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    • 专利摘要:
    MICROFLUIDIC CAPTURE DEVICE A microfluidic capture device that comprises a channel and an impedance sensor within the channel. The impedance sensor comprises a local ground and an electrode within the channel. The local ground and electrode must form an electric field region that is elongated along the channel.
    公开号:BR112016017466B1
    申请号:R112016017466-6
    申请日:2014-01-30
    公开日:2021-05-18
    发明作者:Nicholas Matthew Cooper Mcguinness；Melinda M. Valencia；Manish Giri；Chantelle Elizabeth Domingue；Jeremy Sells；Matthew David Smith
    申请人:Hewlett-Packard Development Company, L.P.；
    IPC主号:
    专利说明:

    BACKGROUND
    [001] Some microfluidic pickup devices employ an impedance sensor to differentiate cell or particle size in flow cytometry applications. The impedance sensor depends on a signal magnitude. When a cell or particle is damaged, its dielectric properties can change, reducing the accuracy of such microfluidic pickup devices. BRIEF DESCRIPTION OF THE DRAWINGS
    [002] Figure 1 is a top view of an exemplary microfluidic capture system.
    [003] Figure 2 is a top view of another exemplary microfluidic capture system.
    [004] Figure 3 is a flowchart of an exemplary method that can be performed by the system in Figure 1 or by the system in Figure 2.
    [005] Figure 4 is a top view of another exemplary microfluidic capture system.
    [006] Figure 5 is a top view of another exemplary microfluidic capture system.
    [007] Figure 6 is a perspective view of the microfluidic capture system of Figure 5
    [008] Figure 7 is a top view of another exemplary microfluidic capture system.
    [009] Figure 8 is a top view of another exemplary microfluidic capture system.
    [010] Figure 9 is a top view of another exemplary microfluidic capture system.
    [011] Figure 10 is a top view of another exemplary microfluidic capture system.
    [012] Figure 11 is a top view of another exemplary microfluidic capture system.
    [013] Figure 12 is a top view of another exemplary microfluidic capture system.
    [014] Figure 13 is a top view of another exemplary microfluidic capture system.
    [015] Figure 14 is a top view of another exemplary microfluidic capture system.
    [016] Figure 15 is a perspective view of another exemplary microfluidic capture system.
    [017] Figure 16 is a side view of the microfluidic capture system of Figure 15.
    [018] Figure 17 is a side view of the microfluidic capture system of Figure 15 illustrating the obstruction of an electric field region by particle.
    [019] Figure 18 is a graph of impedance over time during the passage of a particle through the microfluidic capture system of Figure 15.
    [020] Figure 19 is a graph of impedance versus displacement of B for the microfluidic capture systems of Figures 2, 5, 8, 9, 12, 13 and 14.
    [021] Figure 20 is a top view of another exemplary microfluidic capture system.
    [022] Figure 21 is a top view of another exemplary microfluidic capture system.
    [023] Figure 22 is a top view of another exemplary microfluidic capture system.
    [024] Figure 23 is a top view of another exemplary microfluidic capture system. DETAILED DESCRIPTION OF PREFERRED MODALITIES
    [025] Figure 1 illustrates an exemplary microfluidic capture system 20. The microfluidic capture system 20 uses an impedance sensor to detect through a sensor one or more characteristics of particles that flow through the impedance sensor. As will be described hereinafter, the microfluidic pickup system 20 provides improved pickup accuracy.
    [026] The microfluidic capture system 20 comprises the channel 22 and the impedance sensor 24. The channel 22 comprises a microfluidic passage through which the fluid 26 carries one or more particles 28. For purposes of the present disclosure, the term "microfluidic " refers to devices and/or passageways that interact with fluids that have a volume or carry particles that have dimensions in the "micro", microliter or micrometer range, respectively. For purposes of the present disclosure, the term "particle" encompasses any small part, fragment or amount, including, without limitation, a biological cell or group of biological cells. A "fluid" can comprise a liquid, a gas or mixtures thereof. Channel 22 directs the flow of fluid 26 and particles 28 along or through an electric field region 30 (shown schematically) formed within channel 22 by impedance sensor 24. Examples of a fluid containing particles include, however, , without limitation, a blood sample and pigments/particles containing ink or the like.
    [027] The impedance sensor 24 forms the electric field region 30 within the channel 22. The impedance sensor 24 comprises a local electrical ground 32 and an electrode 34 that cooperate to form region 30 of electric field lines extending within of channel area 22. Both electrical ground 32 and electrode 34 are "local" in that electrical ground 32 and electrode 34 are provided by electrically conductive contacts adjacent to the interior of channel 22 or relatively very close to the interior of the channel. channel 22, such as immediately below or behind an interior surface or lining of channel 22. In contrast to a remote ground located outside channel 22 or distant from channel 22, a substantial majority of the electric field region 30, if not the entire region, between ground 32 and electrode 34 is contained within the interior of channel 22. As a result, the distance at which the electric field lines between ground 32 and the electrode 34 extend is not so long as to reduce or weaken the signal strength to a point that substantially impairs the accuracy of the system 20.
    [028] When the particle 28 passes through a region of electric field 30, the electric field lines of region 30 are at least partially obstructed by the particle 28 so that the electric field lines of region 30 are changed and run around of particle 28. The increased length of the electric field lines of region 30, resulting from having to travel through particle 28, increases or raises the electrical impedance that can be detected at electrode 34. As a result, the increase in impedance resulting from obstruction of the electric field region 30 by particle 28 serves as an indicator of one or more characteristics of particle 28, such as the size of particle 28.
    [029] The ground 32 and the electrode 34 of the impedance sensor 24 are arranged or otherwise configured so that the electric field region 30 is elongated within the channel 22 and along it. In other words, the electric field region 30 extends in a direction along the direction of the channel 22, or parallel thereto, and parallel to the direction of fluid flow 26 through the channel 22 so that the particle 28 interrupts or obstructs the electric field lines of electric field region 30 for a longer and longer period of time. As a result, electrical signals representing changes in impedance as part of the 28 fluxes through the electric field region 30 have longer characteristic rises and falls, which facilitates improved accuracy for particle size capture 28.
