Microfluidic system including a cooling device

Abstract

To provide a microfluidic system including a microfluidic device for separating biological entities and a heat transmission device for cooling the microfluidic device.SOLUTION: A microfluidic system for separating biological entities includes: a cooling device 150 including a thermoelectric heat pump 152, a first fan 156, and a first heat exchanger 154 disposed between the first fan and the thermoelectric heat pump; a first housing structure 184 having a first shell 186 that encases the first fan and the first heat exchanger; a microfluidic device 202 and one or more piezoelectric transducers attached thereto; and a second housing structure 198 reversibly attached to the first housing structure and having a second shell 200 that encloses the microfluidic device and the one or more piezoelectric transducers therein.SELECTED DRAWING: Figure 5

Description

Technical Field

[0001] This application claims priority based on Provisional Application No. 63 / 109,264, filed on November 3, 2020, and Non-Provisional Application No. 17 / 167,744, filed on February 4, 2021. All of these applications are hereby incorporated by reference in their entirety, including their specifications and drawings.

[0002] The present invention relates to an apparatus for separating biological entities suspended in a fluid, and more particularly, to embodiments of a microfluidic system including a microfluidic device and a heat transfer device for cooling the microfluidic device. Background Art

[0003] Acoustic particle separation methods for extracting or separating various biological entities suspended in a fluid sample, such as blood, are of great interest in biological and biomedical applications. This method uses the acoustic radiation pressure generated by a piezoelectric transducer attached to a microfluidic device to separate particles having different sizes or acoustic contrasts. Since relatively high power can be applied to the piezoelectric transducer during operation, the heat generated by the transducer can heat the fluid sample flowing through the microfluidic device and damage the biological entities therein. Therefore, the microfluidic device and / or the piezoelectric transducer need to be properly cooled during operation.

[0004] For the above reasons, there is a need for a small cooling device that can reliably cool the microfluidic device during operation. Summary of the Invention

[0005] The present invention relates to an apparatus that meets this need. A microfluidic system for separating biological entities includes a thermoelectric heat pump, a first fan, a first heat exchanger disposed between the first fan and the thermoelectric heat pump, a second fan, and a second heat exchanger disposed between the second fan and the thermoelectric heat pump; a first housing structure having a first shell that houses the first fan and the first heat exchanger, the first housing structure having first and second cavities that respectively expose two sides of the first heat exchanger, and a third cavity formed adjacent to the first fan on the opposite side of the first heat exchanger; a microfluidic device and one or more piezoelectric transducers attached thereto; and a second housing structure reversibly attached to the first housing structure and having a second shell that surrounds the microfluidic device and the one or more piezoelectric transducers therein, the second housing structure including fourth and fifth cavities that respectively expose two ends of the microfluidic device and a sixth cavity. When the first and second housing structures are coupled, the first and second cavities are respectively aligned with the fourth and fifth cavities to form first and second air passages between two sides of the first heat exchanger and two ends of the microfluidic device, and the third and sixth cavities are aligned to form a third air passage between the first fan and the one or more piezoelectric transducers, thereby enabling air to circulate between the third air passage and the first and second air passages.

[0006] According to another aspect of the present invention, a microfluidic system for separating biological entities includes a thermoelectric heat pump, a first fan, a first heat exchanger disposed between the first fan and the thermoelectric heat pump, a second fan, and a second heat exchanger disposed between the second fan and the thermoelectric heat pump; a first housing structure having a first shell that houses the first fan and the first heat exchanger, the first housing structure having a first cavity that exposes a side surface of the first heat exchanger and a second cavity formed adjacent to the first fan on the opposite side of the first heat exchanger; a microfluidic device and one or more piezoelectric transducers attached thereto; and a second housing structure reversibly attached to the first housing structure and having a second shell that encloses the microfluidic device and the one or more piezoelectric transducers therein, the second housing structure including a third cavity and a fourth cavity that expose ends of the microfluidic device. When the first and second housing structures are coupled, the first and third cavities are aligned to form a first air passage between the side surface of the first heat exchanger and the end of the microfluidic device, and the second and fourth cavities are aligned to form a second air passage between the first fan and the one or more piezoelectric transducers, thereby enabling air to circulate between the first and second air passages.

Brief Description of the Drawings

[0007] These and other features, aspects, and advantages of the present invention will be better understood with reference to the following description, the appended claims, and the accompanying drawings:

[0008] FIG. 1A is a top view of a microfluidic device for separating biological entities according to an embodiment of the present invention;

[0009] FIGS. 1B and 1C are cross-sectional views of a microfluidic device showing alternative positions of an inlet port;

[0010] Figures 1D and 1E are cross-sectional views of a microfluidic device at the upstream end of a fluid channel showing alternative locations for attaching a piezoelectric transducer;

[0011] Figures 1F and 1G are cross-sectional views of a microfluidic device at the downstream end of a fluid channel showing alternative locations for attaching a piezoelectric transducer;

[0012] Figure 2 shows the operation of the microfluidic device under single pressure node conditions;

[0013] Figure 3 shows the components of a cooling device for cooling a microfluidic device according to an embodiment of the present invention;

[0014] Figure 4 is a cross-sectional view showing the cooling device of Figure 3 partially surrounded by a lower housing structure according to an embodiment of the present invention;

[0015] Figure 5 is a cross-sectional view showing an upper housing structure that can be reversibly attached to a lower housing structure according to an embodiment of the present invention;

[0016] Figure 6 shows the coupling of the upper and lower housing structures to form a central air passage and two side air passages to allow air circulation therebetween;

[0017] Figure 7 is a cross-sectional view showing alternative arrangements of the microfluidic device and heat-generating components in the upper housing structure shown in Figure 6;

[0018] Figure 8 is a cross-sectional view showing another upper housing structure that can be reversibly attached to a lower housing structure according to an embodiment of the present invention;

[0019] Figure 9 is a cross-sectional view showing the reversible coupling of an upper housing structure and a lower housing structure to form a central air passage and side air passages for circulating air therebetween according to another embodiment of the present invention;

[0020] FIG. 10 is a cross-sectional view showing an alternative arrangement of a microfluidic device and a heat-generating component in the upper housing structure shown in FIG. 9; and

[0021] FIG. 11 shows another cooling device for cooling a microfluidic device according to an embodiment of the present invention.

