area along the flow direction with a cross sectional fluid flow output area that restricts particles flowing therethrough to exiting one at a time, wherein the flow focusing guide is positioned upstream of the sensing gate along the microchannel. 19. An electrokinetic microfluidic flow cytometer apparatus comprising: a substrate having defined therein an input port, an output port, and a microchannel that fluidly connects the input port and the output port to allow fluid to flow therebetween;a pair of signal and noise detection channels that are defined in the substrate and fluidly connected to the microchannel from locations adjacent to each other and which extend in opposite directions away from the microchannel to receive ambient electrical noise; anda particle detection circuit that is electrically connected to the signal and noise detection channels and generates a particle detection signal in response to a differential voltage across the signal and noise detection channels, which tracks changes in resistivity across an adjacent portion of the microchannel as particles within the fluid move responsive to an electric field along that portion of the microchannel, while at least substantially canceling a common component of the ambient electrical noise received by the signal and noise detection channels,wherein a cross-sectional area of each signal and noise detection channel is less than a cross-sectional area of the microchannel adjacent to where the signal and noise detection channels fluidly connect to the microchannel. 20. The electrokinetic microfluidic flow cytometer apparatus of claim 19, wherein: a width of each signal and noise detection channel is less than half a width of the microchannel adjacent to where the signal and noise detection channels fluidly connect to the microchannel. 21. The electrokinetic microfluidic flow cytometer apparatus of claim 19, wherein: the signal and noise detection channels extend a distance away from the microchannel that is at least 2 times a width of the microchannel adjacent to where the signal and noise detection channels are fluidly connected to the microchannel. 22. An electrokinetic microfluidic flow cytometer apparatus comprising: a substrate having defined therein an input port, a plurality of particle sorting output ports, and a microchannel that fluidly connects the input port and the plurality of particle sorting output ports to allow fluid to flow therebetween responsive to an electric field along the microchannel;at least one optical fiber that is positioned to guide at least one wavelength of light from at least one light source to illuminate an optical detection region of the microchannel and to collect light that is emitted from at least one particle present in fluid within the optical detection region;a first primary photodetector that is connected to the at least one optical fiber to receive at least first wavelength light therefrom and configured to generate a first output signal responsive thereto, the first output signal containing a noise component;a reference photodetector that generates a reference noise signal that is not responsive to any light collected from the optical detection region of the microchannel and is characteristic of the noise component in the first output signal; anda first comparator circuit that generates a first characterization signal responsive to a difference between the first output signal and the reference noise signal so that the first characterization signal is at least substantially free of the noise component from the first output signal. 23. The electrokinetic microfluidic flow cytometer apparatus of claim 22, wherein: the reference photodetector is configured to have substantially the same operational characteristics as the first primary photodetector. 24. The electrokinetic microfluidic flow cytometer apparatus of claim 23, wherein: the first comparator circuit comprise a differential amplifier having a pair of input terminals;one of the input terminals is connected to receive the first output signal from the first primary photodetector and the other input terminal is connected to receive the reference noise signal from the reference photodetector; andthe differential amplifier is configured to generate a first particle characterization signal responsive to a voltage difference between the input terminals that indicates a detected optical characteristic of a particle within the optical detection region responsive to illumination by the at least one wavelength of light. 25. The electrokinetic microfluidic flow cytometer apparatus of claim 22, further comprising a control circuit that is configured to classify the particle as being a defined particle type in response to the first particle characterization signal. 26. The electrokinetic microfluidic flow cytometer apparatus of claim 22: wherein the at least one optical fiber is positioned to guide at least two wavelengths of coherent laser light from at least two laser light sources to illuminate the optical detection region of the microchannel and to collect light that is emitted from the least one particle present in fluid within the optical detection region;further comprising a filter apparatus that is configured to receive the light collected by the at least one optical fiber and to split the collected light to pass a plurality of different defined wavelengths, when present, through different corresponding ones of a plurality of filter output fibers;wherein the first primary photodetector is connected to receive a first wavelength light through one of the filter output fibers and to generate the first output signal responsive thereto;further comprising at least a second primary photodetector that is connected to receive a second wavelength light through another one of the filter output fibers and to generate a second output signal responsive thereto, the second output signal containing a noise component,wherein the reference photodetector is configured to have substantially the same operational characteristics as the first and second primary photodetectors and the reference noise signal is further characteristic of the noise component in the second output signal; andfurther comprising at least a second comparator circuit that generates a second particle characterization signal responsive to a difference between the second output signal and the reference noise signal so that the second particle characterization signal is at least substantially free of the noise component from the second output signal. 