US20230032890A1 - Microfluidic chip - Google Patents
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- US20230032890A1 US20230032890A1 US17/936,523 US202217936523A US2023032890A1 US 20230032890 A1 US20230032890 A1 US 20230032890A1 US 202217936523 A US202217936523 A US 202217936523A US 2023032890 A1 US2023032890 A1 US 2023032890A1
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Abstract
A microfluidic chip orients and isolates components in a sample fluid mixture by two step focusing, where sheath fluids compress the sample fluid mixture in a sample input channel in one direction, such that the sample fluid mixture becomes a narrower stream bounded by the sheath fluids, and by having the sheath fluids compress the sample fluid mixture in a second direction further downstream, such that the components are compressed and oriented in a selected direction to pass through an interrogation chamber in single file formation for identification and separation by various methods. The isolation mechanism utilizes external, stacked piezoelectric actuator assemblies disposed on a microfluidic chip holder, or piezoelectric actuator assemblies on-chip, so that the actuator assemblies are triggered by an electronic signal to actuate jet chambers on either side of the sample input channel, to jet selected components in the sample input channel into one of the output channels.
Description
- The present application is a continuation and claims benefit of U.S. patent application Ser. No. 17/403,642, filed on Aug. 16, 2021, which is a continuation and claims benefit of U.S. patent application Ser. No. 16/597,235, filed on Oct. 9, 2019, now U.S. Pat. No. 11,187,224, which is a continuation and claims benefit of U.S. patent application Ser. No. 14/579,441, filed on Dec. 22, 2014, now U.S. Pat. No. 10,488,320, which is a continuation-in-part and claims benefit of U.S. patent application Ser. No. 13/943,322, filed on Jul. 16, 2013, now U.S. Pat. No. 8,961,904, the specifications of which are incorporated herein in their entireties by reference.
- The present invention relates to a microfluidic chip design which is used to isolate particles or cellular materials into various components and fractions, using laminar flows.
- The present invention relates to a microfluidic chip design which is used to isolate particles or cellular materials into various components and fractions, using laminar flows.
- In the separation of various particles or cellular materials—for example, the separation of sperm into viable and motile sperm from non-viable or non-motile sperm, or separation by gender—the process is often a time-consuming task, with severe volume restrictions. Thus, current separation techniques cannot, for example, produce the desired yield, or process volumes of cellular materials in a timely fashion.
- Thus, there is needed a separation technique and apparatus which is continuous, has high throughput, provides time saving, and which causes negligible or minimal damage to the various components of the separation. In addition, such an apparatus and method should have further applicability to biological and medical areas, not just in sperm sorting, but in the separation of blood and other cellular materials, including viral, cell organelle, globular structures, colloidal suspensions, and other biological materials.
- The present invention relates to a microfluidic chip system, which includes a microfluidic chip loaded on a microfluidic chip cassette which is mounted on a microfluidic chip holder.
- In one embodiment, the microfluidic chip includes a plurality of layers in which are disposed a plurality of channels including: a sample input channel into which a sample fluid mixture of components to be isolated is inputted; a first plurality of sheath fluid channels into which sheath fluids are inputted, the first plurality of sheath fluid channels which intersect the sample input channel at a first intersection, such that the sheath fluids compress the sample fluid mixture on at least two sides, such that the sample fluid mixture becomes a relatively smaller, narrower stream, bounded by the sheath fluids, while maintaining laminar flow in the sample input channel; a second plurality of sheath fluid channels, substantially of the same dimensions as the first plurality of sheath fluid channels, into which sheath fluids are inputted, the second plurality of sheath fluid channels which intersect the sample input channel at a second intersection downstream from the first intersection, in a second direction substantially 90 degrees above and below the sample input channel, such that the sheath fluids from the second plurality of sheath fluid channels compress the sample fluid mixture, such that the components in the sample fluid mixture are compressed and oriented in a predetermined direction, while still maintaining laminar flow in the sample input channel; and a plurality of output channels stemming from the sample input channel, the plurality of output channels which removes the components and the sheath fluids from the microfluidic chip.
- In one embodiment, the microfluidic chip includes an interrogation apparatus which interrogates and identifies said components in said sample fluid mixture in said sample input channel, in an interrogation chamber disposed downstream from said second intersection.
- In one embodiment, the microfluidic chip includes an isolating mechanism which isolates selected of said components in said sample fluid mixture downstream from said interrogation chamber, by displacing a trajectory of a stream of said sample fluid mixture in said sample input channel, and pushing said selected components in said displaced stream of sample fluid mixture into one of said plurality of output channels which lead from said interrogation chamber.
- In one embodiment, the microfluidic chip further includes at least one jet chamber containing sheath fluids introduced into said jet chamber by at least one air vent; and at least one jet channel which is connected to said at least one jet chamber, said at least one jet channel which enters said sample input channel to said interrogation chamber.
- In one embodiment, the isolating mechanism includes at least one piezoelectric actuator assembly disposed on at least one side of said sample input channel.
- In one embodiment, the piezoelectric actuator assembly is an external, stacked piezoelectric actuator assembly.
- In one embodiment, the microfluidic chip further includes a diaphragm which covers each said jet chamber; and wherein said external, stacked piezoelectric actuator assembly aligns with and displaces said diaphragm, to drive said sheath fluids in said jet chamber into said sample input channel, to displace said trajectory of said stream of said sample fluid mixture in said sample input channel into one of said plurality of output channels.
- In one embodiment, the external, stacked piezoelectric actuator assembly is disposed in a microfluidic chip holder.
- In one embodiment, the microfluidic chip further includes an electronic circuit connected to the piezoelectric actuator assembly, the electronic circuit which amplifies an electronic signal generated by a resistance force from the piezoelectric actuator being in contact with the diaphragm.
- In one embodiment, an electric signal from the piezoelectric film shows how much strain is generated by the external, stacked piezoelectric actuator assembly.
- In one embodiment, an indicator of contact is turned on automatically when contact between the piezoelectric actuator and the diaphragm is made.
- In one embodiment, when sensing of the contact is made, the electronic signal exceeds a set threshold, and the piezoelectric actuator assembly compresses the jet chamber to jet sheath fluids from the jet chamber into the sample fluid channel.
- In one embodiment, the indicator of contact includes a light, a sound, a haptic, or any combination thereof.
- In one embodiment, the piezoelectric actuator assembly includes a flexible diaphragm which covers said jet chamber; and a piezoelectric material bonded on a top surface of said diaphragm by an adhering mechanism.
- In one embodiment, when voltage is applied across electrodes of the piezoelectric actuator assembly, the flexible diaphragm bends into the jet chamber and squeezes the sheath fluids from the jet chamber into the sample input channel to deflect the selected components into one of the plurality of output channels.
- In one embodiment, the jet channel is tapered when it connects to the sample input channel.
- In one embodiment, the microfluidic chip further includes a plurality of outputs disposed at ends of said plurality of output channels.
- In one embodiment, the plurality of output channels increase in dimension from the sample input channel.
- In one embodiment, the microfluidic chip further includes a plurality of notches disposed at a bottom edge of the microfluidic chip to isolate the plurality of outputs.
- In one embodiment, the sample input channel and the plurality of sheath channels are disposed in one or more planes of the microfluidic chip.
- In one embodiment, the sample input channel and the plurality of sheath channels are disposed in one or more structural layers, or in-between structural layers of the microfluidic chip.
- In one embodiment, at least one of the plurality of sheath channels is disposed in a different plane than a plane in which the sample input channel is disposed.
- In one embodiment, at least one of the plurality of sheath channels is disposed in a different structural layer than a structural layer in which the sample input channel is disposed.
- In one embodiment, the sample input channel tapers at an entry point into the first intersection with said plurality of sheath channels.
- In one embodiment, the sample input channel tapers into said interrogation chamber.
- In one embodiment, the plurality of sheath fluid channels taper at entry points into the sample input channel at least one of the first intersection or the second intersection.