[0022] For clarity and brevity, like elements and components have the same name and numbering throughout the figures which are not necessarily drawn to scale. DETAILED DESCRIPTION OF THE INVENTION

[0023] In the above summary and detailed description, and in the following claims, and in the accompanying drawings, specific features of the invention (including method steps) are referenced. It is to be understood that the disclosure of the invention herein includes all possible combinations of such specific features. For example, if a particular feature is disclosed in the context of a particular aspect or embodiment of the invention, or a particular claim, that feature can, to the extent possible, be combined with other particular aspects and embodiments of the invention and / or used generally in the invention in that context.

[0024] The term "at least" followed by a number is used herein to indicate the start of a range beginning with that number, and may be a range with an upper limit or without an upper limit depending on the defined variable. For example, "at least 1" means 1 or greater than 1. The fact that a number follows the term "at most" is used herein to indicate the end of a range ending with that number, and may be a range having 1 or 0 as its lower limit or without a lower limit depending on the defined variable. For example, "at most 4" means 4 or less than 4, and "at most 40%" means 40% or less than 40%. In this specification, when a range is described as "from a first number to a second number" or "the first number to the second number", it means a range with the first number as the lower limit and the second number as the upper limit. For example, "from 25 nm to 100 nm" means a range with a lower limit of 25 nm and an upper limit of 100 nm.

[0025] The term "acoustic contrast" may be used herein to mean the relative difference in the density / compressibility ratio between an object and a host medium with respect to the ability to manipulate its position by acoustic radiation pressure. An object having a higher density / compressibility ratio than the host medium can have a positive acoustic contrast, which tends to move the object towards a pressure node. Conversely, an object having a lower density / compressibility ratio than the host medium can have a negative acoustic contrast that tends to move the object towards a pressure antinode.

[0026] The term "biological entity" may be used herein to include cells, bacteria, viruses, molecules, particles including RNA and DNA, cell clusters, bacterial clusters, molecular clusters, and particle clusters.

[0027] The term "biological sample" can be used herein to include blood, body fluids, tissues extracted from any part of the body, bone marrow, hair, nails, bone, teeth, liquids and solids from body excretions, or surface swabs from any part of the body. "Bulk liquid" or "fluid sample" or "liquid sample" or "sample solution" can include a biological sample in its original liquid form, a biological entity dissolved or dispersed in a buffer, or a biological sample dissociated from its original non-liquid form and dispersed in a buffer. A buffer is a liquid that can dissolve or disperse a biological entity without introducing contaminants or unwanted biological entities. Biological entities and biological samples can be obtained from humans or animals. Biological entities can also be obtained from plants and the environment, including air, water, and soil. A bulk liquid or fluid sample can contain various types of magnetic or optical labels, or one or more chemical reagents that can be added during various processes according to the present invention.

[0028] The term "sample flow rate" or "flow rate" can be used herein to represent the volume amount of a fluid sample flowing through a cross-section of a channel or a fluid portion or a fluid path per unit time.

[0029] The term "relative fraction" can be used herein to represent the ratio of a given amount of a biological entity or particle to all biological entities or particles present in a fluid sample.

[0030] Here, embodiments of the present invention applied to a microfluidic device for separating particles or biological entities based on physical size and acoustic contrast will be described with reference to FIGS. 1 to 2. FIG. 1A is a top view of a microfluidic device 100, which includes a main channel 102, a central inlet port 104 connected to the main channel 102 at its upstream end for introducing a first input fluid into the main channel 102, side inlet ports 106 for introducing a second input fluid into the main channel 102 near two sidewalls thereof, two side input channels 108 connecting the side inlet ports 106 to the main channel 102 at or near its upstream end, a central outlet port 110 connected to the main channel 102 at its downstream end for extracting a first output fluid, side outlet ports 112 for extracting a second output fluid flowing near two sidewalls of the main channel 102, and two side output channels 114 connecting the side outlet ports 112 to the main channel 102 at or near its downstream end. The microfluidic device 100 further includes one or more piezoelectric transducers 113 and 115 for generating acoustic radiation pressure for acoustic particle separation.

[0031] Continuing to refer to FIG. 1A, the main channel 102 can have a linear shape with a nominal width W between two sidewalls. A portion of the main channel 102 between the central inlet port 104 and the side input channels 108 may be narrower than the nominal width. Similarly, another portion of the main channel 102 between the central outlet port 110 and the side output channels 1114 may be narrower than the nominal width. The widths of the side input channels 108 and the side output channels 114 may be narrower than the nominal width of the main channel 102.

[0032] The two side input channels 108 are connected to the main channel 102 at or near its upstream end at two sidewalls thereof. Thus, the second input fluid flowing through the two side input channels 108 is introduced into the main channel 102 as two flows flowing near two sidewalls of the main flow channel 102. The first input fluid is introduced into the center of the main channel 102 and is constricted between two flows of the second input fluid at or near the upstream end of the main channel 102.

[0033] The two side output channels 114 connect to the main channel 102 at its two side walls at or near the downstream end. Thus, the fluid flowing near the two side walls at or near the downstream end of the main channel 102 is diverted by the two side output channels 114 to become the second output fluid and exits through the side outlet ports 112. The remaining fluid not diverted by the two side output channels 114 becomes the first output fluid and exits through the central outlet port 110.

[0034] FIG. 1B is a cross-sectional view of a portion of a microfluidic device 100 showing the central and side inlet ports 104 and 106 according to an embodiment of the present invention. The above-described features 102-114 of the microfluidic device 100 are recessed into the substrate 116 from its upper surface 118. A substrate lid or cover 120 is attached to the substrate 116 at its upper surface 118 and can cover the features 102-114 of the microfluidic device 100. The substrate lid or cover 120 includes two holes or openings 122 and 124 aligned with the central and side inlet ports 104 and 106, respectively. The first input fluid 126 and the second input fluid 128 may flow into the central and side inlet ports 104 and 106 through the openings 122 and 124 of the substrate lid or cover 120, respectively. The substrate cover 120 may further include two additional holes or openings (not shown) aligned with the central and side outlet ports 110 and 112, respectively, for extracting the first and second output fluids. The main channel 102 can have a nominal channel depth D measured from the upper surface 118.

