Microfluidic mixing and / or separator

Abstract

The microfluidic device may have at least one inlet channel; a microfluidic channel (214) having a first portion fluidly connected to the at least one inlet channel (210, 212); and at least one outlet channel (225a, 225b, 225c) fluidly connected to a second portion of the microfluidic channel, where the microfluidic channel has a plurality of dimples (220a, 220b, 220c) extending away from an axis of the microfluidic channel. The at least one inlet channel includes a first inlet channel and a second inlet channel, and / or the at least one outlet channel includes a first outlet channel and a second outlet channel. In some embodiments, the plurality of dimples may be configured to separate nanoparticles of different sizes to the first outlet channel and the second outlet channel.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 378,230, filed on October 3, 2022, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to devices, systems, and methods of use for mixing at least two substances to produce drug complexes and / or to separate monodisperse nanoparticles. Background Art

[0004] Recent immunology developments include the newly approved messenger RNA-lipid nanoparticle (mRNA-LNP) vaccine. The advantage of messenger RNA (mRNA) technology is that it can be quickly adapted to new antigen designs by changing the mRNA sequence without having to completely overhaul the chemistry and manufacturing control (CMC) of vaccine production. However, mRNA provided alone is not easily absorbed or delivered to human immune cells and has unstable chemical and physical properties, so it cannot be effectively used as a vaccine. The latest developments show that if mRNA is encapsulated in a lipid nanoparticle (LNP) carrier, its absorption and stability can be increased to effective levels.

[0005] mRNA-LNP vaccines are prepared by mixing ethanol-dissolved lipids with RNA in a buffered solution under strictly controlled conditions. This mixing is typically performed in the laboratory using equipment that is often not suitable for large-scale distribution due to low durability, high cost, high complexity, low batch-to-batch consistency, and / or large batch-to-batch variability. Summary of the Invention

[0006] The inventors recognize that the shelf life of mRNA-LNP at room temperature is limited. To extend the shelf life, mRNA-LNP vaccines must be stored at extremely low temperatures (typically -20 degrees Celsius to -80 degrees Celsius). This is a problem because low-temperature distribution is expensive and logistics are complex. In addition, if the low-temperature environment fails at any stage of the distribution chain, for example, there is a risk that the mRNA-LNP vaccine will be wasted.

[0007] Non-messenger RNA drugs such as RNAi, siRNA, and other oligonucleotides can also be formed into lipid nanoparticle compositions (RNA-LNPs). RNA-LNP drugs can be chemically modified to improve their stability and shelf life at room temperature (such chemical modifications are not possible for mRNA-LNP technology, which requires interaction with cellular proteins to function properly). Chemical modification of RNA-LNPs can be difficult and costly to implement, but chemical modification is generally preferred to avoid the high distribution costs associated with unmodified RNA-LNP drugs (which must also be stored at very low temperatures) and the difficulty associated with managing drug efficacy over time due to the limited half-life of the molecules.

[0008] In summary, the low temperature requirement presents a major challenge to distribution and development. Other problems associated with known systems for producing nanoparticle compositions include limited scalability, usability, and / or reliability. Various embodiments as disclosed herein meet one or more of the aforementioned needs.

[0009] A first aspect of the present disclosure relates to a microfluidic device having at least one inlet channel; a microfluidic channel having a first portion fluidically connected to the at least one inlet channel; and at least one outlet channel fluidically connected to a second portion of the microfluidic channel, wherein the microfluidic channel has a plurality of recesses extending away from an axis of the microfluidic channel.