- In one embodiment, the interrogation chamber includes an opening cut through the structural layers in the microfluidic chip; and a top window is configured to receive a first covering in an opening in at least one layer of the structural layers; and a bottom window is configured to receive a second covering in an opening in at least one layer of the structural layers.
- In one embodiment, the interrogation chamber includes an opening cut through the planes in the microfluidic chip; and a top window is configured to receive a first covering in an opening in at least one plane of the planes of the microfluidic chip; and a bottom window is configured to receive a second covering in an opening in at least one plane of the planes of the microfluidic chip.
- In one embodiment, the interrogation apparatus includes a light source configured to emit a beam through the first covering, to illuminate and excite the components in said sample fluid mixture; and wherein emitted light induced by the beam passes through said second covering and is received by an objective lens.
- In one embodiment, the interrogation apparatus includes a light source configured to emit a beam through structural layers of the microfluidic chip, to illuminate and excite the components in the sample fluid mixture; and wherein emitted light induced by the beam is received by an objective lens.
- In one embodiment, the interrogation apparatus includes a light source configured to emit a beam through the planes of the microfluidic chip, to illuminate and excite said components in said sample fluid mixture; and wherein emitted light induced by said beam is received by an objective lens.
- In one embodiment, the emitted light received by the objective lens is converted into an electronic signal which triggers said piezoelectric actuator assembly.
- In one embodiment, one of the sample fluid mixture or the sheath fluids is pumped into the microfluidic chip by a pumping apparatus.
- In one embodiment, the external tubing communicates fluids to the microfluidic chip.
- In one embodiment, the components are cells.
- In one embodiment, wherein the cells to be isolated include at least one of viable and motile sperm from non-viable or non-motile sperm; sperm isolated by gender and other sex sorting variations; stem cells isolated from cells in a population; one or more labeled cells isolated from un-labeled cells including sperm cells; cells, including sperm cells, distinguished by desirable or undesirable traits; genes isolated in nuclear DNA according to a specified characteristic; cells isolated based on surface markers; cells isolated based on membrane integrity or viability; cells isolated based on potential or predicted reproductive status; cells isolated based on an ability to survive freezing; cells isolated from contaminants or debris; healthy cells isolated from damaged cells; red blood cells isolated from white blood cells and platelets in a plasma mixture; or any cells isolated from any other cellular components into corresponding fractions.
- In one embodiment, the isolated components are moved into one of the plurality of output channels, and unselected components flow out through another of the plurality of output channels.
- In one embodiment, the microfluidic chip further includes a computer which controls the pumping of one of the sample fluid mixture or the sheath fluids into the microfluidic chip.
- In one embodiment, the microfluidic chip further includes a computer which displays the components in a field of view acquired by a CCD camera disposed over the opening in the microfluidic chip.
- In one embodiment, the microfluidic chip system, includes: a microfluidic chip loaded on a microfluidic chip cassette which is mounted on a microfluidic chip holder, the microfluidic chip having a sample input for introducing sample fluid into the microfluidic chip, and sheath inputs for introducing sheath fluid into the microfluidic chip; and a pumping mechanism which pumps said sample fluid from a reservoir into the sample input of the microfluidic chip, and pumps the sheath fluids into the sheath inputs of the microfluidic chip.
- In one embodiment, a method of orienting and isolating components in a fluid mixture, includes: inputting a sample fluid mixture containing components into a sample input channel of a microfluidic chip; inputting sheath fluids into a plurality of first sheath fluid channels of the microfluidic chip, the sheath fluids from the first sheath fluid channels which join the sample fluid mixture in the sample input channel at a first intersection of the plurality of first sheath fluid channels and the sample input channel; wherein the sheath fluids from the first sheath fluid channels compress the sample fluid mixture in one direction in the sample input channel to focus the components in the sample fluid mixture around a center of the sample input channel; and inputting sheath fluids into a plurality of second sheath fluid channels of the microfluidic chip, the sheath fluids from the plurality of second sheath channels which join the sample fluid mixture in the sample input channel at a second intersection of the plurality of second sheath fluid channels and the sample input channel, downstream from the first intersection; wherein the sheath fluids from the plurality of second sheath fluid channels further compress the sample fluid mixture at the second intersection, in a second direction, such that the components are focused and aligned in a center of the sample input channel by both width and depth as the components flow through the sample input channel; and wherein the sheath fluids act on the components to compress and orient the components in a selected direction as the components flow through the sample fluid channel.
- Thus has been outlined, some features consistent with the present invention in order that the detailed description thereof that follows may be better understood, and in order that the present contribution to the art may be better appreciated. There are, of course, additional features consistent with the present invention that will be described below and which will form the subject matter of the claims appended hereto.
- In this respect, before explaining at least one embodiment consistent with the present invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. Methods and apparatuses consistent with the present invention are capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein, as well as the abstract included below, are for the purpose of description and should not be regarded as limiting.
- As such, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the methods and apparatuses consistent with the present invention.
- The objects, features and advantages of the present invention will be more readily appreciated upon reference to the following disclosure when considered in conjunction with the accompanying drawings, in which:
-
FIG. 1 shows an exploded perspective view of an illustrative embodiment of a microfluidic chip according to one embodiment consistent with the present invention. -
FIGS. 2A-2C show top views of the assembled microfluidic chip ofFIG. 1 , according to variant embodiments consistent with the present invention. -
FIG. 3 shows a cross-sectional view of an interrogation chamber of the microfluidic chip ofFIGS. 1-2C , according to one embodiment consistent with the present invention. -
FIG. 4 shows a cross-sectional internal view of an illustrative interrogation by a light source of components flowing in a fluid mixture, through the microfluidic chip ofFIGS. 1-2C , and an illustrative action of one of two (mirrored) piezoelectric actuator assemblies, according to one embodiment consistent with the present invention. -
FIG. 5A shows a perspective internal, and oblique view of components flowing through the microfluidic chip ofFIGS. 1-2C , and an illustrative operation of two-step focusing, according to one embodiment consistent with the present invention. -
FIG. 5B shows a perspective oblique view of the channels and interrogation chamber disposed in the microfluidic chip ofFIGS. 1-2C , according to one embodiment consistent with the present invention. -
FIG. 6 shows a schematic illustration of a front view of a main body of a microfluidic chip holder, according to one embodiment consistent with the present invention. -
FIG. 7 shows a schematic illustration of a side view of a piezoelectric actuator assembly of the microfluidic chip holder ofFIG. 6 , according to one embodiment consistent with the present invention. -
FIG. 8 shows a schematic illustration of a front view of a microfluidic chip holder, according to one embodiment consistent with the present invention. -
FIG. 9 shows a pumping mechanism which pumps sample fluid and sheath or buffer fluids into the microfluidic chip, according to one embodiment consistent with the present invention. - Before turning to the figures, which illustrate the illustrative embodiments in detail, it should be understood that the present disclosure is not limited to the details or methodology set forth in the description or illustrated in the figures. It should also be understood that the terminology is for the purpose of description only and should not be regarded as limiting. An effort has been made to use the same or like reference numbers throughout the drawings to refer to the same or like parts.
- The present disclosure relates to a microfluidic chip design, which is used to isolate particles or cellular materials, such as sperm, and other particles or cells, into various components and fractions, using laminar flows.
- The various embodiments of the present invention provide for isolating components in a mixture, such as, for example; isolating viable and motile sperm from non-viable or non-motile sperm; isolating sperm by gender, and other sex sorting variations; isolating stems cells from cells in a population; isolating one or more labeled cells from un-labeled cells distinguishing desirable/undesirable traits; isolating genes in nuclear DNA according to a specified characteristic; isolating cells based on surface markers; isolating cells based on membrane integrity (viability), potential or predicted reproductive status (fertility), ability to survive freezing, etc.; isolating cells from contaminants or debris; isolating healthy cells from damaged cells (i.e., cancerous cells) (as in bone marrow extractions); red blood cells from white blood cells and platelets in a plasma mixture; and isolating any cells from any other cellular components, into corresponding fractions.