[0035] Alternatively, the central and side inlet ports 104 and 106 can access through the bottom of the microfluidic device 100 as shown in the cross-sectional view of FIG. 1C. Similar to the embodiment shown in FIG. 1B, the channels 102, 108, 114 and ports 104, 106, 110, 112 of the microfluidic device 100 are recessed into the substrate 130 from its upper surface 132. Further, the central and side inlet ports 104 and 106 extend further to pierce the bottom surface 134 of the substrate 130 to receive the first and second input fluids 126 and 130. The central and side outlet ports 110 and 112 (not shown in FIG. 1C) may also extend further to pierce the bottom surface 134 of the substrate 130 to output the first and second output fluids. The substrate lid or cover 136 is attached to the substrate 130 at its upper surface 132 and can cover the channels 102, 108, 114 and ports 104, 106, 110, 112 of the microfluidic device 100.

[0036] FIGS. 1B and 1C show that a first input fluid 126, which can be a buffer fluid, is introduced into the central inlet port 104, and a second input fluid 128, which can contain particles or biological entities for acoustic separation, is introduced into the side inlet port 106. However, the first and second input fluids 126 and 128 may alternatively be introduced into the side and central inlet ports 106 and 104, respectively, depending on the operating mode of the microfluidic device 100. Further, the second input fluid 128 can contain large particles or biological entities 138 and small particles or biological entities 140 for separation by acoustic radiation pressure. Alternatively, the particles or biological entities 138 and 140 can have sufficiently different acoustic contrasts for acoustic separation.

[0037] Continuing to refer to FIGS. 1A - 1C, the substrate 116 / 130 can comprise any suitable material such as, but not limited to, glass, quartz, fused silica, metal, ceramic material, silicon, silicon carbide, aluminum nitride, titanium carbide, aluminum oxide, zirconium oxide, lithium niobate, magnesium oxide, or any combination thereof. The channels 102, 108, 114 and ports 104, 106, 110, 112 can be formed in the substrate by removing material from the substrate 116 / 130 by any suitable method such as, but not limited to, waterjet machining, machining, laser machining, wet etching, plasma etching, or any combination thereof. The substrate cover 120 / 136 can comprise any suitable material such as, but not limited to, glass, quartz, fused silica, metal, polymer material, ceramic material, silicon, silicon carbide, aluminum nitride, titanium carbide, aluminum oxide, zirconium oxide, lithium niobate, magnesium oxide, or any combination thereof. In one embodiment, the substrate 116 / 130 and the substrate cover 120 / 136 are made of the same material. The substrate cover 120 / 136 can be permanently or irreversibly attached to the substrate 116 / 130 by any suitable bonding method such as, but not limited to, adhesive bonding, fusion bonding, anodic bonding, or any combination thereof.

[0038] Alternatively, the substrate 116 / 130 can comprise a moldable rubber or polymer material such as, but not limited to, polycarbonate or PDMS, that can be molded to form the channels 102, 108, 114 and ports 104, 106, 110, 112 of the microfluidic device 100. If the substrate 116 / 130 is made of a soft or rubbery material such as PDMS or silicone that lacks structural integrity and may even sag under its own weight, a substrate cover 120 / 136 made of a relatively hard material can be used to support the substrate 116 / 130.

[0039] Figure 1D shows a cross-section of the microfluidic device 100 near the upstream end of the main channel 102 according to an embodiment of the present invention. In the figure, reference numerals 113, 116, 120, 130 and 136 - 140 denote the same components as those shown in FIGS. 1A - 1C. Referring now to FIG. 1D, a first piezoelectric transducer 113 in the form of a lead zirconate titanate (PZT) transducer is attached to the outer or bottom surface of the substrate 116 / 130. Alternatively, the first piezoelectric transducer 113 may comprise any suitable piezoelectric material such as, but not limited to, potassium niobate, sodium niobate, sodium tungstate, zinc oxide, bismuth ferrite, bismuth titanate, polyvinylidene fluoride, polyvinylidene chloride, polyimide, or any combination thereof. The first piezoelectric transducer 113 may be permanently or irreversibly attached to the bottom surface of the substrate 116 / 130 by soldering or an adhesive such as, but not limited to, epoxy, cyanoacrylate, methacrylate, or any combination thereof.

[0040] The first piezoelectric transducer 113 can receive power in the form of an oscillating voltage having a frequency in the range of 100 kHz to 100 MHz and generate a sound pressure wave in the main channel 102 between the two side walls when liquid is present therein. If the channel width W is an integer multiple of half the wavelength of the sound pressure wave, an acoustic standing wave can be formed in the main channel 102, which can depend on the excitation frequency of the power applied to the first piezoelectric transducer 113 as well as the compressibility and density of the liquid in the main channel 102. FIG. 1D shows that an acoustic standing wave having a half wavelength of W is formed between the two side walls of the main channel 102, resulting in the formation of a single sound pressure node at the center of the main channel 102.

[0041] Alternatively, the first piezoelectric transducer 113 may be attached to the outer or top surface of the substrate cover 120 / 136 by soldering or an adhesive such as, but not limited to, epoxy, cyanoacrylate, methacrylate, or any combination thereof, as shown in FIG. 1E.

[0042] Figure 1F shows a cross-sectional view of the microfluidic device 100 near the downstream end of the main channel 102 according to an embodiment of the present invention. In the figure, reference numerals 115, 116, 120, 130, and 136-140 denote the same components as those shown in FIGS. 1A-1C. Referring now to FIG. 1F, a second piezoelectric transducer 115 in the form of a lead zirconate titanate (PZT) transducer is attached to the outer or bottom surface of the substrate 116 / 130. Alternatively, the second piezoelectric transducer 115 may comprise any suitable piezoelectric material described above for the first piezoelectric transducer 113. The second piezoelectric transducer 115 may be permanently or irreversibly attached to the bottom surface of the substrate 116 / 130 by soldering or an adhesive as described above.