    [030] Figure 1 illustrates two alternative arrangements for the ground 32 and for the electrode 34 to form the electric field region 30 that is elongated along the channel 22. In a first arrangement, as indicated by the solid lines, both the ground 32 and electrode 34, or one of them, have large dimensions, length L, which extend along the sides of channel 22 parallel to channel 22. In one deployment, ground 32 and electrode 34 are formed on the side walls of channel 22. In another implementation, both ground 32 and electrode 34 are formed on a face or surface of channel 22 that extends along or parallel to the side walls of channel 22. For example, in one deployment, both ground 32 and electrode 34 are formed in a floor of channel 22, where ground 32 and electrode 34 each extend adjacent to or along the side walls of channel 22 .
    [031] In a second arrangement, as indicated by the dashed lines, the ground 32' and the electrode 34' are spaced apart in a direction along channel 32. The electric field region 30 is elongated as a result of the spacing a upstream or downstream of ground 32' and electrode 34'. In one deployment, both the 32' ground and the 34' electrode are formed on the same face or surface within the channel 22. In other deployments, the 32' ground and the 34' electrode are formed on different surfaces along the channel. 22. Although ground 32' is illustrated as being downstream of electrode 34', this relationship can be reversed.
    [032] Figure 2 is a diagram illustrating the microfluidic capture system 120, a particular implementation of the microfluidic capture system 20. As for the microfluidic capture system 20, the microfluidic capture system 120 uses an impedance sensor that produces an elongated electric field region along a channel to detect characteristics of particles that are cells passing through the electric field region. The microfluidic pickup system 120 comprises a source reservoir 200, a pump 202, a thermal sensor 203, a channel 122, a container reservoir 204, an impedance sensor 124, a controller 206, and an outlet 208. The source reservoir 200 comprises a structure for receiving a supply of fluid 26 containing particles 28. The source reservoir communicates with channel 122 to supply fluid 26 and particles 28 by being conducted or withdrawn through channel 122 via impedance sensor 124 .
    [033] The pump 202 comprises a mechanism for moving the fluid 26 and the particles 28 through the impedance sensor 124. In the illustrated example, the pump 202 drives the fluid 26 and the particles 28 from the source reservoir 200 along the channel 122 and through impedance sensor 124 towards container reservoir 204. In another embodiment, pump 202 may alternatively be located within container reservoir 204 so as to extract fluid 26 and particles 28 from source reservoir 200 at along channel 122 and through impedance sensor 124. Although one pump is illustrated, in other implementations, system 120 may include more than one pump.
    [034] In one deployment, the pump 202 comprises a bubble jet pump, also called a thermal ink jet pump (TIJ) or resistive in which a resistor is heated to a temperature in order to vaporize a portion of the liquid in order to form a bubble that conducts the liquid and surrounding particles. In such an implementation, the TIJ resistor that serves as the pump 202 can additionally serve as a heating device to heat the system 120 to a prescribed temperature. In other implementations, the pump 202 may comprise other types of pumps, such as piezoelement pumps (PZT) or other pumps that have electrically, magnetically or mechanically activated deflection membranes.
    [035] The temperature sensor 203 comprises one or more temperature or thermal sensing devices to detect the temperature at which the system 120 has been heated by the TIJ resistor, which also serves as a heating device, or by another heating device or independent component of pump 202. Temperature sensor 203 is in communication with controller 206 and provides closed-loop feedback regarding heating of system 120 by resistive heater TIJ which serves as a pump 202 or as an independent heating component .
    [036] The channel directs fluid 26 and particles 28 from source reservoir 200 to container reservoir 204. Container reservoir 204 receives fluid 26 and particles 28 after particles 20 8/2 pass through reservoir of impedance 124. In some implementations, container reservoir 204 is connected to source reservoir 200, which facilitates recirculation of fluid 26 and particles 28. In some implementations, channel 122 may additionally comprise one or more filters or the like. structures through which fluid 26 must flow during passage from reservoir 200 to reservoir 204. In some implementations, system 120 may comprise multiple differently sized channels, wherein different sizes of channels are used to classify and separate particles 28 of different sizes.
    [037] The impedance sensor 124 is similar to the impedance sensor 24. The impedance sensor 124 comprises the local ground 132 and the electrode 134. The ground 32 and the electrode 34 have large dimensions, length L, which extend along from the sides of channel 122 parallel to channel 122. In the illustrated example, both ground 132 and electrode 134 are formed on a face or surface of channel 22 and extend along or parallel to the side walls of channel 122. In the illustrated example, both the ground 132 and the electrode 134 are formed in a floor of the channel 22, where the ground 32 and the electrode 34 each extend adjacent to or along the side walls of the channel 22. Because both ground 132 and electrode 134 are formed on the floor of channel 122, the fabrication and formation of channel 122 with ground ground 132 and electrode 134 can be less complex and less expensive. Ground 132 and electrode 134 produce an elongated electric field region along a channel 122 for improved accuracy in detecting characteristics of particles 28 passing through electric field region 130.
    [038] The controller 206 controls the operation of the impedance sensor 124. The controller 206 regulates the supply of electrical charge to the electrode 134 and controls the detection of the impedance by the sensor 124. In an implementation, the controller 206 additionally controls the operation of a or more pumps, such as pump 202 to control the flow of fluid 26 and particles 28 along channel 122. In one deployment, controller 206 further controls heating of a system 120 by the TIJ resistor of pump 202 or by an independent heating component. Controller 206 comprises a processing unit 210 and a memory 212. For purposes of the present application, the term "processing unit" shall mean a presently developed or future developed processing unit that executes the sequences of instructions contained in a non-transient memory or in a persistent storage device such as a memory 212. Executing the sequences of instructions causes the processing unit to perform steps such as generating control signals. Instructions can be loaded into random access memory (RAM) for execution by the processing unit from read-only memory (ROM), a mass storage device, or some other persistent storage. In other embodiments, a directly connected circuitry can be used in place of software instructions to implement the described functions. For example, controller 206 can be incorporated as part of one or more application-specific integrated circuits (ASICs). Unless specifically noted otherwise, the controller is not limited to any specific combination of hardware and software circuitry, nor to any particular source for the instructions executed by the processing unit.