- In addition, the subject matter of the present disclosure is also suitable for other medical applications as well. For example, the various laminar flows discussed below may be utilized as part of a kidney dialysis process, in which whole blood is cleansed of waste products and returned to the patient. Further, the various embodiments of the present disclosure may have further applicability to other biological or medical areas, such as for separations of cells, viruses, bacteria, cellular organelles or subparts, globular structures, colloidal suspensions, lipids and lipid globules, gels, immiscible particles, blastomeres, aggregations of cells, microorganisms, and other biological materials. For example, the component separation in accordance with the present disclosure may include cell “washing”, in which contaminants (such as bacteria) are removed from cellular suspensions, which may be particularly useful in medical and food industry applications. Significantly, prior art flow-based techniques have not recognized any applicability to separation of non-motile cellular components, as have the present invention.
- The subject matter of the present disclosure may also be utilized to move a species from one solution to another solution where separation by filtering or centrifugation is not practical or desirable. In addition to the applications discussed above, additional applications include isolating colloids of a given size from colloids of other sizes (for research or commercial applications), and washing particles such as cells, egg cells, etc. (effectively replacing the medium in which they are contained and removing contaminants), or washing particles such as nanotubes from a solution of salts and surfactants with a different salt concentration or without surfactants, for example.
- The action of isolating species may rely on a number of physical properties of the objects or components including self-motility, self-diffusivity, free-fall velocity, or action under an external force, such as an actuator, an electromagnetic field or a holographic optical trap. The properties which may be sorted upon include, for example, cell motility, cell viability, object size, object mass, object density, the tendency of objects to attract or repel one another or other objects in the flow, object charge, object surface chemistry, and the tendency of certain other objects (i.e., molecules) to adhere to the object.
- The various embodiments of the microfluidics chip, as described below, utilize one or more flow channels, having a plurality of substantially laminar flows, allowing one or more components to be interrogated for identification, and to be isolated into flows that exit into one or more outputs. In addition, the various components in the mixture may be isolated on-chip by using further isolation mechanisms, such as, for example, flow mechanisms, or optical tweezing or holographic optical trapping, or by magnetics (i.e., using magnetic beads). The various embodiments of the present invention thereby provide separation of components on a continuous basis, such as, within a continuous, closed system without the potential damage and contamination of prior art methods, particularly as provided in sperm separation. The continuous process of the present invention also provides significant time savings in isolating components.
- While discussion below focuses on the separation of sperm into viable and motile sperm from non-viable or non-motile sperm, or isolating sperm by gender and other sex sorting variations, or isolating one or more labeled cells from un-labeled cells distinguishing desirable/undesirable traits, etc., the apparatus, methods and systems of the present invention may be extended to other types of particulate, biological or cellular matter, which are capable of being interrogated by fluorescence techniques within a fluid flow, or which are capable of being manipulated between different fluid flows into different outputs.
- While the present subject matter is discussed in detail with respect to a
microfluidic chip 100 illustrated inFIGS. 1-5B and amicrofluidic chip holder 200 illustrated inFIGS. 6-9 , it should be understood that this discussion applies equally to the various other embodiments discussed herein or any variation thereof. -
FIG. 1 is an illustrative embodiment of amicrofluidic chip 100. Themicrofluidic chip 100 is manufactured of a suitable thermoplastic (e.g., low auto-fluorescing polymer etc.) through an embossing process or injection molding process, as well known to one of ordinary skill in the art, and is of suitable size. - The
microfluidic chip 100 includes a plurality of structural layers in which are disposed micro-channels which serve as sample input channel(s), sheath or buffer fluid channel(s), output channel(s), etc. The micro-channels are of suitable size to accommodate a particulate laminar flow, and may be disposed in any of the layers of thechip 100 in the appropriate length, as long as the object of the present invention is realized. The desired flow rate through themicrofluidic chip 100 may be controlled by a predetermined introduction flow rate into thechip 100, maintaining the appropriate micro-channel dimensions within thechip 100, by pumping mechanisms, providing narrowing of the micro-channels at various locations, and/or by providing obstacles or dividers within the micro-channels. - A plurality of inputs is provided into the
microfluidic chip 100, which provides access to the micro-channels/channels. In one embodiment, as shown inFIGS. 1-2C , asample input 106 is used for introducing a sample ofcomponents 160 in a sample fluid mixture 120 (seeFIGS. 4-5B ) into asample input channel 164A of themicrofluidic chip 100 from a reservoir source (seeFIG. 9 ). Themicrofluidic chip 100 also includes at least one sheath/buffer input (in one embodiment, sheath/buffer inputs 107, 108) for the introduction of sheath or buffer fluids. In one embodiment, there are two sheath/buffer inputs in themicrofluidic chip 100, which include a sheath/buffer input 107 and sheath/buffer input 108, both disposed proximate to thesample input 106, and which both introduce sheath or buffer fluids into themicrofluidic chip 100. The sheath or buffer fluids are well known in the art of microfluidics, and in one embodiment, may contain nutrients well known in the art to maintain the viability of the components 160 (i.e., sperm cells) in the fluid mixture. The location of the sheath/buffer inputs chip 100 which are in the same or different structural layers. - In one embodiment, fill holes or
air vents jet chambers 130, 131 (described later). - In one embodiment, a plurality of output channels stemming from main channel 164 (see
FIG. 2A ) is provided for removal of fluid which has flowed through themicrofluidic chip 100, including theisolated components 160 and/or sheath or buffer fluids. In one embodiment as shown inFIGS. 1-2C , there are three output channels 140-142 which include a leftside output channel 140, acenter output channel 141, and a rightside output channel 142. The leftside output channel 140 ends at afirst output 111, thecenter output channel 141 ends at asecond output 112 and the rightside output channel 142 ends at athird output 113. However, the number of outputs may be less or more depending on the number ofcomponents 160 to be isolated from thefluid mixture 120. - In one embodiment, instead of a straight edge, where necessary, a plurality of notches or recesses 146 is disposed at a bottom edge of the
microfluidic chip 100 to separate the outputs (i.e., outputs 111-113) and for attachment of external tubing etc. Thefirst output 111, thesecond output 112 and thethird output 113 are reached via output channels 140-142 which originate from interrogation chamber 129 (seeFIGS. 2A-4 ). - In one embodiment, the
microfluidic chip 100 has a plurality of structural layers in which the micro-channels are disposed. The channels may be disposed in one or more layers or in-between layers. In one embodiment, as shown inFIG. 1 , as an example, four structural plastic layers 101-104 are shown to comprise themicrofluidic chip 100. However, one of ordinary skill in the art would know that less or additional layers may be used, and the channels may be disposed in any of the layers as long as the object of the present invention is achieved. - A gasket of any desired shape, or O-rings, may be provided to maintain a tight seal between the
microfluidic chip 100 and the microfluidic chip holder 200 (seeFIG. 6 ). In the case of a gasket, it may be a single sheet or a plurality of components, in any configuration, or material (i.e., rubber, silicone, etc.) as desired. In one embodiment, as shown inFIG. 1 , afirst gasket 105 is disposed at one end of themicrofluidic chip 100 and interfaces, or is bonded (using an epoxy) withlayer 104. A plurality ofholes 144 are provided in thefirst gasket 105 and are configured to align with thesample input 106, sheath/buffer input 107, sheath/buffer input 108, andair vents - In one embodiment, a
second gasket 143 is disposed at another end of themicrofluidic chip 100 opposite to thefirst gasket 105, and interfaces or is bonded with (using epoxy) the topstructural layer 104. Thesecond gasket 143 is configured to assist scaling, as well as stabilizing or balancing themicrofluidic chip 100 in the microfluidic chip holder 200 (seeFIG. 6 ). - In one embodiment, holes and
posts 145 are disposed at various convenient positions in themicrofluidic chip 100 to fix and align the multiple layers (i.e., layers 101-104) during chip fabrication. - In one embodiment, a