[0043] Similar to the first piezoelectric transducer 113, the second piezoelectric transducer 115 can receive power in the form of an oscillating voltage having a frequency in the range of 100 kHz to 100 MHz and generate a sound pressure wave in the main channel 102 between the two side walls when liquid is present. FIG. 1F shows that an acoustic standing wave having a half wavelength of W is formed between the two side walls of the main channel 102, resulting in the formation of a single sound pressure node at the center of the main channel 102.

[0044] Alternatively, the second piezoelectric transducer 115 may be attached to the outer or top surface of the substrate cover 120 / 136 by soldering or an adhesive such as, but not limited to, epoxy, cyanoacrylate, methacrylate, or any combination thereof, as shown in FIG. 1G.

[0045] Both the first and second piezoelectric transducers 113 and 115 may be attached to the bottom surface of the substrate 116 / 130 or the top surface of the substrate cover 120 / 136. Alternatively, one of the piezoelectric transducers 113 and 115 may be attached to the bottom surface of the substrate 116 / 130 and the other may be attached to the top surface of the substrate cover 120 / 136.

[0046] Figures 1D and 1E further show particles or biological entities 138 and 140 from a second input fluid 128 flowing along two sidewalls of the main channel 108 near its upstream end when the second input fluid 128 is introduced into the main channel 102 through two side input channels 102. Acoustic radiation pressure can drive large particles or biological entities 138 towards a pressure node at the center of the main channel 102. As shown in Figures 1F and 1G, by the time particles or biological entities 138 and 140 reach the downstream end of the main channel 102, large particles or biological entities 138 have moved mostly towards the center of the main channel 102, and small particles or biological entities 140 remain mainly close to the sidewalls, thereby allowing small particles or biological entities 140 to be diverted from the main channel 102 through two side output channels 114.

[0047] Figure 1A shows a microfluidic device 100 including two piezoelectric transducers 113 and 115, although any number of piezoelectric transducers can be used, each covering at least a portion of the main channel 102. For example, two piezoelectric transducers 113, 115 can be integrated into one piezoelectric transducer.

[0048] Figures 1D - 1G show the formation of a single pressure node within the main channel 102. However, the microfluidic device 100 of the present invention can operate with multiple pressure nodes by adjusting the nominal width of the main channel 102 and / or the excitation frequency of the power applied to the piezoelectric transducers 113 and 115. In one embodiment, all piezoelectric transducers operate at the same frequency. In another embodiment, at least one of the piezoelectric transducers operates at a different frequency from the other piezoelectric transducers, such that a portion of the main channel 102 has a different number of pressure nodes than other portions. For example, without limitation, the first piezoelectric transducer 113 may operate at twice the frequency compared to the second piezoelectric transducer 115, such that the upstream and downstream portions of the main channel 102 have two and one pressure nodes, respectively.

[0049] Here, with reference to FIG. 2, the operation of the microfluidic device 100 under the conditions of a single pressure node will be described. In the figure, reference numerals 102 to 114 denote the same components as those shown in FIG. 1A, and the piezoelectric transducer is omitted for clarity. Referring to FIG. 2 here, a fluid sample containing the first type of particles or biological entities 142 and the second type of particles or biological entities 144 is introduced into the side inlet port 106, while the buffer solution 146 is introduced into the central inlet port 104. The first and second types of particles or biological entities 142 and 144 may have sufficiently different physical sizes and / or acoustic contrasts to enable them to be separated by acoustic radiation pressure. For example, the first type of particles or biological entities 142 can have a larger physical size and / or a higher acoustic contrast such as a higher mass density and / or a lower compressibility, whereby the acoustic radiation pressure can push the first type of particles or biological entities 142 towards the pressure node located along the center of the main channel 102.

[0050] A fluid sample containing first and second types of particles or biological entities 142 and 144 is introduced into the main channel 102 via two lateral input channels 108 as two flows that flow near the sidewalls. Two flows of the fluid sample in the main channel 102, which can behave like laminar flows, are separated by a buffer fluid 146 that can act as a sheath fluid to retard or prevent the movement of the second type of particles or biological entities 144 towards a pressure node along the center of the main channel 102. As the fluid sample progresses downstream within the main channel 102, the acoustic radiation pressure pushes the first type of particles or biological entities 142 towards the pressure node along the center of the main channel 102, while the second type of particles or biological entities 144 remain mostly close to the sidewalls. At the downstream end of the main channel 102, the central first type of particles or biological entities 142 exit the microfluidic device 100 through the central outlet port 110, and the second type of particles or biological entities 144 near the sidewalls are diverted to the side outlet port 112 through the side output channel 114.

[0051] The acoustic separation process shown in FIG. 2 can be sensitive to the power (e.g., voltage or current) applied to the piezoelectric transducer, as well as the flow rate of the fluid sample containing the first and second types of particles or biological entities 142 and 144. Too high a power or too low a flow rate may cause some of the second type of particles or biological entities 144 to move to the central outlet port 110. Using a buffer fluid with too low a density and / or viscosity may also cause some of the second type of particles or biological entities 144 to move to the central outlet port 110. Conversely, too low a power or too high a flow rate may cause some of the first type of particles or biological entities 142 to be diverted to the side outlet port 112 through the side output channel 114. Using a buffer fluid with too high a density and / or viscosity may also cause some of the first type of particles or biological entities 142 to be diverted to the side outlet port 112.