27. The electrokinetic microfluidic flow cytometer apparatus of claim 26, further comprising a control circuit that is configured to classify the particle as being one of a plurality of different defined particle types in response to the first and second particle characterization signals. 28. The electrokinetic microfluidic flow cytometer apparatus of claim 26, wherein: the filter apparatus is configured to split the collected light to pass a green wavelength component of the collected light through a first filter output fiber to the first primary photodetector and to pass a red wavelength light component of the collected light through a second filter output fiber to the second primary photodetector;the first particle characterization signal indicates when the at least one particle present in the fluid within the optical detection region emits green light responsive to the illumination; andthe second particle characterization signal indicates when the at least one particle present in the fluid within the optical detection region emits red light responsive to the illumination. 29. The electrokinetic microfluidic flow cytometer apparatus of claim 26, further comprising: a particle sorting circuit that separately controls voltages between each of the particle sorting output ports and at least the optical detection region of the microchannel in response to the first and second characterization signals to transport the at least one particle by electrokinetic flow of the fluid from the optical detection region to one of the output ports that is selected responsive to the first and second particle characterization signals. 30. The electrokinetic microfluidic flow cytometer apparatus of claim 26, wherein: the at least one particle comprises a plurality of different types of blood cells, at least two of the types of blood cells are labeled with different fluorescent dyes that emit different defined wavelengths of light responsive to illumination by the coherent laser light;the first primary photodetector generates the first output signal responsive to first wavelength light being received from the filter apparatus;the first differential amplifier regulates the first particle characterization signal to indicate that a first type of blood cell is present in the optical detection region of the microchannel in response to the first output signal differing from the reference noise signal by at least a threshold amount; andthe second primary photodetector generates the second output signal responsive to second wavelength light being received from the filter apparatus; andthe second differential amplifier regulates the second particle characterization signal to indicate that a second type of blood cell is present in the optical detection region of the microchannel in response to the second output signal differing from the reference noise signal by at least a threshold amount. 31. The electrokinetic microfluidic flow cytometer apparatus of claim 30, further comprising: a particle sorting circuit that separately controls voltages between each of the particle sorting output ports and at least the optical detection region of the microchannel in response to the first and second particle characterization signals to sort the detected types of blood cells by controlling electrokinetic flow of the fluid from the optical detection region to different ones of the output ports. 32. The electrokinetic microfluidic flow cytometer apparatus of claim 26, wherein the filter apparatus comprises a wavelength division multiplexing (WDM) filter apparatus that is configured to direct a combined plurality of wavelengths of coherent laser light through a single optical fiber that is positioned to illuminate the optical detection region of the microchannel with the combined wavelength light and to collect light that is reflected therefrom, and is configured to receive the light collected by the single optical fiber and to split the collected light so that a plurality of different defined wavelengths, when present, pass through different corresponding ones of the plurality of filter output fibers. 33. The electrokinetic microfluidic flow cytometer apparatus of claim 32, wherein: the single optical fiber is positioned to illuminate the optical detection region of the microchannel from a same side of the substrate from which the input port and the plurality of particle sorting output ports are exposed. 34. The electrokinetic microfluidic flow cytometer apparatus of claim 32, further comprising: a wavelength combiner apparatus that is configured to receive light from a plurality of different laser sources and to combine the received light to generate the combined plurality of wavelengths of coherent laser light that is provided to the WDM filter apparatus to be directed through the single optical fiber to illuminate the optical detection region of the microchannel.