sample fluid mixture 120 includingcomponents 160 is introduced intosample input 106, and thefluid mixture 120 flows throughmain channel 164 toward interrogation chamber 129 (seeFIGS. 2A, 4 , and SA). The sheath orbuffer fluids 163 are introduced into sheath/buffer inputs channels main channel 164, and towards theinterrogation chamber 129 before flowing out through output channels 140-142. - In one embodiment, sheath or
buffer fluids 163 can be introduced intojet chambers air vents chambers microfluidic chip 110, if thechambers buffer fluids 163 during manufacture. As stated above, the sheath orbuffer fluids 163 used are well known to one of ordinary skill in the art of microfluidics. - In one embodiment, the
fluid mixture 120 frommain channel 164 joins with the sheath orbuffer fluids 163 fromchannels intersection 161 in the same plane of themicrofluidic chip 100. In one embodiment,buffer fluids 163 fromchannels fluid mixture 120 and sheath orbuffer fluids 163 fromfirst intersection 161, downstream atsecond intersection 162. In one embodiment,channels channels - In one embodiment, channels 114-117, 123, 124, 140-142, 125 a, 125 b, 126 a, 126 b, 127, 128 may have substantially the same dimensions, however, one of ordinary skill in the art would know that the size of any or all of the channels in the
microfluidic chip 100 may vary in dimension (i.e., between 50 and 500 microns), as long as the desired flow rate(s) is achieved to accomplish the object of the present invention. - In one embodiment, the channels 114-117, 123, 124, 140-142, 125 a, 125 b, 126 a, 126 b, 127, 128, of the
microfluidic chip 100, may not just vary in dimension, but may have tapered shapes at entry points to other channels in thechip 100 in order to control the flow of fluid through the channels. For example,main channel 164 may taper at the entry point into intersection 161 (seeFIG. 5B ), to control and speed up the flow ofsample 120 into theintersection 161, and allow the sheath orbuffer fluids 163 fromchannels sample 120 fluid mixture in a first direction (i.e., horizontally), on at least two sides, if not all sides (depending on where the taperedchannel 164 joinschannel 164A). Thus, thesample fluid mixture 120 becomes a relatively smaller, narrower stream, bounded or surrounded by sheath orbuffer fluids 163, while maintaining laminar flow inchannel 164A. However, one of ordinary skill in the art would know that themain channel 164 entering intointersection 161 could be of any physical arrangement, such as a rectangular or circular-shaped channel, as long as the object of the present invention is obtained. - In one exemplary embodiment, at least one of the
channels microfluidic chip 100, than the layer in which thechannel 164 is disposed. For example,channel 116 may be disposed inlayer 103 andchannel 117 may be disposed in layer 101 (seeFIG. 1 ), such thatchannels other channels buffer fluids 163 join thefluid mixture 120 atintersection 162. In one embodiment,main channel 164 is disposed betweenlayers 102, 103 (seeFIG. 3 ), however, one of ordinary skill in the art would know that the channels 114-117, 164, 123, 124, 140-142, 125 a, 125 b, 126 a, 126 b, 127, 128 etc., can be disposed in any layer or between any two layers. Further, although the channels 114-117, 164, 123, 124, 140-142, 125 a, 125 b, 126 a, 126 b, 127, 128, etc., are described in exemplary embodiments as shown in the Figures, one of ordinary skill in the art would know that the particular arrangement or layout of the channels on thechip 100 may be in any desired arrangement as long as they achieve the described features of the present invention. - In one embodiment, the sheath or buffer fluids in
channels intersection 162. The sheath or buffer fluids fromchannels fluid mixture 120 flow in a perpendicular manner with respect tochannel 164B, such that thecomponents 160 in thefluid mixture 120 are compressed or flattened, and oriented in the selected or desired direction (see below), while still maintaining laminar flow inchannel 164B. - In one embodiment, as shown in
FIGS. 1-2C ,channels sample input 106. Thus, in one embodiment,channels channels main channel 164. However, one of ordinary skill in the art would recognize that the depicted configuration may be different as long as it achieves the desired features of the present invention. - Further, in one embodiment,
channels intersection 161 in the same plane, at an angle of 45 degrees or less, whereaschannels sample input channel 164A, joinintersection 162 from different layers, at an angle of substantially 90 degrees. However, one of ordinary skill in the art would appreciate that the depicted configurations, angles, and structural arrangements of themicrofluidic chip 100 layers and channels may be different as long as they achieve the desired features of the present invention. - In one embodiment, downstream from
intersection 162, thecomponents 160 in thefluid mixture 120 flow throughchannel 164B into aninterrogation chamber 129, where thecomponents 160 are interrogated. - In one embodiment, a
flexible diaphragm 170, 171 (seeFIG. 1 ) made from a suitable material, such as one of stainless steel, brass, titanium, nickel alloy, polymer, or other suitable material with desired elastic response, coversjet chambers channel 164B and the interrogation chamber 129 (seeFIGS. 2A and 2B ), in order to cause mechanical displacement of thediaphragm buffer fluids 163 from one of thejet chambers components 160 from channel 164C into one of theoutput channels channel 164B. In other words, the actuator would jet sheath orbuffer fluids 163 fromjet chamber 130 into channel 164C, and pushtarget components 160 in channel 164C intooutput channel 142 to isolate the target components from thefluid mixture 120. This embodiment is useful when only one type oftarget components 160 are isolated (which may require only twooutput channels FIG. 2B ). - The actuator may be one of a piezoelectric, magnetic, electrostatic, hydraulic, or pneumatic type actuator. Although a disc-shaped actuator assembly (i.e., 109, 110) is shown in
FIGS. 1-2C , one of ordinary skill in the art would know that any type or shape of actuator which performs the needed function could be used. - In other embodiments, the actuator is disposed on either side of
channel 164B (as shown inFIG. 2A ), but in other embodiments, more than one actuator (of a relatively smaller size) may be disposed on one or more sides ofchannel 164B and connected to channel 164B via jet channels (seeFIG. 2C ). - The following description of the function of the actuator(s) will be made with reference to
FIG. 2A , although one of ordinary skill in the art would know that any type of actuator disposed in a location on thechip 100 would be acceptable, as long as it achieved the features of the present invention. - In one embodiment, in order to activate the
diaphragms buffer fluids 163 fromchambers channel 164B, two external, stackedpiezoelectric actuator assemblies FIGS. 6 and 7 ) which align with and actuate thediaphragms piezoelectric actuator assemblies microfluidic chip holder 200. The stackedpiezoelectric actuator assemblies piezoelectric actuator diaphragm buffer fluids 163 from thechamber - The
microfluidic chip holder 200 may be of any type known to one of ordinary skill in the art, and is configured to precisely positionpiezoelectric actuators piezoelectric actuators diaphragms microfluidic chip 100. For example, in one embodiment, this is accomplished by eachpiezoelectric actuator assembly piezoelectric actuators diaphragms thumb screws 202 with threaded bodies that act to move thescrews 202 against thediaphragms spacer 203 attached to thepiezoelectric actuator diaphragm microfluidic chip 100. The adjustment screws 201 allow a user to adjust the position of thepiezoelectric actuators microfluidic chip 100 for both coarse and fine adjustment. The thumb screws 202 may be tightened to secure thepiezoelectric assemblies main chip body 100 or loosened to remove thepiezoelectric actuator assemblies main chip body 100. - In one embodiment, at least one piezoelectric actuator (209 or 210) is mounted on a plate (not shown) which can be translated in direction normal to the diaphragm (170 or 171) of the
microfluidic chip 100. Anadjustment screw 201 is mounted on theholder 200 and can be extended and retracted by turning thescrew 201. The tip of theadjustment screw 201 is against the plate. As thescrew 201 is extended, the plate along with thepiezoelectric actuator diaphragm piezoelectric actuator diaphragm piezoelectric actuators piezoelectric actuators piezoelectric actuator adjustment screw 201, the positioning of thepiezoelectric actuator piezoelectric actuator piezoelectric actuator - In another embodiment, an electronic circuit is connected to the stacked
piezoelectric actuator assembly piezoelectric actuators respective diaphragm diaphragm piezoelectric actuator piezoelectric actuator diaphragm piezoelectric actuator diaphragm actuators chambers jet fluid 163 into thechannel 164B. - It would be clear to one of ordinary skill in the art that the LED is one example of an indicator of contact. For example, once contact is made, and the electronic signal exceeds a set threshold, a feedback is generated for the user, which can be in any of the following forms: a light (i.e., LED), a sound (i.e., buzzer), a haptic (i.e., vibrator), or any combination thereof. Thus, the user can stop adjusting the contact and sustain the contact. Of course, in one embodiment, the above-described procedure may be automated.