[0052] Figure 3 shows the components of a cooling device 150 according to an embodiment of the present invention. The small cooling device 150 can be used to cool any small electronic device, particularly a microfluidic device 100 incorporating one or more piezoelectric transducers 113 and 115 that generate heat during operation. The cooling device 150 includes a thermoelectric heat pump 152 that can operate via the Peltier effect, a first heat exchanger 154, a first cooling fan 156, a second heat exchanger 158, and a second cooling fan 160. The thermoelectric heat pump 152 may have a plate shape having a cooling surface 162 and a high-temperature surface 164 formed on an opposing plate surface when a voltage is applied via a set of wires 166, whereby heat flows from the cooling surface 162 to the high-temperature surface 164. The first heat exchanger 154 may include a heat conduction plate 168 having a plurality of convection fins 170 protruding at least from its surface. Alternatively, the convection fins 170 may be replaced with convection pillars or other convection structures that cool the hot air passing therethrough. The heat conduction plate 168 may function as a heat sink. The surface 172 of the first heat exchanger 154 on the opposite side of the surface having the fins 170 may be in contact with the low-temperature surface 162 of the thermoelectric heat pump 152. Similarly, the second heat exchanger 158 may include a heat conduction plate 174 having a plurality of convection fins 176 protruding at least from its surface. The convection fins 176 may be replaced with convection pillars or other convection structures that can transfer heat to the air passing therethrough. The heat conduction plate 174 of the second heat exchanger 158 may function as a heat sink. The surface 178 of the second heat exchanger 158 on the opposite side of the surface having the fins 176 may be in contact with the high-temperature surface 164 of the thermoelectric heat pump 152. The first and second heat exchangers 154 and 158 may each be made of a metal or alloy having good thermal conductivity, such as, but not limited to, copper, silver, aluminum, or any combination thereof. The first cooling fan 156, which can include a plurality of fan blades 180, is disposed close to the fins 170 of the first heat exchanger 154 and may cool the hot air by pushing or pulling the hot air through the convection fins 170.The second cooling fan 160, which can include a plurality of fan blades 182, is disposed proximate to the fins 176 of the second heat exchanger 158 and can cool by pushing or pulling cooling air through the hot fins 176.

[0053] FIG. 4 shows that the cooling device 150 may be partially surrounded by and / or attached to a lower housing structure 184 having a lower shell 186 that houses the first cooling fan 156 and the first heat exchanger 154. The lower housing structure 184 has a lower central cavity 188 that opens at the top of the lower housing structure 184 and is located above the first cooling fan 156 to expose the first cooling fan 156 from the top of the lower housing structure 184. The lower central cavity 188 is formed adjacent to the first cooling fan 156 on the opposite side of the first heat exchanger 154. The lower housing structure 184 further includes two lower side cavities 190 and 192 that expose two sides of the first heat exchanger 154 at the top of the lower housing structure 184. The lower shell 186 may further partially or completely house the thermoelectric heat pump 152. When the fan blades 180 of the first cooling fan 156 rotate, hot air is drawn through the fins 170 of the first heat exchanger 154 from the lower side cavities 190 and 192, as indicated by the air flow 194, and discharged into the lower central cavity 188 as cold air. By reversing the direction of rotation of the fan blades 180, the direction of the air flow 194 can be reversed, so that hot air enters the first heat exchanger 154 through the lower central cavity 188 and exits into the lower side cavities 190 and 192 as cold air instead. When the fan blades 182 of the second cooling fan 160 rotate, cold air is drawn through the fins 176 of the second heat exchanger 158 from its side and discharged as hot air to the second cooling fan 160 disposed adjacent to the fins 176 of the second heat exchanger 158, as indicated by the air flow 196. By reversing the direction of rotation of the fan blades 182, the direction of the air flow 196 can be reversed, so that cold air collides with the fins 176 of the second heat exchanger 158 through the second cooling fan 160 and exits the second heat exchanger 158 as hot air passing through its side.

[0054] Continuing to refer to FIG. 4, in one embodiment, the first cooling fan 156 is in contact with the fins 170 of the first heat exchanger 154. In another embodiment, the second cooling fan 160 is in contact with the fins 176 of the second heat exchanger 158. FIG. 4 shows the first heat exchanger 154 in contact with the low-temperature surface 162 of the thermoelectric heat pump 152, but an additional layer of heat conductor or structure may be inserted between the first heat exchanger 154 and the thermoelectric heat pump 152. Similarly, an additional layer of heat conductor or structure may be inserted between the second heat exchanger 158 and the thermoelectric heat pump 152.

[0055] FIG. 5 shows an upper housing structure 198 having an upper shell 200 that encloses therein a microfluidic device 202 in the form of an elongated strip of chips and a heat-generating component 204 that can benefit from active cooling during operation. For example, but not limited to, the microfluidic device 202 may be similar to the microfluidic device 100 shown in FIGS. 1A-1G. The microfluidic device 202 in the form of a chip may be supported at its two ends and may have a length of 30 to 150 mm. The heat-generating component 204 may be, but is not limited to, a vibration source that generates or dissipates heat during operation, such as a piezoelectric transducer. Alternatively, the heat-generating component 204 may be any active device or component that generates heat during operation, including but not limited to an optical detector, a central processing unit (CPU), a laser, an electronic controller, an actuator, and a voice coil. In FIG. 5, the heat-generating component 204 is shown as a single component, but the component 204 can represent several individual components or a cluster of components attached to the microfluidic device 202. The microfluidic device 202 and the heat-generating component 204 may be replaced by any heat-generating electronic device that requires active cooling during operation.

[0056] The upper housing structure 198 shown in FIG. 5 has an upper central cavity 206 that exposes the microfluidic device 202 and the heating component 204 to the atmosphere, and two upper side cavities 208 and 210 that expose the two ends of the microfluidic device 202 to the atmosphere along its length. The upper housing structure 198 can further include an external electrical contact (not shown) for connection to an external power source and electrical wires that connect the electrical contact to the microfluidic device 202 and / or the heating component 204. The upper housing structure 198 can further include an external port (not shown) and fluid tubes (not shown) that connect the port to the microfluidic device 202 for introducing a fluid sample into the microfluidic device 202 and extracting the processed fluid sample from the same device 202.