    [039] The output 208 comprises a device through which the results of the impedance sensor 124 are presented or otherwise made available for use in the analysis of the particles 28. In an implementation, the output 208 comprises a port, a transceiver or wireless transmitter or signal transmission contact through which electrical signals representing changes in impedance detected by sensor 124 are made available to external devices for analysis and for use in identifying characteristics associated with particle 28. For example, in a implementation, output 208 may comprise a universal serial bus port through which impedance signals are transmitted to an external computing device and/or another host device, such as a smart phone, tablet computer, computer type laptop, or the like, for the determination of characteristics of the 28 particle, such as the size of the 28 particle. In one deployment, the results of the signals produced by the impedance sensor 124 are stored in memory 212 for later retrieval and analysis by a host device.
    [040] In another implementation, memory 212 contains computer readable instructions to instruct processor 210 to determine one or more characteristics in place from the impedance signals produced by impedance sensor 124. For example, in an implementation, the memory 212 may contain code or instructions to instruct processor 210 to determine or estimate the size of particle 28 based on impedance signals from sensor 124 as particle 28 passes through electric field region 130. In such deployment, output 208 comprises a visual display or an auditory device to indicate the particular characteristic of particle 28, such as the particular size of particle 28. In some implementations, output 208 may further facilitate communication with a user of system 120 in order to to provide instructions for the operation of the 120 system or to provide confirmation or feedback regarding the proper use of the 120 system or test vision.
    [041] In one deployment, system 120 is deployed as a chip-based device supported on a single 216 platform. In one deployment, the 216 platform may be a portable platform. As a result, system 120 can provide a microfluidic diagnostic system that offers a configurable, mobile platform for one-stop healthcare diagnostics such as cell-based diagnostics to detect infectious diseases and chronic diseases.
    [042] In one deployment, the platform 216 comprises a silicon substrate on which an impedance measurement circuit is provided to operate and/or control the electrode 134 in order to produce the electric field region 130 for impedance capture. In an implant, the platform silicone substrate 216 further supports the circuitry for analyzing the captured impedance signals to identify the one or more characteristics of the particle 28. According to an implant, the silicone substrate that serves as the platform 216 comprises a silicon chip that has a size of between 0.5 mm2 to 5 mm2, where the silicon substrate supports each of the one or more TIJ resistors, which serves both as a pump 202 and a heater, the one or more impedance sensor electrodes 134 (and associated ground 132) and the one or more thermal sensors 203 in close proximity to one another on the substrate with associated circuitry. In one deployment, the silicone substrate supports each of the one or more TIJ resistors, which serve as both the pump 202 and a heater, the one or more impedance sensor electrodes 134 (and associated ground 132), and a or more thermal sensors 203 at a spacing from each other less than or equal to 5 mm and nominally at a spacing from each other less than or equal to 0.5 mm.
    [043] In one deployment, the 216 platform comprises a power supply. In another deployment, the 216 platform is configured to be connected to a remote power source. In one deployment, the 216 platform and the 120 system component set are available. In such an implementation, the structures and components of system 120 can be fabricated using integrated circuit microfabrication techniques such as electroforming, laser ablation, anisotropic engraving, ion bombardment, dry and wet engraving, photolithography, casting, molding, stamping, machining, spin coating, laminating and so on.
    [044] Figure 3 is a flowchart of an exemplary method 300 of capturing in determining particle characteristics based on impedance changes. Method 300 can be performed by either one of impedance pickup system 20 or 120. As indicated by step 310, electrodes 34, 34', 134 are electrically charged so as to cooperate with local grounds 32, 32' and 132, respectively, to form the electric field region 30, 130 which is elongated along the channel 22, 122. As indicated by step 312, the controller 206 senses impedance changes in the electric field region 30, 130 during flow. of fluid 26 containing particles 28 within channel 22, 122. As indicated by step 314, controller 206 or a remote host device uses the captured impedance changes to identify one or more characteristics of the particle 28, such as the size of the particle. particle 28. Because the electric field region 30, 130 is elongated along the channel 122, the time that the particle 28 remains within the electric field region 30, 130 is prolonged, enhancing the reliability. signal strength and detection accuracy.
    [045] Figure 4 is a top view of the microfluidic capture system 320, an exemplary implementation of the microfluidic capture system 20. The microfluidic capture system 320 is similar to the microfluidic capture system 120 in that such system 320 also comprises a channel 122 as well as the source reservoir 200, the pump 202, the container reservoir 204, the controller 206, the outlet 208 and the platform 216, among which each is shown and described above in relation to the system 120. In contrast to the microfluidic pickup system 120, the microfluidic pickup system 320 comprises 324A, 324B, 324C, 324D, 324E, 324F impedance sensors (collectively called 324 impedance sensors). Each impedance sensor 324 is similar to impedance sensor 124, which forms an electric field region that is elongated along channel 122. In the illustrated example, impedance sensors 324 form differently shaped or sized electric field regions 330 to along channel 122. In the illustrated example, impedance sensor 324D forms an electric field region 330 that is larger than electric field regions 330A, 330B, 330E and 330F formed by impedance sensors 324A, 324B, 324E and 324F, respectively. The 324C impedance sensor forms a 330C electric field region that is larger than the 330D electric field region. In the illustrated example, the larger electric field regions are provided by the larger electrodes 134. In other deployments, the larger electric fields may be provided by the larger site grounds 132 or either by the larger site grounds 132 or by the larger electrodes 134. impedance 324 located along channel 122 produce signals that have impedance peaks at each time the particle 28 passes through each of the impedance sensors 324. The difference signals produced by the multiple impedance sensors 324 are compared and analyzed statistically. in order to identify particle size 28. For example, an average or median can be determined from the signals from multiple impedance sensors 324 to estimate a particle size 28.
    [046] In the illustrated example in which some of the electric field regions 330 are endowed with different sizes with different sizes, the differentiation between the particles is enhanced. Sufficiently large particles - particles larger than a region of electric field - can saturate a region of electric field 330. At the same time, particles small relative to a region of electric field 330 may not result in an intense signal to determine changes of impedance. Because the system 320 forms differently sized electric field regions 330, the size of the electric field regions is customized to accommodate both small-sized and large-sized particles while reducing the inaccuracy caused by saturation by large particle of an impedance sensor by the weak signal strength of small particle.
    [047] In a deployment, the controller 206 is configured to selectively and independently vary the frequency at which two or more of the 324 impedance sensors are operated. For example, the 324D impedance sensor can be operated at a first frequency whereas the 324E impedance sensor is operated at a second, distinct frequency. By varying the frequency among the different impedance sensors 324, the system 320 can analyze additional characteristics of the particle 28. For example, in the case of biological cells, different frequencies can be used to differently excite the cell membrane cytoplasm. Such different excitation of a different portion of the cell can result in logic signals for identifying additional characteristics associated with the cell or particle 28.