- In an alternative embodiment, instead of at least one external stacked piezoelectric actuator assembly, a thin film of piezoelectric material (well-known to one of ordinary skill in the art) is directly deposited on the top surface of at least one
diaphragms piezoelectric actuator assembly 109, 110 (seeFIGS. 2A and 4 ) to displace (bend) therespective diaphragm respective jet chamber flexible diaphragm piezoelectric actuator assembly whole diaphragm chamber components 160 into aside output channel - As stated above, with respect to either the external stacked
piezoelectric actuator assemblies piezoelectric actuator assemblies buffer fluids 163 fromjet chamber 130 into channel 164C, and pushtarget components 160 in channel 164C intooutput channel 142 to isolate the target components from thefluid mixture 120, as shown inFIG. 2B . - In one embodiment, the
piezoelectric actuator assemblies jet chambers layer 103, for example—but one of ordinary skill in the art would know that it could be in any structural layer—after thechambers buffer fluids 163, to make themicrofluidic chip 100 impervious to fluid leakage. - Thus, the
piezoelectric actuator assemblies diaphragms piezoelectric actuator assemblies actuator assemblies microfluidic chip 100 based upon the different operation speeds and flow rate requirements. - In one embodiment, a thin piezoelectric film disposed on top of the
diaphragm piezoelectric actuator assemblies respective diaphragms piezoelectric actuator diaphragm diaphragm - The filling of the
jet chambers air vents jet chambers FIG. 2A ), after manufacturing when thechambers buffer fluids 163—forcing air out through the air vents 121, 122—and before thechambers buffer fluids 163 therein. Alternatively, in another embodiment, if the air vents 121, 122 are left open, then sheath orbuffer fluids 163 may be introduced through thevents chambers other fluids 163 disposed in thejet chambers buffer fluids 163 inputted throughchannels - In one embodiment, if sheath or
buffer fluids 163 are used to fill up thejet chambers inputs channels jet chamber 130 viachannels jet chamber 131 viachannels - In one embodiment,
jet channel 127 leavesjet chamber 130, andjet channel 128 leavesjet chamber 131, and bothjet channels FIG. 2A ). Thejet channels chip 100 and enter the channel 164C at any angle in the same plane. - In one embodiment, in order to form a strong, instantaneous jet stream, the
jet channels jet channels - In one embodiment, the
jet channels diaphragms buffer fluids 163 into the channel 164C. However, when thediaphragms jet channels jet chambers jet chambers chambers buffer fluids 163. - In one embodiment, output channels 140-142 depart from channel 164C within
interrogation chamber 129 to outputs 111-113. As stated above, in one embodiment, more than one on-chippiezoelectric actuator assembly piezoelectric actuator assembly 209, 210 (in any size or location) may be used to connect to each ofjet channels buffer fluids 163 fromjet chambers jet channels components 160, to avoidtarget components 160 mixing with undesired components 160 (further described below). In one embodiment, the cross-section and the length of the output channels 140-142 should be maintained at a predetermined volume ratio (i.e., 2:1:2, or 1:2:1 etc.) to obtain the desired hydraulic resistance of the output channels 140-142. - In one embodiment, an interrogation apparatus is disposed downstream from where
channels channel 164B. In one embodiment,channel 164B tapers into theinterrogation chamber 129, which speeds up the flow of the fluid mixture through theinterrogation chamber 129. However, one of ordinary skill in the art would know that thechannel 164B need not taper and could be of any dimension and size as long as the present invention performs according to the desired requirements. - An interrogation apparatus is used to interrogate and identify the
components 160 in the fluid mixture inchannel 164B passing through theinterrogation chamber 129. Note thatchannel 164B may be disposed in a single layer (i.e., layer 102) or disposed in between layers (i.e., layers 102, 103). In one embodiment, theinterrogation chamber 129 includes an opening or window 149 (seeFIG. 3 ) cut into themicrofluidic chip 100 in at least the uppermost layer (i.e.,layer 104 or other), and another opening orwindow 152 is cut into thechip 110 in at least the lowermost layer (i.e.,layer 101 or other). - In one embodiment, an
opening 150 is cut into the microfluidic chip through layers 101-104. In one embodiment, thetop window 149 is configured to receive afirst covering 133 and thebottom window 152 is configured to receive asecond covering 132. However, thewindows coverings windows opening 150 are shown inFIG. 3 , these may vary according to manufacturing considerations. - In one embodiment, the above-mentioned first and
second coverings interrogation chamber 129. Thewindows coverings 133, 132 (seeFIG. 3 ), allow thecomponents 160 flowing in thefluid mixture 120 inchannel 164B (seeFIG. 5A ) through theinterrogation chamber 129, to be viewed throughopening 150, and acted upon by a suitablelight source 147 configured to emit ahigh intensity beam 148 with any wavelength that matches excitable components in thefluid mixture 120. Although alaser 147 is shown, any suitable other light sources may be used, such as a light emitting diode (LED), arc lamp, etc. to emit a beam which excites the components. - In one embodiment, a high
intensity laser beam 148 from asuitable laser 147 of a preselected wavelength—such as a 355 nm continuous wave (CW) (or quasi-CW)laser 147—is required to excite thecomponents 160 in the fluid mixture (i.e., sperm cells). In one embodiment, the laser 147 (seeFIG. 3 ) emits alaser beam 148 throughwindow 149 inlayer 104, through the covering 133 at an uppermost portion of thechip 100, throughopening 150, and through covering 132 andwindow 152 inlayer 101 of thechip 100, to illuminate thecomponents 160 flowing throughchannel 164B ininterrogation region 129 of thechip 100. - In one embodiment, the
light beam 148 can be delivered to thecomponents 160 by an optical fiber that is embedded in themicrofluidic chip 100 atopening 150. - The
high intensity beam 148 interacts with the components 160 (see detailed explanation below), and passes through the first andsecond coverings bottom window 152, such that the emittedlight 151, which is induced by thebeam 148, is received by anobjective lens 153. Theobjective lens 153 may be disposed in any suitable position with respect to themicrofluidic chip 100. Because theinterrogation chamber 129 is sealed by the first andsecond coverings high intensity beam 148 does not impinge on themicrofluidic chip 100 and damage the layers 101-104. Thus, the first andsecond coverings microfluidic chip 100 from thehigh intensity beam 148 and photonic noise induced from the microfluidic chip material (i.e., plastic). - In one embodiment, the emitted light 151 received by the
objective lens 153 is converted into an electronic signal by anoptical sensor 154, such as a photomultiplier tube (PMT) or photodiode, etc. The electronic signal can be digitized by an analog-to-digital converter (ADC) 155 and sent to a digital signal processor (DSP) basedcontroller 156. The DSP basedcontroller 156 monitors the electronic signal and may then trigger one of two actuator drivers (i.e., 157 a, 157 b) at a predetermined value, to drive a relevant one of the two piezoelectric actuator assemblies (109, 110, or 209, 210). In one embodiment (shown inFIG. 2A ), the piezoelectric drivers and piezoelectric actuators (158 a, 158 b, or 219, 220) are part of two piezoelectric actuator assemblies (109, 110, or 209, 210) respectively, disposed on either side of theinterrogation chamber 129. The trigger signal sent to the piezoelectric actuators (109, 110, or 219, 220) is determined by the sensor raw signal, to activate the particular piezoelectric actuator assembly (109, 110, 209, 210) when the selected component is detected. - In the embodiment with the bonded
piezoelectric actuator assemblies diaphragm actuator assembly chip 100. When the electronic signal is sent through an electronic circuit directly to the actuator assemblies (i.e., 109, 110), thediaphragms chambers - The at least one of the piezoelectric actuator assemblies (109, 110, or 209, 210) is used to act upon the desired
components 160 in the fluid mixture in channel 164C, as thecomponents 160 leave theopening 150 forinterrogation area 129 after interrogation. Although actuator driver 157 b andpiezoelectric actuator assembly 110 are not illustrated inFIG. 4 , the operation and configuration of actuator driver 157 b andpiezoelectric actuator assembly 110 are the same as that of theactuator driver 157 a and thepiezoelectric actuator assembly 109. Thus, piezoelectric actuator 157 b acts to deflectcomponents 160 in the flow stream in channel 164C to theright output channel 142, and to thethird output 113. The same operation applies for thepiezoelectric actuator assembly 110, which jets sheath or buffer fluid 163 from thejet chamber 131 viajet channel 128, and deflects target or selectedcomponents 160 to theleft output channel 140 and thethird output 113. - In an alternative embodiment, a piezoelectric actuator assembly 106A (i.e., a piezoelectric disc similar to the