[0057] The upper housing structure 198 may be designed to be reversibly attached to the lower housing structure 184, as shown in FIGS. 5 and 6. The upper housing structure 198 may be attached to the lower housing structure 184 by any reversible latching mechanism (not shown), such as a magnetic latch or a mechanical clip, without limitation. When the two housing structures 184 and 198 are coupled as shown in FIG. 6, the upper central cavity 206 aligns with the lower central cavity 188 to form a central air passage between the first cooling fan 156 and the assembly of the microfluidic device 202 and the heat-generating component 204, and the two upper side cavities 208 and 210 align with the two lower side cavities 190 and 192, respectively, to form two side air passages between the two sides of the first heat exchanger 154 and the two ends of the microfluidic device 202. The coupling of the upper housing structure 198 and the lower housing structure 184 may seal the microfluidic device 202, the heat-generating component 204, the first cooling fan 156, and at least the convection fins 170 of the first heat exchanger 154 therein. The first cooling fan 156 extrudes cold air through the central air passage onto the surfaces of the heat-generating component 204 and the microfluidic device 202, cools them by convection, and then the air is heated and returns to the first heat exchanger 154 through the side air passage as shown by the air flow 194. The heated air is cooled again by convection when passing through the fins 170 of the first heat exchanger 154 and circulates back to the first cooling fan 156 as cold air. Thus, the heat generated by the heat-generating component 204 is transferred to the first heat exchanger 154 by convection with the air circulating between the central air passage and the two side air passages.

[0058] Each of the microfluidic device 202 and the heat-generating component 204 may be arranged such that the maximum surface faces the cold air flowing in from the first cooling fan 156 to maximize the cooling efficiency. In one embodiment, the heat-generating component 204 is arranged between the microfluidic device 202 and the first cooling fan 156, thereby enabling the heat-generating component 204 to be directly cooled by the incident air flow from the first cooling fan 156.

[0059] By reversing the rotational direction of the fan blade 180 of the first cooling fan 156, the circulating air flow 194 may be reversed so that the cold air emerging from the side of the first heat exchanger 154 flows through the side air passages formed by the upper and lower side cavities 208, 210, 190, and 192 towards the assembly of the microfluidic device 202 and the heat generating components 204. The cold air is heated by the assembly of the microfluidic device 202 and the heat generating components 204 via convection, returns to the first cooling fan 156 through the central air passage, and then returns to the first heat exchanger 154, where the heated air is cooled again via convection.

[0060] After passing through the first heat exchanger 154, the cold air surrounded by the upper and lower housing structures 198 and 184 may have a temperature lower than the ambient air outside the housing structures 198 and 184 during operation. Before entering the first heat exchanger 154, the hot air surrounded by the upper and lower housing structures 198 and 184 can have a temperature higher than the ambient air outside the housing structures 198 and 184 during operation.

[0061] Continuing to refer to FIG. 6, the heat generated by the assembly of the microfluidic device 202 and the heat generating components 204 is transferred to the first heat exchanger 154 by convection. Then, the thermoelectric heat pump 152 transfers the heat from the first heat exchanger 154 to the second heat exchanger 158, and the heat is finally dissipated to the surrounding air via convection through the convection fins 176.

[0062] Once set up, the assembly of the microfluidic device 202 and the heating component 204 can permanently reside within the upper housing structure 198. Thus, when replacing the microfluidic device 202 and the heating component 204, the removable upper housing structure 198 can be easily replaced with another one. The modular approach of the present invention has several other advantages. The coupling of the upper housing structure 198 and the lower housing structure 184 insulates the microfluidic device 202 and the heating component 204 from the surrounding air that can be heated by other devices or components. Further, the relatively small amount of air enclosed by the housing structures 198 and 184 eliminates or minimizes the problem of condensation caused by humidity.

[0063] FIG. 7 shows that the removable upper housing structure 198 can accommodate different assemblies of the microfluidic device 202 as well as the heating components 203 and 205. The heating components 203 and 205 are attached to two ends of the microfluidic device 202 and are exposed to the side air passages formed from the upper and lower side cavities 208, 210, 190, and 192. Thus, the cold air exiting from the sides of the first heat exchanger 154, when propelled by the first cooling fan 156, can flow through the two side air passages towards the heating components 203, 205 as indicated by the circulating air flow 195. The cold air is heated by the heating components 203 and 205 by convection, returns to the first cooling fan 156 through the central air passage, and then returns to the first heat exchanger 154, where the heated air is cooled again by convection.

[0064] Each of the heat generating components 203 and 205 may be, but is not limited to, a vibration source that generates or dissipates heat during operation, such as a piezoelectric transducer. Alternatively, each of the heat generating components 203 and 205 may be, but is not limited to, any active device or component that generates heat during operation, such as an optical detector, a central processing unit (CPU), a laser, an electronic controller, an actuator, and a voice coil. The microfluidic device 202 and the heat generating components 203 and 205 may be replaced by any heat generating electronic device that requires active cooling during operation.

[0065] The detachable upper housing structure 198 can be modified to accommodate different microfluidic devices and / or different heat-generating components. For example, FIG. 8 shows another detachable upper housing structure 212 having an upper shell 214 that contains internally two heat-generating devices 216 and 218 attached to the microfluidic device 202 at two different positions along the length of the microfluidic device 202. Similar to the upper housing structure 198 shown in FIG. 6, the upper housing structure 212 has two upper side cavities 220 and 222 that are respectively aligned with the two lower side cavities 190 and 192 of the lower housing structure 184, and when the two housing structures 212 and 184 are coupled, two side air passages are formed between the two ends of the microfluidic device 202 and the two sides of the first heat exchanger 154. The upper housing structure 212 further includes two upper central openings or cavities 224 and 226 that are respectively aligned with the two heat-generating components 216 and 218 at one end and the lower central cavity 188 at the other end, whereby the cold air from the first cooling fan is divided into two flows that concentrate on the two heat-generating components 216 and 218. Each of the heat-generating components 216 and 218 may be, without limitation, a vibration source that generates or dissipates heat during operation, such as a piezoelectric transducer. Alternatively, each of the heat-generating components 216 and 218 may be, without limitation, any active device or component that generates heat during operation, such as an optical detector, a central processing unit (CPU), a laser, an electronic controller, an actuator, and a voice coil. The microfluidic device 202 and the heat-generating components 216 and 218 may be replaced with any heat-generating electronic device that requires active cooling during operation.