[0010] The microfluidic device may include one or more of the following features. The at least one inlet channel may include a first inlet channel and a second inlet channel. The at least one outlet channel may include a first outlet channel and a second outlet channel. A plurality of dimples may be arranged circumferentially around the microfluidic channel. The plurality of dimples may be arranged in longitudinally overlapping groups. The plurality of dimples may include a first group of dimples arranged longitudinally along the microfluidic channel and a second group of dimples arranged longitudinally along the microfluidic channel, the first group of dimples and the second group of dimples being laterally offset, and the first group of dimples and the second group of dimples being configured to separate nanoparticles by size. The first group of dimples may have a first width or diameter, the second group of dimples may have a second width or diameter of a second size, and the first width or diameter and the second width or diameter may be different. The first width or diameter may be between about 50 μm and about 200 μm, and the second width or diameter may be between about 200 μm and about 500 μm. The at least one outlet channel may include a first outlet channel and a second outlet channel, the first group of dimples being arranged to direct nanoparticles of a first size to the first outlet channel, and the second group of dimples being arranged to direct nanoparticles of a second size to the second outlet channel. The at least one outlet channel may include a third outlet channel, and the plurality of wells may include a third group of wells arranged longitudinally along the microfluidic channel. The third group of wells may be configured to direct nanoparticles of the second size to the third outlet channel.

[0011] A second aspect of the present disclosure relates to a microfluidic device having: a plurality of inlet channels; a microfluidic channel having a first portion fluidically connected to the plurality of inlet channels; and a plurality of outlet channels fluidically connected to a second portion of the microfluidic channel, wherein the microfluidic channel has a plurality of recesses extending away from an axis of the microfluidic channel.

[0012] The microfluidic device may include one or more of the following features: The plurality of outlet channels may include a first outlet channel, a second outlet channel, and a third outlet channel. The plurality of wells may include a first group of wells arranged to direct nanoparticles of a first size to the first outlet channel, a second group of wells arranged to direct nanoparticles of a second size to the second outlet channel, and a third group of wells arranged to direct nanoparticles of the second size to the second outlet channel.

[0013] A third aspect of the present disclosure relates to a method for fabricating a microfluidic channel. The method may include injecting one or more elastomeric materials into a mold cavity surrounding a core pin, wherein the core pin has an elongated shaft with a plurality of protrusions extending from the axis of the core pin; forming a component including a microfluidic channel having a plurality of recesses from the one or more elastomeric materials; and removing the core pin from the component.

[0014] The method may include one or more of the following features. The method may also include removing the component and the center core from the mold cavity before removing the core pin from the component. The one or more elastomeric materials may include silicone, rubber, and / or thermoplastic elastomers. Removing the core pin from the component may be performed using a compressed air ejector system. Removing the core pin from the component may be performed by sliding the component off the core pin. The protrusion may be spherical. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Specific embodiments of the present disclosure are described in the following detailed description, by way of example only, and with reference to the accompanying drawings, in which:

[0016] Figure 1 A side view of an exemplary system according to the present disclosure is shown.

[0017] Figure 2 Shown Figure 1 An exemplary microfluidic channel of a microfluidic device.

[0018] Figure 3 Shows the manufacturing Figure 1 and Figure 2 An exemplary method of a microfluidic device.

[0019] Figure 4 Shown in Figure 3 An exemplary core pin used in the method.

[0020] Figure 5 Shown Figure 1 A second embodiment of the microfluidic device.

[0021] The same reference numbers are used in the drawings and the following detailed description to refer to the same or like parts. DETAILED DESCRIPTION

[0022] Provided is a microfluidic device for connecting one or more fluid containers for mixing a first substance and a second substance to produce a drug complex. The microfluidic device may include a first port or connector component configured to be connected to the first container, a second port or connector component configured to be connected to the second container, and a third port or connector component configured to be connected to a receiving container. The microfluidic device may also include a microfluidic channel extending from a first portion connected to the first and second port fluids to a second portion connected to the third port. The microfluidic device may include obstacles configured to generate chaotic mixing of fluids, for example, to allow charged nanoparticles to self-assemble in a predetermined arrangement and structure based on their chemical composition, charge and / or shape. When a specific flow rate is reached, pits in the flow channel may create obstacles that form vortex channels together with the flow path. The size, shape, orientation, and pattern of the obstacle geometry can be specifically and purposefully designed to produce flow paths with different chaos and turbulence for different applications. In some embodiments, the microfluidic device can additionally or alternatively be configured to separate the formed nanoparticles by size due to the obstacle geometry of the channel. The microfluidic device can generate targeted turbulence caused by the obstacle geometry, wherein nanoparticles of different sizes will move to specific flow regions of the microfluidic channel, substantially separating the nanoparticles by size due to the flow characteristics of the channel.