    [048] Figures 5 and 6 illustrate the microfluidic capture system 420, an exemplary implementation of the microfluidic capture system 20. The microfluidic capture system 420 is similar to the microfluidic capture system 120 in that the 420 system also comprises a channel 122 as well as source reservoir 200, pump 202, container reservoir 204, controller 206, outlet 208 and platform 216, among which each is shown and described above in connection with system 120. to the microfluidic pickup system 120, the microfluidic pickup system 420 comprises the impedance sensor 424. The impedance sensor 424 forms a focused electric field region 430 through the channel 122. The impedance sensor 424 comprises the local ground 432 and the electrode 434. Ground ground 432 and electrode 434 extend along opposite surfaces of channel 122 and are separated by a varying size span 436. The term "span d and "variant size" refers to the distance across the opposing surfaces or faces of the local ground 432 and the corresponding opposite electrode 434, wherein the distance or span size varies as one travels upstream or downstream along channel 122. Variant size span 436 results in the formation of electric field 430 that has a focused center or core region 438 with greater density of electric field lines within the narrower portions of the span. As a result, the electrical impedance signals produced by sensor 424 as particle 28 passes through electric field region 430 have a broader, sharper signal peak that indicates how well particle 28 is blocking or obstructing the region. of electric field 430. The wider or sharper signal peak produced by particle 28 that passes through the focused field region 430 facilitates more reliable capture of particle size.
    [049] In the illustrated example, span 436 has a larger width substantially equal to the width of channel 122 and a smaller width W corresponding to the separation of opposing points 440 from ground 432 and electrode 434. Points 440 provide enhanced focus field lines that extend between them. In one deployment, the width W between points 440 is adjusted to accommodate the largest expected particle size 28 that must pass through the electric field region 430. Although the largest span width 436 corresponds to the channel width 122, in other deployments , the largest span width 436 may alternatively be smaller than the channel width 122.
    [050] Although each of ground 432 and electrode 434 are each illustrated as being pointed out, in other deployments, one of ground 432 and electrode 434 may alternatively comprise a flat bar that has a surface parallel to the sides of the channel. 122. Although each of ground 432 and electrode 434 are illustrated as having a point 440 that is centered, in other deployments, ground electrode 434 may have a point 440 that is asymmetric. For example, both ground 432 and electrode 434 can alternatively have a configuration that provides a gap that is the widest closest to source reservoir 200 and which is the narrowest closest to vessel reservoir 204. 432 and electrode 434 are each illustrated as having single points 440 opposite each other, in other deployments both ground 432 and electrode 434, or one of them, may alternatively have a series of serrated points or teeth along the channels 122 or may have curved surfaces that are convex or concave along channel 122.
    [051] As shown in Figure 6, ground 432 and electrode 434 are formed along a single surface or face of channel 122. In the illustrated example, both ground 432 and electrode 434 are formed along floor 442 of the channel 122 extending from or adjacent opposite sidewalls 444, 446 of channel 122. Because ground 432 and electrode 434 are formed along the same face of channel number 122, such as floor 442, reliable and accurate control of the spacing of points 440 and span 436 during fabrication is made easy. In addition, ground 432 and electrode 434 do not obstruct the cross-sectional area of channel 122 and fluid flow 26. In other deployments, ground 432 and electrode 434 are formed along and protrude from opposite surfaces within of channel 122.
    [052] Figure 7 illustrates the microfluidic capture system 520, another exemplary implementation of the microfluidic capture system 20. The microfluidic capture system 520 is similar to the microfluidic capture system 420 with the exception that the microfluidic capture system 520 comprises an impedance sensor 524 instead of the impedance sensor 424. These remaining components of the 520 system are enumerated similarly in Figure 7 or are shown in Figure 2.
    [053] Impedance sensor 524 is similar to impedance sensor 424 except that impedance sensor 524 comprises ground 532 and electrode 534 which cooperate to form an electric field region 530. Ground 532 and electrode 534 are similar to ground 432 and electrode 434 except that ground 532 and electrode 534 are spaced apart along channel 122. In other words, one of ground 532 and electrode 534 is located upstream of the other ground 532 and electrode 534. As a result, instead of extending generally perpendicularly through channel 122, electric field region 530 extends obliquely or diagonally through channel 122. increases the time during which a particle 28 passing through the electric field region 530 obstructs the electric field region 530. As a result, such obstruction of the electric field region 530 results ta at longer rise and fall moments of the electrical impedance signal, which facilitates reliable and accurate detection of the particle size 28. As for the impedance sensor 424, the local ground 532 and electrode 534 are separated by a gap of varying size across channel 1222 form a focused region 538 of electric field lines that produces a sharper impedance signal peak, which further facilitates particle size detection.
    [054] Figure 7 illustrates the microfluidic capture system 620, another exemplary implementation of the microfluidic capture system 20. The microfluidic capture system 620 is similar to the microfluidic capture system 120 in that the system 620 also comprises a channel 122 as well as the source reservoir 200, the pump 202, the container reservoir 204, the controller 206, the outlet 208 and the platform 216, of which each is shown and described above in relation to the system 120. In contrast to the system of microfluidic pickup 120, the microfluidic pickup system 620 comprises the impedance sensor 624 which forms an elongated electric field region along channel 122 by spacing the local ground 632 of electrode 634 along channel 122. In one deployment, local ground 632 and electrode 634 have an S spacing between 2 µ and 5 µ, which provides enhanced signal strength. In other deployments, ground electrode 64 632 may have other spacings.
    [055] In the illustrated example, the local ground 632 and the electrode 634 comprise electrically conductive surfaces or bars that extend completely through the channel 122 orthogonal to the sides of the channel 122. For example, in an deployment, the local ground 632 and the electrode 634 comprise exposed tantalum bars. In other deployments, ground 632 and electrode 634 may be formed from other electrically conductive materials or metals covered by film or exposed. In other deployments, either local ground 632 or electrode 634, or one of them, may alternatively extend partially through channel 122. Although ground 632 is illustrated as being downstream of electrode 634, in other deployments, this relationship can be reversed.