piezoelectric actuator assemblies FIG. 2C ), or a suitable pumping system (seeFIG. 9 , for example—discussed later), is used to pumpsample fluid 120 inchannel 164 towardintersection 161. The sample piezoelectric actuator assembly 106A would be disposed atsample input 106. By pumping thesample fluid mixture 120 into themain channel 164, a measure of control can be made over the spacing of thecomponents 160 therein, such that a more controlled relationship may be made between thecomponents 160 as they enter themain channel 164. - If the
piezoelectric actuator assemblies components 160 proceed frommain channel 164 to thecenter output channel 141, and to thesecond output 112, and the sheath orbuffer fluids 163 proceed throughoutput channels outputs - In one embodiment, the output channels 140-142 increase in dimension from the channel 164C, leaving the
interrogation chamber 129, such that the output ratio for enrichment of theisolated component 160, is increased through the relevant channel(s). - In one embodiment, the
microfluidic chip 100 is provided in a sterile state, and may be primed with one or more solutions (i.e., sheath or buffer fluids 163), or purged of any fluids or materials by either draining themicrofluidic chip 100 or by flowing sheath orbuffer fluids 153 or other solutions through themicrofluidic chip 100, according to known methods. Once themicrofluidic chip 100 is primed and thejet chambers buffer fluids 163, either during manufacturing or thereafter (as described above), the air vents 121, 122 are sealed. As stated above, in another embodiment, the air vents 121, 122 may be left open for additional sheath orbuffer fluids 163 to be added to thechambers - In one embodiment, as stated above, the
components 160 that are to be isolated include, for example: isolating viable and motile sperm from non-viable or non-motile sperm; isolating sperm by gender, and other sex sorting variations; isolating stems cells from cells in a population; isolating one or more labeled cells from un-labeled cells distinguishing desirable/undesirable traits; sperm cells with different desirable characteristics; isolating genes in nuclear DNA according to a specified characteristic; isolating cells based on surface markers; isolating cells based on membrane integrity (viability), potential or predicted reproductive status (fertility), ability to survive freezing, etc.; isolating cells from contaminants or debris; isolating healthy cells from damaged cells (i.e., cancerous cells) (as in bone marrow extractions), red blood cells from white blood cells and platelets in a plasma mixture; and isolating any cells from any other cellular components, into corresponding fractions; damaged cells, or contaminants or debris, or any other biological materials that are desired to isolated. Thecomponents 160 may be cells or beads treated or coated with linker molecules, or embedded with a fluorescent or luminescent label molecule(s). Thecomponents 160 may have a variety of physical or chemical attributes, such as size, shape, materials, texture, etc. - In one embodiment, a heterogeneous population of
components 160 may be measured simultaneously, with eachcomponent 160 being examined for different quantities or regimes in similar quantities (e.g., multiplexed measurements), or thecomponents 160 may be examined and distinguished based on a label (e.g., fluorescent), image (due to size, shape, different absorption, scattering, fluorescence, luminescence characteristics, fluorescence or luminescence emission profiles, fluorescent or luminescent decay lifetime), and/or particle position etc. - In one embodiment, a two-step focusing method of a component sorting system consistent with the present invention may be used, as illustrated in
FIG. 5A , in order to position thecomponents 160 inchannel 164B for interrogation in theinterrogation chamber 129. - In one embodiment, the first focusing step of the present invention is accomplished by inputting a
fluid sample 120 containingcomponents 160, such as sperm cells etc., throughsample input 106, and inputting sheath orbuffer fluids 163 through sheath orbuffer inputs components 160 are pre-stained with dye (e.g., Hoechst dye), in order to allow fluorescence, and for imaging to be detected. In one embodiment, sheath orbuffer fluids 163 are disposed injet chambers inputs - In one embodiment, as shown in
FIG. 5A ,components 160 in thesample fluid mixture 120 flow throughmain channel 164, and have random orientation and position (see inset A). Atintersection 161, thesample mixture 120 flowing inmain channel 164 is compressed by the sheath orbuffer fluids 163 fromchannels main channel 164 enters the intersection 161), when the sheath orbuffer fluids 163 meet with thesample mixture 120. As a result, thecomponents 160 are focused around the center of thechannel 164, and may be compressed into a thin strip across the depth of thechannel 164A. Theintersection 161 leading intochannel 164A is the focusing region. Thus, atintersection 161, as thesample 120 is being compressed by the sheath orbuffer fluids 163 fromchannels channel 164A, the components 160 (i.e., sperm cells) move toward the center of thechannel 164 width. - In one embodiment, the present invention includes a second focusing step, where the
sample mixture 120 containingcomponents 160, is further compressed by sheath orbuffer fluids 163 from a second direction (i.e., the vertical direction, from the top and the bottom) entering fromchannels intersection 162. Theintersection 162 leading intochannel 164B is the second focusing region. Note that although the entrances intointersection 162 fromchannels buffer fluids 163 in thechannels 116, 117 (which may be disposed in different layers of themicrofluidic chip 100 fromchannels 164A-B) enter at different planes into thechannel 164A-B, to align thecomponents 160 in the center of thechannel 164B by both width and depth (i.e., horizontally and vertically) as they flow alongchannel 164B. - Thus, in one embodiment, with the second focusing step of the present invention, the
sample mixture 120 is again compressed by the vertical sheath orbuffer fluids 163 entering atchannels sample 120 stream is focused at the center of thechannel 164B depth, as illustrated inFIG. 5A , and thecomponents 160 flow along the center of thechannel 164B in approximately single file formation. - In one embodiment, the
components 160 aresperm cells 160, and because of their pancake-type or flattened teardrop shaped head, thesperm cells 160 will re-orient themselves in a predetermined direction as they undergo the second focusing step—i.e., with their flat surfaces perpendicular to the direction of light beam 148 (seeFIG. 5A ). Thus, thesperm cells 160 develop a preference on their body orientation while passing through the two-step focusing process. Specifically, thesperm cells 160 tend to be more stable with their flat bodies perpendicular to the direction of the compression. Hence, with the control of the sheath orbuffer fluids 163, thesperm cells 160 which start with random orientation, now achieve uniform orientation. Thus, thesperm cells 160 not only make a single file formation at the center of thechannel 164B, but they also achieve a uniform orientation with their flat surface normal to the direction of compression in the second focusing step. - Thus, all
components 160 introduced intosample input 106, which may be other types of cells or other materials as described above, etc., undergo the two-step focusing steps, which allow thecomponents 160 to move through thechannel 164B in a single file formation, in a more uniform orientation (depending on the type of components 160), which allows for easier interrogation of thecomponents 160. - In one embodiment, further downstream in
channel 164B, thecomponents 160 are detected in theinterrogation chamber 129 at opening 150 throughcoverings light source 147.Light source 147 emits a light beam 148 (which may be via an optical fiber) which is focused at the center of the channel 164C atopening 150. In one embodiment, thecomponents 160, such assperm cells 160, are oriented by the focusing streams (i.e., sheath orbuffer fluid 163 streams which act on sample stream 120) such that the flat surfaces of thecomponents 160 are facing toward thebeam 148. In addition, allcomponents 160 are moved into single file formation by focusing as they pass underbeam 148. As thecomponents 160 pass underlight source 147 and are acted upon bybeam 148, thecomponents 160 emit the fluorescence which indicates the desiredcomponents 160. For example, with respect to sperm cells, X chromosome cells fluoresce at a different intensity from Y chromosome cells; or cells carrying one trait may fluoresce in a different intensity or wavelength from cells carrying a different set of traits. In addition, thecomponents 160 can be viewed for shape, size, or any other distinguishing indicators. - In the embodiment of beam-induced fluorescence, the emitted light beam 151 (in