[0066] During operation, the first cooling fan 156 pushes cold air through the lower central cavity 188 and the two upper central cavities 224 and 226 onto the surfaces of the heat-generating components 216 and 218 and the microfluidic device 202, cooling the components 216 and 218 and the device 202 by convection. Thereafter, the air is heated and returns to the first heat exchanger 154 through the two side air passages, as indicated by the air flow 194. The heated air is cooled again by convection as it passes through the fins 170 of the first heat exchanger 154 and circulates back to the first cooling fan 156 as cold air. Each of the microfluidic device 202 and the heat-generating components 216 and 218 may be arranged such that the maximum surface faces the cold air flowing in from the first cooling fan 156 to maximize the cooling efficiency. In one embodiment, the heat-generating components 216 and 218 are arranged between the microfluidic device 202 and the first cooling fan 156, thereby enabling the heat-generating components 216 and 218 to be directly cooled by the incident air flow from the first cooling fan 156.

[0067] FIG. 9 is a cross-sectional view showing an upper housing structure 228 that can be reversibly attached to a lower housing structure 230 according to another embodiment of the present invention. The cooling device 150 may be partially surrounded by and / or attached to a lower housing structure 230 having a lower shell 232 that houses a first cooling fan 156 and a first heat exchanger 154. The lower housing structure 230 is formed adjacent to the first cooling fan 156 on the opposite side of the first heat exchanger 154 and has a lower central cavity 234 that opens to the upper part of the lower housing structure 230, thereby exposing the first cooling fan 156 from the upper part of the lower housing structure 230. The lower housing structure 230 further includes a lower side cavity 236 formed adjacent to the side surface of the first heat exchanger 154. The lower side cavity 236 opens to the upper part of the lower housing structure 230, and thus exposes the side surface of the first heat exchanger 154 from the upper part of the lower housing structure 230. The lower shell 232 may further partially or completely house the thermoelectric heat pump 152. When the fan blades 180 of the first cooling fan 156 rotate, hot air can be drawn from the lower side cavity 236 through the fins 170 of the first heat exchanger 154 by an air flow 238 and discharged as cold air into the lower central cavity 234.

[0068] Continuing to refer to FIG. 9, the upper housing structure 228 has an upper shell 240 that encloses internally a microfluidic device 202 in the form of an elongated strip of chips and heat-generating components 204 that can benefit from active cooling during operation. For example, but not limited to, the microfluidic device 202 may be similar to the microfluidic device 100 shown in FIGS. 1A-1G. The microfluidic device 202 in the form of chips may be supported at its two ends and may have a length of 30 to 150 mm. The heat-generating component 204 may be, but is not limited to, a vibration source that generates or dissipates heat during operation, such as a piezoelectric transducer. Alternatively, the heat-generating component 204 may be any active device or component that generates heat during operation, such as, but not limited to, an optical detector, a central processing unit (CPU), a laser, an electronic controller, an actuator, and a voice coil. The microfluidic device 202 and the heat-generating component 204 can be replaced with any heat-generating electronic device that can benefit from active cooling during operation.

[0069] The upper housing structure 228 is formed adjacent to the heat-generating component 204 and has an upper central cavity 242 that opens at the bottom of the upper housing structure 228, thereby exposing the microfluidic device 202 and the heat-generating component 204 from the bottom of the upper housing structure 228. The upper housing structure 228 further includes an upper side cavity 244 that exposes one end of the microfluidic device 202 along its length to the bottom of the upper housing structure 228. The upper housing structure 228 can further include an external electrical contact (not shown) for connection to an external power source and an electrical wire that connects the electrical contact to the microfluidic device 202 and / or the heat-generating component 204. The upper housing structure 228 can further include an external port (not shown) and a fluid tube (not shown) that connects the port to the microfluidic device 202 for introducing a fluid sample into the microfluidic device 202 and extracting the processed fluid sample from the same device 202.

[0070] The upper housing structure 228 may be designed to be reversibly attached to the lower housing structure 230. The upper housing structure 228 may be attached to the lower housing structure 230 by any reversible latch mechanism, such as, but not limited to, a magnetic latch or a mechanical clip. As shown in FIG. 9, when the two housing structures 228 and 230 are coupled, the upper central cavity 242 aligns with the lower central cavity 234 to form a central air passage between the first cooling fan 156 and the assembly of the microfluidic device 202 and the heat generating component 204, and the upper side cavity 244 aligns with the lower side cavity 236 to form a side air passage between one side of the first heat exchanger 154 and one end of the microfluidic device 202. The coupling of the upper housing structure 228 and the lower housing structure 230 may seal the microfluidic device 202, the heat generating component 204, the first cooling fan 156, and at least the convection fins 170 of the first heat exchanger 154 therein. The first cooling fan 156 extrudes cold air through the central air passage onto the surfaces of the heat generating component 204 and the microfluidic device 202, cools them by convection, and then the air is heated and returns to the first heat exchanger 154 through the side air passage as shown by the air flow 238. The heated air is cooled again by convection when passing through the fins 170 of the first heat exchanger 154 and circulates back to the first cooling fan 156 as cold air. Thus, the heat generated by the heat generating component 204 is transferred to the first heat exchanger 154 by convection with the air circulating between the central air passage and the side air passage.

[0071] FIG. 10 shows that the heat-generating component 205 can be attached to one end of the microfluidic device 202 within the upper housing structure 228. In such a configuration, the airflow 238 shown in FIG. 9, where the cold air exiting from one side of the first heat exchanger 154 is propelled by the first cooling fan 156, can be reversed so that it flows towards the heat-generating component 205 through the side air passages formed from the upper and lower side cavities 236 and 244, as indicated by the circulating airflow 246. The cold air is heated by the heat-generating component 205 via convection, returns to the first cooling fan 156 through the central air passage, and then returns to the first heat exchanger 154, where the heated air is cooled again via convection.