    [056] Figure 8 illustrates the microfluidic pickup system 720, another implementation of the microfluidic pickup system 20. The microfluidic pickup system 720 is similar to the microfluidic pickup system 620 except that system 720 comprises the impedance sensor 724 in the place of impedance sensor 624. Impedance sensor 724 comprises local ground 732 and electrode 734 which are similar to ground 632 and electrode 634 of sensor 624 except that ground 732 and electrode 734 extend obliquely across or diagonally across channel 122. As a result, the elongated electric field region formed by ground 732 and electrode 734, when electrode 734 is charged, extends obliquely through channel 122. Consequently, the obstruction of the field region electrical by a 28 particle results in longer rise and fall moments of the electrical impedance signal, which facilitates reliable and accurate detection of particle size 28.
    [057] Figure 9 illustrates the microfluidic capture system 820, another implementation of the microfluidic capture system 20. The microfluidic capture system 820 is similar to the microfluidic capture system 120 in that the system 820 also comprises a channel 122 as well. such as the source reservoir 200, the pump 202, the container reservoir 204, the controller 206, the outlet 208 and the platform 216, of which each is shown and described above in relation to the system 120. In contrast to the system of microfluidic pickup 120, microfluidic pickup system 820 comprises a plurality of impedance sensors 824A and 824B (collectively termed impedance sensors 824) spaced along channel 122. Due to the fact that system 820 comprises a plurality of sensors impedance 824, system 820 can determine the size of a particle 28 using multiple signals that can be compared and statistically analyzed to in order to provide the improved accuracy of particle size detection 28.
    [058] The 824A impedance sensor comprises the local ground 832 and the 834A electrode. Ground 832 and electrode 834A extend along opposite sides of channel 1222 from a diagonally extending electric field region 830A. Impedance sensor 824B comprises local ground 832 and electrode 834B. Ground 832 and electrode 834 extend along opposite sides of channel 122 to form a diagonally extending electric field region 830B downstream of electric field region 830A provided by impedance sensor 824A. As shown in Figure 9, the 824 sensors share a single 832 ground, which reduces manufacturing complexity. In addition, the diagonally extending electric fields 8304 can provide, via sensors 824, greater rise and fall signals as particle 28 passes through electric field regions 830 for enhanced size detection accuracy for particle 28.
    [059] In the illustrated example, the impedance sensors 824 form differently shaped or sized electric field regions 830 along the channel 122. In the illustrated example, the impedance sensor 824B has a longer electrode 834B so as to form the region of 830B electric field that is greater than the 830A electric field region formed by the 824A impedance sensors. As a result, size differentiation among particles is enhanced. Sufficiently large particles - particles larger than an electric field region - can saturate an 830 electric field region. At the same time, particles small relative to an 830 electric field region may not result in a strong signal to determine changes of impedance. Due to the fact that the 820 system forms differently sized 830A, 830B electric field regions, the size of the electric field regions is customized to accommodate both small size particles and large size particles while reducing inaccuracy caused. by large particle saturation and by weak small particle signal intensity.
    [060] In a deployment, the controller 206 (shown in Figure 2) is configured to independently and selectively vary the frequency at which two or more of the 824 impedance sensors are operated. For example, impedance sensor 824A can be operated at a first frequency whereas impedance sensor 824B is operated at a second, distinct frequency. By varying the frequency among the different impedance sensors 324, the system 820 can analyze additional characteristics of the particle 28. For example, in the case of biological cells, different frequencies can be used to differently excite the cell membrane cytoplasm. Such different excitation of a different portion of the cell can result in logic signals for identifying additional characteristics associated with the cell or particle 28.
    [061] Although the 824 impedance sensors are illustrated as comprising a pair of 834 electrodes that share a single local ground 832, in other deployments, the 824 sensors may alternatively comprise a pair of 832 local grounds that share a single 834 electrode. site ground 832 and electrodes 834 illustrated as being formed along channel 122 on the floor of channel 122, in other deployments site ground 832 and electrode 834 (or electrode 834 and site grounds 832) can be formed into walls sides of channel 122 or either on the floor or on a side wall of channel 122.
    [062] Figure 10 illustrates the microfluidic capture system 920, another implementation of the microfluidic capture system 20. The microfluidic capture system 820 is similar to the microfluidic capture system 620 in that the system 920 also comprises a channel 122 as well. such as the source reservoir 200, the pump 202, the container reservoir 204, the controller 206, the outlet 208 and the platform 216, of which each is shown and described above in relation to the system 120. In contrast to the system of microfluidic pickup 120, microfluidic pickup system 820 comprises a plurality of impedance sensors 924A and 924B (collectively termed impedance sensors 824) spaced along channel 122. Due to the fact that system 920 comprises a plurality of sensors impedance 924, system 920 can determine the size of a particle 28 using multiple signals that can be compared and analyzed statistically. to provide improved accuracy for particle size detection or estimation 28.
    [063] The 924A impedance sensor comprises local ground 932 and the electrode 934A. Ground 932 and electrode 934A are spaced along channel 122 upstream or downstream from each other. Impedance sensor 924B comprises local ground 932 and electrode 934B. Ground 932 and electrode 934B extend along channel 122 to form an electric field 930B downstream of the electric field 930A provided by impedance sensor 924A. As shown in Figure 10, sensors 924 share a single ground 932, which reduces manufacturing complexity.
    [064] In an deployment, electrode 934A is closer to ground 932 compared to electrode 934B so that the 930 electric field regions formed by the 924 impedance sensors are sized differently. As a result, particle 28 passing through such different electric field regions 930 can produce different impedance signals that can be compared and analyzed for enhanced size detection accuracy for particle 28.
    [065] Figure 11 illustrates the 1020 microfluidic capture system, another implementation of the 20 microfluidic capture system. The 1020 microfluidic capture system is similar to the 120 microfluidic capture system in that the 920 system also comprises a channel 122 as well. such as source reservoir 200, pump 202, container reservoir 204, controller 206, outlet 208, and platform 216, of which each is shown and described above in connection with system 120. The microfluidic pickup system 1020 is also similar to the 920 microfluidic pickup system with the exception that the grounded pair of ground-pressed electrodes extends longitudinally through channel 122.