FIG. 3 ) is then collected by theobjective lens 153, and subsequently converted to an electronic signal by theoptical sensor 154. The electronic signal is then digitized by an analog-digital converter (ADC) 155 and sent to anelectronic controller 156 for signal processing. The electronic controller can be any electronic processor with adequate processing power, such as a DSP, a Micro Controller Unit (MCU). a Field Programmable Gate Array (FPGA), or even a Central Processing Unit (CPU). In one embodiment, the DSP-basedcontroller 156 monitors the electronic signal and may then trigger at least one actuator driver (i.e., 157 a or 157 b), to drive one of the two piezoelectric actuator assemblies (109, 110, or 219, 220—part of the respectivepiezoelectric actuator assemblies component 160 is detected. In another embodiment, the FPGA-based controller monitors the electronic signal and then either communicates with the DSP controller or acts independently to trigger at least one actuator driver (i.e., 157 a or 157 b), to drive one of the two piezoelectric actuator assemblies (109, 110, or 219, 220—part of the respectivepiezoelectric actuator assemblies component 160 is detected. - Thus, in one embodiment, selected or desired
components 160 in channel 164C in theinterrogation chamber 129, are isolated by a jet stream of buffer orsheath fluids 163 from one of thejet channels output channel component 160. In one exemplary embodiment, the electronic signal activates the driver to trigger external stacked piezoelectric actuator 219 (or activatesdriver 157 a to trigger actuator 109), at the moment when the target or selectedcomponent 160 arrives at the cross-section point of thejet channels diaphragm 170 and push it, compressingjet chamber 130, and squeezing a strong jet of buffer orsheath fluids 163 fromjet chamber 130 viajet channel 127, into the main channel 164C, which pushes the selected or desiredcomponent 160 intooutput channel 142. Note that, similarly to the performance of stacked externalpiezoelectric actuator assembly 209, the triggering of piezoelectric actuator assembly 210 (or 110), would push a desiredcomponent 160 into theoutput channel 140 on the opposite side from thejet 128. - Thus, sheath or
buffer fluids 163 jetted from one of thejet channels components 160 from their ordinary paths in channel 164C, toward one of the selected or desired,respective output channels target components 160, and enriching the flows in thoseoutput channels sample fluid 120 which continues straight out throughoutput channel 141 with unselected components, if any. Thus, no triggering of thepiezoelectric actuator assemblies unselected components 160 in thefluid mixture 120 continue straight out throughoutput channel 141. - In one embodiment, the
isolated components 160 are collected from one of thefirst output 111, or thethird output 113, using known methods in the art, for storing, for further separation, or for processing, such as cryopreservation. Of course,components 160 that were not isolated intooutputs second output 112. Portions of the first, second, and third outputs 111-113 may be characterized electronically, to detect concentrations of components, pH measuring, cell counts, electrolyte concentration, etc. - In one embodiment, interrogation of the
sample 120 containing components 160 (i.e., biological material), is accomplished by other methods. Thus, portions of, or outputs from, themicrofluidic chip 100 may be inspected optically or visually. Overall, methods for interrogation may include direct visual imaging, such as with a camera, and may utilize direct bright-light imaging or fluorescent imaging; or, more sophisticated techniques may be used such as spectroscopy, transmission spectroscopy, spectral imaging, or scattering such as dynamic light scattering or diffusive wave spectroscopy. - In some cases, the
optical interrogation region 129 may be used in conjunction with additives, such as chemicals which bind to or affect components of thesample mixture 120 or heads which are functionalized to bind and/or fluoresce in the presence of certain materials or diseases. These techniques may be used to measure cell concentrations, to detect disease, or to detect other parameters which characterize thecomponents 160. - However, in another embodiment, if fluorescence is not used, then polarized light back scattering methods may also be used. Using spectroscopic methods, the
components 160 are interrogated as described above. The spectrum of thosecomponents 160 which had positive results and fluoresced (i.e., thosecomponents 160 which reacted with a label) are identified for separation by the activation of thepiezoelectric assemblies - In one embodiment, the
components 160 may be identified based on the reaction or binding of the components with additives or sheath orbuffer fluids 163, or by using the natural fluorescence of thecomponents 160, or the fluorescence of a substance associated with thecomponent 160, as an identity tag or background tag, or met a selected size, dimension, or surface feature, etc., are selected for separation. - In one embodiment, upon completion of an assay, selection may be made, via computer 182 (which monitors the electronic signal and triggers the
piezoelectric assemblies components 160 to discard and which to collect. - In one embodiment, after selection is made, a focused energy device may emit a focused energy beam which damages or kills the selected components in the sample fluid mixture. The focused energy beam in such an instance could be a laser effective to damage the selected components, such as cells. In a similar embodiment, after the damaging and killing by the focused energy beam, the selected and unselected components exit the microfluidic chip and are gathered in the same pool.
- In one embodiment, the user interface of the
computer system 182 includes a computer screen which displays thecomponents 160 in a field of view acquired by aCCD camera 183 over themicrofluidic chip 100. - In one embodiment, the
computer 182 controls any external devices such as pumps (i.e., pumping mechanism ofFIG. 9 ), if used, to pump anysample fluids 120, sheath orbuffer fluids 163 into themicrofluidic chip 100, and also controls any heating devices which set the temperature of thefluids microfluidic chip 100. - The
microfluidic chip 100 is loaded on achip cassette 212, which is mounted onchip holder 200. Thechip holder 200 is mounted to a translation stage (not shown) to allow fine positioning of theholder 200. Themicrofluidic chip holder 200 is configured to hold themicrofluidic chip 100 in a position such that thelight beam 148 may intercept thecomponents 160 in the above described manner, atopening 150. When themicrofluidic chip 100 is in the closed position, a gasket layer 105 (seeFIG. 1 ) forms a substantially leak-free seal between themain body 211 and themicrofluidic chip 100. - As illustrated in
FIG. 6 , in one embodiment, amicrofluidic chip holder 200 is made of a suitable material, such as aluminum alloy, or other suitable metallic/polymer material, and includes amain body 211, and at least one stacked externalpiezoelectric actuator - The
main body 211 of theholder 200 may be any suitable shape, but its configuration depends on the layout of thechip 100. For example, the stacked externalpiezoelectric actuators piezoelectric actuator diaphragm microfluidic chip 100. Themain body 211 of theholder 200 is configured to receive and engage with external tubing (seeFIG. 9 ) for communicating fluids/samples to themicrofluidic chip 100. - The details of these
cassette 212 andholder 200 and the mechanisms for attachment of thechip 100 to thecassette 212 andholder 200, are not described in any detail, as one of ordinary skill in the art would know that these devices are well-known and may be of any configuration to accommodate themicrofluidic chip 100, as long as the objectives of the present invention are met. - As shown in
FIG. 9 , in one embodiment, a pumping mechanism includes a system having apressurized gas 235 which provides pressure for pumpingsample fluid mixture 120 from reservoir 233 (i.e., sample tube) intosample input 106 of thechip 100. - A
collapsible container 237 having sheath orbuffer fluid 163 therein, is disposed in apressurized vessel 236, and thepressurized gas 235 pushes fluid 163 to a manifold 238 having a plurality of different outputs, such thatfluid 163 is delivered viatubing buffer inputs chip 100. - A
pressure regulator 234 regulates the pressure ofgas 235 within thereservoir 233, and apressure regulator 239 regulates the pressure ofgas 235 within thevessel 236. Amass flow regulator 232 a, 232 b controls the fluid 163 pumped viatubing buffer inputs tubing fluids 120 into thechip 100, and may be used throughoutchip 100 to loadsample fluid 120 intosample input 106, or sheath orbuffer inputs manifold 238 intoair vents chambers - In accordance with an illustrative embodiment, any of the operations, steps, control options, etc. may be implemented by instructions that are stored on a computer-readable medium such as a computer memory, database, etc. Upon execution of the instructions stored on the computer-readable medium, the instructions can cause a computing device to perform any of the operations, steps, control options, etc. described herein.