[0072] The cooling device 150 shown in FIGS. 3-10 may further include an additional layer of heat conductor or structure between the second heat exchanger 158 and the thermoelectric heat pump 152. FIG. 11 shows a cooling device 248 attached to the lower housing structure 184. The cooling device 248 differs from the cooling device 150 of FIGS. 3-10 in that a heat conduction plate 250 contacts the hot surface 164 of the thermoelectric heat pump 152, and an electrically conductive pipe 252 is disposed between the heat conduction plate 250 and the heat conduction plate 174 of the second heat exchanger 158. The length of the electrically conductive pipe 252 may contact the heat conduction plate 250, and another length of the electrically conductive pipe 252 may contact the heat conduction plate 174. The electrically conductive pipe 252 may contain a fluid circulating therein and transfer heat between the heat conduction plate 250 and the second heat exchanger 158.

[0073] Although the present invention has been shown and described with reference to specific preferred embodiments, it should be understood that those skilled in the art will undoubtedly conceive of certain changes and modifications that fall within the true spirit and scope of the present invention. For example, the microfluidic device and the heat-generating component attached thereto may be replaced with other small electronic devices that require active cooling during operation. Therefore, the scope of the present invention should be determined by the appended claims and their legal equivalents, rather than by the given examples.

Claims

**Claim 1** A microfluidic system for separating biological entities, comprising: A cooling device including a thermoelectric heat pump, a first fan, and a first heat exchanger disposed between the first fan and the thermoelectric heat pump; A first housing structure having a first shell that houses the first fan and the first heat exchanger, the first housing structure having first and second cavities that respectively expose two sides of the first heat exchanger, and a third cavity formed adjacent to the first fan on the opposite side of the first heat exchanger; A microfluidic device and one or more piezoelectric transducers attached thereto; and A second housing structure reversibly attached to the first housing structure and having a second shell that encloses the microfluidic device and one or more piezoelectric transducers therein, the second housing structure including fourth and fifth cavities that respectively expose two ends of the microfluidic device and a sixth cavity; When the first and second housing structures are coupled, the first and second cavities are respectively aligned with the fourth and fifth cavities to form first and second air passages between two sides of the first heat exchanger and two ends of the microfluidic device, and the third and sixth cavities are aligned to form a third air passage between the first fan and one or more piezoelectric transducers, thereby enabling air to circulate between the third air passage and the first and second air passages. A microfluidic system. **Claim 2** The microfluidic system according to claim 1, wherein the first heat exchanger includes a plurality of convection fins protruding from a plate of a heat conductor. **Claim 3** The microfluidic system according to claim 1, wherein the microfluidic device and one or more piezoelectric transducers attached thereto are sealed when the first and second housing structures are coupled. **Claim 4** The microfluidic system according to claim 1, wherein the microfluidic device is in the form of an elongated strip of a chip and is supported at its two ends in the second housing structure. **Claim 5** The microfluidic system according to claim 1, wherein one or more piezoelectric transducers are directly cooled by incident air from the first fan. **Claim 6** The heat generated by the one or more piezoelectric transducers is transmitted to the first heat exchanger by convection of air circulating between the third air passage and the first and second air passages, the microfluidic system according to claim 1.

7. The microfluidic device includes a substrate having trenches formed therein and a lid covering the trenches, and one or more piezoelectric transducers are attached to the lid on the opposite side of the substrate, the microfluidic system according to claim 1.

8. The thermoelectric heat pump is a Peltier element, the microfluidic system according to claim 1.

9. The cooling device further includes a second fan and a second heat exchanger disposed between the second fan and the thermoelectric heat pump, the microfluidic system according to claim 1.

10. The thermoelectric heat pump transfers heat from the first heat exchanger to the second heat exchanger, the microfluidic system according to claim 9.

11. A microfluidic system for separating biological entities: A cooling device including a thermoelectric heat pump, a first fan, and a first heat exchanger disposed between the first fan and the thermoelectric heat pump; A first housing structure having a first shell that houses the first fan and the first heat exchanger, the first housing structure having a first cavity that exposes a side surface of the first heat exchanger and a second cavity formed adjacent to the first fan on the opposite side of the first heat exchanger; A microfluidic device and one or more piezoelectric transducers attached thereto; and A second housing structure reversibly attached to the first housing structure and having a second shell that surrounds the microfluidic device and the one or more piezoelectric transducers therein, the second housing structure including a third cavity and a fourth cavity that expose ends of the microfluidic device, When the first and second housing structures are coupled, the first and third cavities are aligned to form a first air passage between the side surface of the first heat exchanger and the end of the microfluidic device, and the second and fourth cavities are aligned to form a second air passage between the first fan and the one or more piezoelectric transducers, thereby enabling air to circulate between the first and second air passages, the microfluidic system.

12. The first heat exchanger includes a plurality of convection fins protruding from the plates of the heat conductor, the microfluidic system according to claim 11.

13. The microfluidic device and one or more piezoelectric transformers attached thereto are sealed when the first and second housing structures are connected, the microfluidic system according to claim 11.

14. The microfluidic device is in the form of an elongated strip of a chip and is supported at its two ends in the second housing structure, the microfluidic system according to claim 11.

15. One or more piezoelectric transformers are directly cooled by the incident air from the first fan, the microfluidic system according to claim 11.

16. The heat generated by one or more piezoelectric transformers is transferred to the first heat exchanger by the convection of the air circulating between the first and second air passages, the microfluidic system according to claim 11.

17. The microfluidic device includes a substrate with trenches formed therein and a lid covering the trenches, and one or more piezoelectric transformers are attached to the lid on the opposite side of the substrate, the microfluidic system according to claim 11.

18. The thermoelectric heat pump is a Peltier element, the microfluidic system according to claim 11.

19. The cooling device further includes a second fan and a second heat exchanger disposed between the second fan and the thermoelectric heat pump, the microfluidic system according to claim 11.

20. The thermoelectric heat pump transfers heat from the first heat exchanger to the second heat exchanger, the microfluidic system according to claim 19.

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