    [066] As shown in Figure 11, the microfluidic pickup system 1020 comprises the 1024A impedance sensor, formed by the 1032 ground and the 1034A electrode, and the 1024B impedance sensor, formed by the 1032 ground and the 1034B electrode. Electrode 1034A and ground 1032 form electric field region 1030A whereas electrode 1034B and ground 1032 form electric field region 1030B. Electric field regions 1030 extend longitudinally through channel 122. As a result, impedance signals that result from a particle 28 passing through electric field regions 1030 have longer rise and fall moments, which facilitates improved size detection accuracy for particle 28. In one deployment, the 1032 ground is spaced equidistantly from the 1034 electrodes. In another deployment, the 1032 ground is spaced differently from the 10342 electrodes of the 1030 differently sized electric field regions for accuracy of improved size detection.
    [067] Figure 12 illustrates the 1120 microfluidic capture system, another implementation of the microfluidic capture system 20. The 1120 microfluidic capture system is similar to the microfluidic capture system 120 in that the 1120 system also comprises a channel 122 as well. such as source reservoir 200, pump 202, container reservoir 204, controller 206, outlet 208, and platform 216, of which each is shown and described above in connection with system 120. The microfluidic pickup system 1120 comprises a large number of impedance sensors 1124A, 1124B, 1124C and 1124D (collectively referred to as sensors 1124) along channel 122. Sensors 1124A, 1124B, 1124C and 1124D share a single local ground 1132 and comprise electrodes 1134A, 1134B , 1134C and 1134D (collectively referred to as electrode 1134), respectively.
    [068] Electrodes 1134 extend on one side of ground 1132 and are spaced differently from ground 1132. In addition, each of electrodes 1134 is separated from an adjacent electrode 1134 by a different spacing. For example, electrode 1134A and electrode 1134B are spaced apart a first distance along channel 122 while electrode 1134B and electrode 1134C are spaced apart a second greater distance along channel 122. Variant spacing between electrodes 1134 provides a first additional differential signal comparison to determine the size of a particle 28 passing through the electric field regions formed by sensors 1124. In another implementation, electrodes 1134 may be equidistantly spaced from ground 1132 .
    [069] Electrodes 1134 cooperate with local ground 1132 to form differently sized overlapping electric field regions. The differently sized electric field regions provided by sensors 1124 accommodate differently sized particles 28, which maintain signal strength or reduce the likelihood of an accuracy due to saturation by a larger sized particle 28. Although ground 1132 is illustrated as being upstream of electrodes 1134, in other deployments, ground 1132 may be formed downstream of electrodes 1134. In some deployments, some of electrodes 1134 or additional electrodes 1134 may be provided upstream of ground 1132 to provide electric field regions additional.
    [070] Figure 13 illustrates the 1220 microfluidic capture system, another implementation of the 20 microfluidic capture system. The 1220 microfluidic capture system is similar to the 120 microfluidic capture system in that the 1220 system also comprises a channel 122, as well as source reservoir 200, pump 202, container reservoir 204, controller 206, outlet 208, and platform 216, among which are each shown and described above in connection with system 120. 1220 microfluidic pickup is similar to the 920 microfluidic pickup system with the exception that the 1220 microfluidic pickup system comprises differently sized electrodes sandwiched together and share the intermediate site ground. The microfluidic pickup system 1220 comprises impedance sensors 1224A and 1224B.
    [071] The 1224A impedance sensor comprises local ground 1232 and electrode 1234A. Ground 1232 and electrode 1234A are spaced along channel 122 upstream or downstream from each other. Impedance sensor 1224B comprises local ground 1232 and electrode 1234B. Ground 1232 and electrode 234B extend along channel 122 to form an electric field region 1230B downstream of electric field region 1230A provided by impedance sensor 1224A. As shown in Figure 13, sensors 1224 share a single local ground 1232, which reduces manufacturing complexity.
    [072] As further shown by Figure 13, electrode 1234A has a shorter length compared to electrode 1234B which extend through a smaller portion of channel 122. Electrodes 1134 cooperate with local ground 1132 to form electric field regions sized differently. The differently sized electric field regions provided by sensors 1224 accommodate differently sized particles 28, which maintain signal strength or reduce accuracy due to saturation by a larger sized particle 28. Although electrodes 1234 are illustrated as being spaced apart equidistant from ground 1232, in other deployments, each of electrodes 1234 is spaced differently relative to ground 1232.
    [073] Figures 14, 15, 16 and 17 illustrate the microfluidic capture system 1320 and its operation. The microfluidic pickup system 1320 is similar to the microfluidic pickup system 1220 described above except that the flow through channel 122 is in a counter-direction with impedance sensor 1324B and electrode 1334B thereof upstream of impedance sensor 1324A and electrode 1334A thereof. Figures 14 and 15 illustrate electric field regions 1330A and 1330B produced by impedance sensors 1324A and 1324B, respectively, an absence of obstruction by particle 28. Figure 16 illustrates an exemplary obstruction of electric field region 1334A by particle 28 which is carried by fluid 26. Figure 16 illustrates how electric field lines need to travel around particle 28, increasing impedance.
    [074] Figure 17 is a graph illustrating an impedance signal over time displayed by the microfluidic pickup system 1320 as the particle 28 successively flows through the electric field regions 1330B and 1330A of the impedance sensors 1324B and 1324A , respectively. As shown by Figure 17, as particle 28 occludes the larger electric field region 1230B to a first point, the impedance signal produces a first peak 1341. As particle 28 continues to flow through the electric field region smaller 1230A, particle 28 obstructs electric field region 1230A to a second larger point due to its larger relative size relative to electric field region 1230A. As a result, the impedance signal produces a second peak 1343 larger than the first peak 1341. The differently sized impedance signal peaks can be compared and analyzed differently to verify and estimate the corresponding size of the particle 28.
    [075] Figure 18 is a graph that compares impedance signals produced by the different microfluidic capture systems described above as one-size-fits-all particle flows through the one or more impedance sensors of each capture system. As shown in Figure 18, the microfluidic pickup system 420 produced the strongest or highest impedance signal. The 120 microfluidic pickup system produced the next highest impedance signal.
    [076] Figure 19 illustrates the 1420 microfluidic capture system, another implementation of the 20 microfluidic capture system. The 1420 microfluidic capture system is similar to the 120 microfluidic capture system in that the 1120 system also comprises the source reservoir 200, pump 202, container reservoir 204, controller 206, outlet 208 and platform 216, of which each is shown and described above in relation to system 120. Microfluidic pickup system 1420 further comprises channel 1422 and sensor of impedance 1424. Channel 122 comprises a first portion 1426 extending from source reservoir 200 (shown in Figure 2) a second portion 1427 extending to container reservoir 204 (shown in Figure 2) and a bypass intermediate 1428 connecting portions 1426 and 1427.