[0023] Figure 1 A system is shown that includes a first container 20, a second container 40, a receiving container 60, and a microfluidic device 100. In some embodiments, the system may also include a first storage container 80 containing a first substance or component and a second storage container 82 containing a second substance or component. The first container 20 may be configured to transfer the first substance from the first storage container 80 to the microfluidic device 100. The second container 40 may be configured to transfer the second substance from the second storage container 82 to the microfluidic device 100. The microfluidic device 100 may include at least one pathway configured to mix the first and second substances and transfer the drug complex to the receiving container 60. The system may constitute a kit that includes at least one or all of the first container 20, the second container 40, the receiving container 60, the microfluidic device 100, the first storage container 80, and / or the second storage container 82. The system and / or kit may also include one or more vial adapters 70 for transferring fluid to or from one or more of the receiving container 60, the first storage container 80, and / or the second storage container 82. The components of the kit may include packaging for shipping to the end user.

[0024] The first container 20 may be a variable volume container, such as a first syringe configured to at least temporarily store a first substance and / or transfer the first substance from the first storage container 80 to the microfluidic device 100. The second container 40 may be a variable volume container, such as a second syringe configured to store a second substance and transfer the second substance from the storage container 82 to the microfluidic device 100. The first syringe 20 may include a first syringe body 22 and a first plunger rod 24, and the second syringe 40 may include a second syringe body 42 and a second plunger rod 44. Each syringe body 22, 42 may have a syringe barrel extending longitudinally from a proximal end to a distal end. Each syringe body 22, 42 may have a syringe tip at the distal end and a flange at the proximal end. The syringe barrel may be tubular, having an inner surface extending longitudinally to define a chamber. The chamber may be configured to receive, store, and / or mix substances for dispensing through the distal opening of the syringe tip. The first plunger rod 24 may have a first flange 25 at its proximal end, and the second plunger rod 44 may have a second flange 45 at its proximal end. The syringe tip of the first syringe body 22 may include a first connector 26 for engaging with an external device such as a syringe needle, a container and / or a microfluidic device 100. The syringe tip of the second syringe body 42 may include a second connector 46 for engaging with the same or different external devices such as a syringe needle, a container and / or a microfluidic device 100. Each connector 26, 46 may also include a male Luer connector comprising a syringe tip and a threaded sleeve around the tip. The syringe tip may be tapered to guide the fluid flow into an external device (e.g., microfluidic device 100), and the sleeve may have an internal thread configured to fix the syringe 20, 40 to a corresponding external device (e.g., microfluidic device 100). The container 20, 40 may be a syringe and / or a reciprocating pump of any conventional type suitable for use in a pharmaceutical environment.

[0025] The flanges 25, 45 can be actuated by being pulled to generate negative pressure to draw the material into the chamber and / or being pushed to generate positive pressure to push the material out of the chamber. At least portions of the first syringe 20 and the second syringe 40 can be integrally or releasably connected to enable joint manipulation and / or actuation of the first and second syringes 20, 40. For example, the system can also include a barrel holder (not shown) having a first lumen configured to receive the first syringe body 22 and a second lumen configured to receive the second syringe body 42, so that the first and second syringes 20, 40 can be manipulated together. Each of the first and second lumens can be closed or formed by a C-shaped wall configured to snap around the respective syringe body 22, 42. The barrel holder can secure the syringe bodies 22, 42 in a substantially parallel arrangement. The system can also include a plunger clamp configured to allow the plunger rods 24, 44 to translate together through the syringe bodies 22, 42, thereby pushing and / or pulling the material with the same longitudinal translation. For example, the plunger clip can be configured to attach to the flanges 25, 26, such as having grooves configured to releasably receive the flanges 25, 26. Embodiments of cartridge holders and / or plunger clips are further discussed in U.S. Patent Nos. 5,104,375, 6,840,921, and 8,240,511, the entire disclosures of which are incorporated herein by reference.