- The operations described in this specification may be implemented as operations performed by a data processing apparatus or processing circuit on data stored on one or more computer-readable storage devices or received from other sources. A computer program (also known as a program, software, software application, script, or code) can be written in any form of programming language, including compiled or interpreted languages, declarative or procedural languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, object, or other unit suitable for use in a computing environment. A computer program may, but need not, correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markup language document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, subprograms, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication network. Processing circuits suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer.
- It should be noted that the orientation of various elements may differ according to other illustrative embodiments, and that such variations are intended to be encompassed by the present disclosure.
- The construction and arrangements of the microfluidic chip, as shown in the various illustrative embodiments, are illustrative only. Although only a few embodiments have been described in detail in this disclosure, many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.) without materially departing from the novel teachings and advantages of the subject matter described herein. Some elements shown as integrally formed may be constructed of multiple parts or elements, the position of elements may be reversed or otherwise varied, and the nature or number of discrete elements or positions may be altered or varied. The order or sequence of any process, logical algorithm, or method steps may be varied or re-sequenced according to alternative embodiments. Other substitutions, modifications, changes and omissions may also be made in the design, operating conditions and arrangement of the various illustrative embodiments without departing from the scope of the present disclosure.
Claims (20)
1. A method of sorting particles using a microfluidics-based flow cytometry apparatus, the method comprising:
flowing a fluid sample comprising a plurality of particles suspended in the fluid sample into a channel of a microfluidic chip;
flowing a first sheath fluid flow and a second sheath fluid flow into the microfluidic chip;
intersecting the fluid sample with the first sheath fluid flow at a first intersection in the channel of the microfluidic chip thereby focusing the fluid sample while maintaining a laminar fluid flow of the fluid sample and the first sheath fluid flow;
intersecting the fluid sample and the first sheath fluid flow with the second sheath fluid flow at a second intersection in the channel of the microfluidic chip, thereby further focusing the fluid sample into a focused fluid flow and maintaining the laminar fluid flow of the fluid sample, the further focusing causing the plurality of particles suspended in the fluid sample to flow in approximately single file formation;
interrogating particles in the plurality of particles suspended in the fluid sample individually at an interrogation location in the channel of the microfluidic chip by the emission of electromagnetic radiation;
distinguishing the particles in the plurality of particles suspended in the fluid sample based on the interrogating;
sorting the particles in the plurality of particles suspended in the fluid sample based on the distinguishing step, the sorting comprising diverting a subset of the plurality of particles suspended in the fluid sample from the focused flow and into one of a plurality of output channels, wherein a cross-section and length of each of the plurality of output channels is maintained at a predetermined volume ratio to provide a desired hydraulic resistance for the diverting of the subset of the plurality of particles suspended in the fluid sample; and
collecting, from the one of the plurality of output channels, the subset of the plurality of particles diverted from the focused flow.
2. The method of claim 1 , wherein the emission of electromagnetic radiation is by an interrogation apparatus, the interrogation apparatus comprising:
a light source configured to emit a light beam which illuminates and excites said plurality of particles suspended in the fluid sample from the focused flow.
3. The method of claim 1 , further comprising:
pumping the fluid sample by a pumping mechanism from a reservoir into said microfluidic chip; and
pumping said first sheath fluid flow and said second sheath fluid flow from a sheath fluid reservoir into said first intersection and second intersection of said microfluidic chip.
4. The method of claim 3 , further comprising:
controlling by a computer the pumping of the fluid sample, the first sheath fluid flow, and the second sheath fluid flow into the microfluidic chip.
5. The method of claim 1 , wherein diverting the subset of the plurality of particles suspended in the fluid sample from the focused flow further comprises:
deflecting by an actuator a flexible membrane when signaled by a detector operating on the microfluidic chip that a particle having a predetermined characteristic is detected in the channel.
6. The method of claim 5 , wherein deflecting the flexible membrane creates a pressure pulse in a fluid flowing through the channel of the microfluidic chip.
7. The method of claim 1 , further comprising expelling the subset of the plurality of particles diverted from the focused flow out of a first outlet of the one of the plurality of output channels.
8. The method of claim 7 , further comprising expelling the focused flow out of a second outlet of another of the plurality of output channels.
9. The method of claim 1 , further comprising cryopreserving the collected subset of the plurality of particles diverted from the focused flow.
10. The method of claim 1 , wherein the particles are sperm cells.
11. A method of sorting components in a fluid sample, the method comprising:
flowing the fluid sample comprising a plurality of the components into a channel of a microfluidic chip;
flowing a first sheath fluid flow and a second sheath fluid flow into the microfluidic chip;
intersecting the fluid sample with the first sheath fluid flow at a first intersection of the microfluidic chip thereby focusing the fluid sample while maintaining laminar flow in the channel;
intersecting the fluid sample and the first sheath fluid flow with the second sheath fluid flow at a second intersection of the microfluidic chip, thereby further focusing the fluid sample and causing the plurality of components to flow in approximately single file formation, while maintaining laminar flow in the channel;
interrogating components of the plurality of components at an interrogation location in the microfluidic chip by emitted light induced by a light source;
distinguishing selected components of the plurality of components based on the interrogating; and
sorting the selected components based on the distinguishing step, the sorting comprising diverting the selected components from the focused flow and into one of a plurality of output channels, wherein the output channels increase in dimension from the channel.
12. The method of claim 11 , wherein the channel tapers prior to at an entry point into the first intersection.
13. The method of claim 11 , wherein the channel tapers into the interrogation location.
14. A method of sorting particles in a fluid mixture, the method comprising:
flowing the fluid sample comprising a plurality of the components into a channel of a microfluidic chip;
flowing a first sheath fluid flow and a second sheath fluid flow into the microfluidic chip;
intersecting the fluid sample with the first sheath fluid flow at a first intersection of the microfluidic chip, wherein the channel tapers prior to at an entry point into the first intersection thereby focusing the fluid sample while maintaining laminar flow in the channel;
intersecting the fluid sample and the first sheath fluid flow with the second sheath fluid flow at a second intersection of the microfluidic chip, thereby further focusing the fluid sample and causing the plurality of components to flow in approximately single file formation and uniform orientation, while maintaining laminar flow in the channel;
interrogating components of the plurality of components at an interrogation location in the microfluidic chip by emitted light induced by a light source;
distinguishing selected components of the plurality of components based on the interrogating; and
damaging or killing the selected components in the sample fluid mixture with a focused energy device which emits a focused energy beam.
15. The method of claim 14 , further comprising collecting the selected components and the unselected components through at least one output channel.
16. The method of claim 14 , wherein the channel tapers into the interrogation location.
17. The method of claim 14 , wherein at the first intersection, the plurality of components in the fluid mixture are compressed by sheath fluid to form a relatively smaller, narrower stream.
18. The method of claim 14 , wherein the second sheath fluid flow intersects from above and below said channel at the second intersection.
19. The method of claim 14 , wherein the plurality of the components are sperm cells.
20. The method of claim 19 , wherein interrogating the sperm cells in the fluid sample selects cells based on viability, motility, gender, label, desirable trait, DNA content, surface marker, membrane integrity, predicted reproductive status, health, or survival characteristics.
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