    [077] The impedance sensor 1424 comprises a local ground 1432 and an electrode 1434 located to form an electric field region 1430 that extends in and around the offset 1428. The elongated electric field region 1430 is occluded as the particle 28 passes through offset 1428 and produces an impedance signal for determining particle size 28. Although ground 1432 is illustrated as being upstream of electrode 1434, in other deployments this relationship may be reversed.
    [078] Figure 20 illustrates the microfluidic pickup system 1520, another implementation of the microfluidic system 20. The microfluidic pickup system 1520 is similar to the microfluidic pickup system 1420 except that the microfluidic pickup system 1520 comprises the impedance sensors 1524A and 1524B (collectively termed impedance sensors 1524). Impedance sensor 1524 comprises local ground 1532 and electrode 1534A. Impedance sensor 1524B comprises local ground 1532 and electrode 1534B. Impedance sensors 1524 share a single ground 1532 and form elongated electric field regions 1530A and 1530B, respectively. The multiple impedance sensors provided by the 1520 system provide multiple electric field region obstructions by a particle 28 passing therethrough that can be compared and analyzed to facilitate improved particle size detection 28. Although sensors 1524A and 1524B are declared to share a single 1532 ground, in other deployments, the 1524 sensors each have a unique local ground. In still other implementations, the capture system 1520 may alternatively comprise impedance sensors that have distinct local grounds that share a single electrode between them within the offset 1428.
    [079] Figure 21 illustrates the microfluidic capture system 1620, another implementation of the microfluidic capture system 20. The microfluidic capture system 820 is similar to the microfluidic capture system 120 in that the system 1620 also comprises a channel 122 as well. such as the source reservoir 200, the pump 202, the container reservoir 204, the controller 206, the outlet 208 and the platform 216, of which each is shown and described above in relation to the system 120. In contrast to the system of microfluidic pickup 120, microfluidic pickup system 1620 comprises an array of impedance sensors disposed across channel 122 and therealong for detecting a size of a particle 28 carried by fluid 26 flowing through channel 122.
    [080] As shown in Figure 21, the microfluidic pickup system 1620 comprises local grounds 1632A, 1632B (collectively called 1632 local ground) and electrodes 1634A1, 1634A2, 1634B1 and 1634B2 (collectively called electrode 1634). Grounds 1632 and electrode 1634 are at the same clock frequency as each other to form an array of electric field regions through and along channel 122, where the impedance signal resulting from the obstruction of the individual electric field regions facilitates in addition to determining or estimating the particle size 28.
    [081] In the illustrated example, the 1632A local ground and the electrodes that are shared by the 1632A local ground, the 1634A1 and 1634A1 electrodes have a first size that forms first sized electric field regions. Local ground 1632B and the electrodes that are shared by local ground 1632B, by electrodes 1634B1 and 1634B2 are smaller in size that form a second sized electric field region. The differently sized electric field regions as well as the different locations of the electric field regions within channel 122 through channel 122 and along channel 122 improve the accuracy of particle size estimation 28 by accommodating the differently sized particles 28 while maintaining the signal strength and reducing the impact of saturation of the electric field region by a large particle 28.
    [082] Although the microfluidic pickup system 1620 is illustrated as comprising a 2 x 2 array of impedance sensors 1524, in other deployments, the microfluidic pickup system six and 28 comprises a large array of impedance sensors. In some deployments, the matrix may comprise local grounds that are shared by the downstream and/or diagonal electrodes to the local ground, forming diagonal electric field regions for the detection of items 28. In still other deployments, the 1620 system can have a configuration similarly, however, in which the electrodes, rather than local grounds, are shared among multiple spaced local grounds that form the array of impedance sensors.
    [083] Figure 22 illustrates the microfluidic capture system 1720, another implementation of the microfluidic capture system 20. The microfluidic capture system is similar to the microfluidic capture system 120 in that the 1720 system also comprises a source reservoir 200 , a pump 202, a container reservoir 204, a controller 206, an outlet 208, and a platform 216, of which each is shown and described above in connection with system 120. The microfluidic pickup system 1720 is similar to the system of pickup system 1420 in that system 1720 comprises channel 1422. Microfluid pickup system 1720 is similar to microfluid pickup system 1620 instead of 1720 which comprises an array 1723 of 1724 impedance sensors.
    [084] As shown in Figure 22, impedance sensors 1724 are formed in a floor of channel 1422 within offset 1428. In the illustrated example, impedance sensors 1724 comprise a single shared local ground 1732 and electrodes 1734A, 1374B, 1374C and 1374D spaced around a local ground 1372 and forming impedance sensors 1724A, 1724B, 1724C and 1724D, respectively. Similar to the impedance sensors of system 1620, impedance sensors 1724 form an array of electric field regions that can be differently obstructed by particle passage 28 to produce impedance signals that can be analyzed to determine a corresponding estimate of particle size. 28.
    [085] In addition to facilitating the detection of a 28 particle size, the 1720 microfluidic capture system can additionally be used to facilitate the detection of a 28 particle mass and density. is flowing around deviation 1428 may impact which electric field region is occluded by particle 28, identifying an individual electric field region 1428 which is occluded by particle 28 may further indicate mass, therefore, particle density 28 Heavier particles will tend to flow out of the by-pass 1428 while lighter particles will tend from the fluid into the by-pass 1428. For example, heavier or denser particles 28 may flow through the by-pass 1428 with greater thrust, being that such particles 28 obstruct the electric field region of the 1724B impedance sensor to a greater point, which produces an electrical impedance a signal or peak with greater amplitude plitude, compared to the point at which such particles obstruct the electrical field region of the 1724D impedance sensor, which produces a smaller amplitude electrical impedance signal or peak.
    [086] Although the present invention has been described with reference to exemplary embodiments, persons skilled in the art will recognize that changes can be made in form and detail without departing from the spirit and scope of the invention. For example, although the different exemplary modalities may have been described as inclusive of one or more features that provide one or more benefits, it is contemplated that the features described may be interchanged with each other or alternatively combined with one another in the described exemplary modalities or in other alternative modalities. Due to the fact that the technology of the present disclosure is relatively complex, not all changes in technologies are anticipated. The present disclosure described with reference to the exemplary embodiments and set forth in the following claims is clearly intended to be as broad as possible. For example, unless specifically noted otherwise, claims reciting a single particular element also encompass a plurality of such particular elements.