[0026] The receiving container 60 can be a fixed volume container, such as a vial that can be attached to the microfluidic device 100 via a vial adapter 70. The vial 60 can include a small glass vial 62 that surrounds a chamber and has a crown and a neck. The chamber can be sealed by a vial seal at the crown that is circumferentially attached by aluminum tape. The vial adapter 70 can have a transverse top wall 72, a connector 74 extending upward from the top wall 72, and a skirt 76 extending downward from the top wall 72. The connector 74 can be a female Luer connector that includes external threads for threaded engagement with a male Luer lock connector, such as the male Luer lock connector of the microfluidic device 100. The skirt 76 can be used to telescopically mount on the crown and / or neck of the vial 60. The skirt 76 can surround a cannula (not shown) extending downward from the top wall 72 and be configured to pierce the vial stopper. The cannula can have an inner cavity that is in fluid communication with the chamber of the vial 62 when piercing the vial stopper. The vial adapter 70 can be vented to draw air into the container 60 and facilitate the drawing of fluid through the system. Further discussion of embodiments of the container 60 and / or vial adapter 70 is provided in U.S. Patent Nos. 8,753,325 and 9,943,463, the entire disclosures of which are expressly incorporated herein by reference. The receiving container 60 can be initially empty and configured to receive materials injected from the first container 20 and the second container 40 and mixed in the microfluidic device 100. Once the first component and the second component are introduced into the microfluidic device 100, the resulting drug complex can be stored in the receiving container 60.

[0027] However, in some embodiments, the receiving container 60 can be a variable volume container, such as a syringe, and one or both of the first container 20 and the second container 40 can be fixed volume containers, such as vials. Further discussion of such embodiments is provided in U.S. Patent Publication No. 2023 / 0105059, the entire disclosure of which is expressly incorporated herein by reference.

[0028] The first storage container 80 and / or the second storage container 82 can have a similar structure to the receiving container 60, the discussion of which is expressly incorporated herein in its entirety. For example, each of the first storage container 80 and the second storage container 82 can be a fixed volume container, such as one having a crown 84 and a neck 85, surrounding a chamber. The chamber can be sealed by a vial seal 86 at the crown 84, which is circumferentially attached by aluminum tape. Each of the first storage container 80 and the second storage container 82 can be attached to the vial adapter 70, as discussed with reference to the receiving container 60.

[0029] The first substance of the first storage container 80 can be an aqueous solution. The aqueous solution can be any aqueous buffer that can be used to dissolve nucleic acids. For example, in some embodiments, the aqueous solution can be a solution of 20mM citrate and 300mM NaCl and have a pH in the range of 3 to 6. In some embodiments, the aqueous solution can be a 20mM phosphate buffered saline (PBS) with a pH of 7. In some embodiments, the aqueous solution can be a solution of 5mM to 25mM sodium acetate buffer with a pH in the range of 4 to 6.

[0030] The second substance of the second storage container 82 can be a lipid solution, the composition of which comprises in whole or in part an organic solvent with a lipid or lipid mixture. The lipid solution can include a clinical grade lipid dissolved in an organic alcohol solution (e.g., ethanol). In some embodiments, the lipid solution can be an alcohol solution of at least 25%. In some embodiments, the lipid solution can be an alcohol solution of at least 40%. In some embodiments, the lipid solution can be an alcohol solution of at least 60%. The alcohol solution is preferably an ethanol solution. Providing lipids in an alcohol with an increased concentration (e.g., an alcohol solution greater than 40%) can subject the lipids in the alcohol solution to dilution by a reconstructing agent without affecting the quality of the resulting drug complex. The lipid composition in the ethanol solution can be composed of ionizable lipids or cationic lipids or synthetic lipids, structural lipids, PEG-lipids or their derivatives and cholesterol or their derivatives. However, the second substance can include other nanoparticles forming solutions.

[0031] The therapeutic agent may be carried in at least one of the first substance and / or the second substance. In a preferred embodiment, the therapeutic agent is carried in the first substance. The therapeutic agent may include nucleic acids, drugs, proteins, oligonucleotides, etc. comprising a gene editing complex. The nucleic acid may include RNA and / or DNA. RNA may be in the form of oligonucleotide RNA, tRNA (transfer RNA), snRNA (small nuclear RNA), rRNA (ribosomal RNA), mRNA (messenger RNA), antisense RNA, siRNA (small interfering RNA), shRNA (short hairpin RNA), ncRNA (non-coding RNA), aptamers, ribozymes, chimeric sequences, or derivatives of these groups. The gene editing complex may include gRNA (guide RNA), cas 9 protein, mRNA or DNA encoding cas 9 protein or CRISPR-cas9 gRNA complex. DNA may be in the form of antisense, plasmid DNA, part of plasmid DNA, pre-condensed DNA, polymerase chain reaction (PCR) product, vector (P1, PAC, BAC, YAC, artificial chromosome), expression cassette, chimeric sequence, chromosomal DNA, or derivatives of these groups.

[0032] In some embodiments, the therapeutic agent can be stored in a dehydrated and / or lyophilized state and reconstituted in an aqueous solution to form the first substance prior to introduction into the microfluidic device 100. In this case, the first storage container 80 can contain the dehydrated therapeutic agent, and the first container 20 can contain the aqueous solution. The aqueous solution can then be introduced from the first container 20 into the first storage container 80 to reconstitute the therapeutic agent. The first solution including the therapeutic agent can then be introduced into the first container 20 for introduction into the adapter.

[0033] The first substance (wherein the therapeutic agent is in a lyophilized state or as a solution) and the second substance can be suitable for transport and medium-term or long-term storage at room temperature. Thus, the system and microfluidic device 100 disclosed herein can make it possible to alleviate the obstacles associated with storing and transporting RNA-LNP complexes at excessively low temperatures. In addition, the microfluidic device 100 can be easily used at the point of care.

[0034] The first substance and the second substance can be mixed with the microfluidic device 100 as described herein. The mixing can produce a liposome formation, which embeds the therapeutic agent while forming the liposome. The electrostatic interaction between the negatively charged therapeutic agent (e.g., nucleic acid) and the positively charged cationic lipid can form an encapsulation, thereby forming a drug complex. The drug complex can be a monodisperse lipid nanoparticle (LNP). Therefore, the system and the microfluidic device 100 can be used to form an RNA-LNP (e.g., mRNA-LNP) complex to be injected by mixing the components of an aqueous solution containing RNA and a lipid solution. Considering the specific example of forming an mRNA-LNP drug complex, the complex can be formed by mixing a first substance containing mRNA (or RNA) from the first container 20 and a second substance from the lipid solution of the second container 40.

[0035] Based on the mixture of expectation, the first storage container 80 and the second storage container 82 can have the same or different sizes. Therefore, any reference to two storage containers 80, 82 herein should be interpreted as comprising three or more storage containers 80, 82. Should be understood that, if more than two components are to be mixed, more than two containers can be provided, wherein each container can include at least one component. In addition, any number of components can be provided in an unmixed state in a single container. In some embodiments, the first container 20 and the second container 40 can be pre-filled with corresponding substances, for example, embodied as a pre-filled syringe, so that the first storage container 80 and the second storage container 82 can be omitted.

[0036] The microfluidic device 100 can define a first port 102 configured to connect to the syringe connector 26 of the first container 20 and a second port or connector member 104 configured to attach to the syringe connector 46 of the second container 40. The first port 102 and the second port 104 can be connected to a first upper portion of a mixing member 106. A third port or connector member 108 can be connected at a second bottom portion of the mixing member 106.