    权利要求:
    Claims (15)
    [0001]
    1. Microfluidic pickup device characterized in that it comprises: a channel (22, 122, 1422) having an impedance sensor (24, 124, 324, 424, 524, 624, 724, 824, 924, 1024, 1124, 1224, 1324, 1424, 1524, 1724) within the channel (22, 122, 1422), the impedance sensor comprising: a local ground (32, 32', 132, 432, 532, 632, 732, 832, 932, 1132, 1232, 1432, 1532, 1632, 1732) within the channel (22, 122, 1422); and an electrode (34, 34', 134, 434, 534, 634, 734, 834, 934, 1034, 1134, 1234, 1334, 1434, 1534, 1634, 1734) within the channel (22, 122, 1422), wherein the local ground and the electrode must form an electric field region (30, 130, 330, 430, 530, 830, 930, 1030, 1230, 1330, 1430) that is elongated along the channel (22, 122, 1422), a circuit for generating an electric field region using the electrode and local grounding of the impedance sensor; a thermal inkjet resistor (TIJ) for moving fluid and particles through the channel (22, 122, 1422); and a thermal sensor (203).
    [0002]
    2. Microfluidic pickup device according to claim 1, characterized in that the electrode (34', 634, 734, 834, 934, 1034, 1134, 1234, 1334, 1434, 1534, 1734A, 1734C) is spaced from the local ground (32', 632, 732, 832, 932, 1032, 1132, 1232, 1332, 1432, 1532, 1732) in one direction along the channel (22, 122, 1422).
    [0003]
    3. Microfluidic pickup device according to claim 1, characterized in that at least one of the electrode and the local ground (32, 34, 132, 134, 532, 534, 832, 834, 1332, 1334, 1532) has a larger dimension along the channel (22, 122, 1422).
    [0004]
    4. Microfluidic pickup device according to claim 1, characterized in that the electrode (534, 734, 1034) is facing obliquely towards the channel.
    [0005]
    5. Microfluidic pickup device according to claim 1, characterized in that it additionally comprises a second impedance sensor (324A-F, 834A-B, 924A-B, 1024A-B, 1124A-D, 1224A-B , 1324A-B, 1524A-B, 1524A1-B2, 1724A-D) within the channel (22, 122, 1422) downstream of the impedance sensor.
    [0006]
    6. Microfluidic pickup device according to claim 5, characterized in that the second impedance sensor (834A-B, 924A-B, 1024A-B, 1124A-D, 1224A-B, 1324A-B, 1524A -B, 1524A1-B2, 1724A-D) comprises a second electrode and the local ground.
    [0007]
    7. Microfluidic pickup device according to claim 6, characterized in that the electrode (1134A, B, C, D) is spaced from the local ground (1132) at a first distance and that the second electrode (1134A) , B, C, D) is spaced from the local ground (1132) by a second distance different from the first distance.
    [0008]
    8. Microfluidic pickup device according to claim 5, characterized in that the impedance sensor (324A) and the second impedance sensor (324C) have electric field regions sized differently.
    [0009]
    9. Microfluidic pickup device according to claim 5, characterized in that the channel (1422) comprises a first portion containing the electrode (1534A), a second portion containing the local ground and a bypass that connects the first portion and the second portion, the bypass contains the local ground (1532).
    [0010]
    10. Microfluidic pickup device according to claim 1, characterized in that it additionally comprises a second impedance sensor (1524A2) located transversely to the impedance sensor (1524A2) within the channel (122).
    [0011]
    11. Microfluidic capture device, according to claim 1, characterized in that it additionally comprises: a platform that supports the channel and the electrode and the local grounding of the impedance sensor; where the circuit is supported on the platform; the thermal inkjet resistor (TIJ) is supported on the platform within 5mm of the impedance sensor; and the thermal sensor (203) is supported on the platform (216) within 5 mm of the impedance sensor and the TIJ resistor.
    [0012]
    12. Microfluidic pickup device according to claim 1, characterized in that the electrode (434) and the local ground (432) are separated by a gap of varying size along the channel (122).
    [0013]
    13. A method characterized in that it comprises: moving fluid containing particles within a channel of a collection device using a bubble jet pump (202); forming a first electric field region within the channel; forming a second electric field region within the channel; capturing impedance changes in the first electric field region and the second electric field region during the flow of fluid containing particles within the channel, wherein the first electric field region and the second electric field region have different sizes; and identify particle characteristics based on captured impedance changes.
    [0014]
    14. Method according to claim 13, characterized in that the first electric field region and the second electric field region have different shapes.
    [0015]
    15. Microfluidic capture device characterized in that it comprises: a platform (216) supporting a channel (22, 122, 1422); and an impedance sensor (24, 124, 324, 424, 524, 624, 724, 824, 924, 1024, 1124, 1224, 1324, 1424, 1524, 1724) within the channel, the impedance sensor comprises a local ground (32, 32', 132, 432, 532, 632, 732, 832, 932, 1132, 1232, 1432, 1532, 1632, 1732) and an electrode (34, 34', 134, 434, 534, 634, 734 , 834, 934, 1034, 1134, 1234, 1334, 1434, 1534, 1634, 1734), wherein the electrode and ground ground are separated by a gap of varying size along the channel; a supported circuit on the platform for generating an electric field region (30, 130, 330, 430, 530, 830, 930, 1030, 1230, 1330, 1430) using the electrode and local grounding of the impedance sensor; a thermal inkjet resistor (TIJ) supported on the platform within 5 mm of the impedance sensor; and a thermal sensor (203) supported on the platform within 5 mm of the impedance sensor and the TIJ resistor.
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    CN105940294B|2020-01-21|
    KR101872380B1|2018-06-28|
    US10495594B2|2019-12-03|
    TW201531700A|2015-08-16|
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    法律状态:
    2018-11-13| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-02-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-06-30| B25G| Requested change of headquarter approved|Owner name: HEWLETT-PACKARD DEVELOPMENT COMPANY, L.P. (US) |
    2021-03-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-05-18| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 30/01/2014, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/US2014/013748|WO2015116083A1|2014-01-30|2014-01-30|Microfluidic sensing device|
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