[0037] The first port 102 can be configured to be received by the first syringe connector 26 and have external threads 103 that are configured to threadably engage the internal threads of the first connector 26. Similarly, the second port 104 can be configured to be received by the second connector 46 and have external threads 105 surrounding the second tubular member 108 that are configured to threadably engage the internal threads of the second syringe connector 46. For example, the ports 102, 104 can be female Luer connectors, and the connectors 26, 46 of the containers 20, 40 can be male Luer connectors. However, additionally or alternatively, the ports 102, 104 can be connected to the containers 20, 40 using other types of connections, such as snap fits, friction fits, and / or press fits. The microfluidic device 100 can be configured to connect to any number of first and second containers 20, 40, and the microfluidic device 100 can have an equal number of ports 102, 104 for connecting to each of the containers 20, 40, respectively. Furthermore, one or more of the ports 102 , 104 may include a one-way valve (not shown) to allow fluid to flow from the container 20 , 40 into the microfluidic device 100 and to limit or substantially prevent fluid flow out of the microfluidic device 100 back into the respective container 20 , 40 .

[0038] The first port 102 can define a first inlet channel 110, and the second connector member 104 can define a second inlet channel 112. In some embodiments, the first inlet channel 110 can be configured to receive the tip of the first syringe 20 so that the chamber of the first syringe body 22 is in fluid communication with the first inlet channel 110, and the second inlet channel 112 can be configured to receive the tip of the second syringe 40 so that the chamber of the second syringe body 42 is in fluid communication with the second connector channel 112. In some embodiments (not shown), the first port 102 and the second port 104 can extend substantially parallel to each other to facilitate joint actuation of the syringes 20 and 40. The first inlet channel 110 and the second inlet channel 112 can extend at an angle to the mixing member 106. The angle can be at least 90 degrees, and in some embodiments, can be between about 120 degrees and about 160 degrees. For example, the mixing member 106, the first port 102, and the second port 104 can form a Y-shaped portion of the microfluidic device 100. The mixing body 106 can define a microfluidic channel 114.

[0039] Figure 2 An embodiment of a microfluidic channel 114 is shown. The microfluidic channel 114 may include a passage extending along the longitudinal axis of the mixing body 106. The passage of the microfluidic channel 114 may include a plurality of dimples 120 formed in the mixing body 106 of the microfluidic device 100. The microfluidic channel 114 may extend along the longitudinal axis of the microfluidic body 106, and the dimples 120 may extend radially outward from the microfluidic channel 114 and be recessed into the mixing body 106. Thus, with this configuration, the path of fluid flowing through the microfluidic channel 114 may be tortuous, extending into and out of the dimples 120. The tortuous path may meander from the longitudinal axis of the mixing body 106. This fluid obstruction geometry defined by the dimples 120 may produce chaotic flow that purposefully induces eddies and turbulence to mix the fluidic substances, thereby improving mixing and producing drug complexes of uniform size.

[0040] like Figure 2As shown, pit 120 can be arranged continuously around the periphery of microfluidic channel 114 and along its longitudinal axis in a three-dimensional manner. Therefore, pit 120 can be formed around microfluidic channel 114 (for example, above, below, side, circumferentially around microfluidic channel, etc.), thereby allowing to make full use of microfluidic channel 114 to perform mixing. In some embodiments, pit 120 can be formed along the entire length of microfluidic channel 114. This configuration can improve the efficiency of two-dimensional channel and provide a predictable fluid flow by microfluidic channel 114. The size, shape, orientation, position and pattern of this fluid obstacle geometry configuration can be tuned to allow the specific chaotic mixing that produces the predicted flow pattern. The pit 120 can be arranged around microfluidic channel 114 circumferentially in groups that are longitudinally staggered or angularly offset so that longitudinally adjacent pits 120 are not aligned along its central axis. These groups can be formed by a first group of pits 120a and a second group of pits 120b, which are rotationally offset and alternately along the longitudinal axis of microfluidic channel 114. Staggering allows adjacent dimples 120 to approach and / or overlap longitudinally, thereby increasing the density of dimples 120. The dimples 120 may have a circular cross-section and / or have a width or diameter w of about 200 μm to about 500 μm. For example, the dimples 120 may be circular with a diameter between about 280 μm and about 325 μm. Based on manufacturing tolerances, the width or diameter of the dimples 120 may be substantially uniform. The longitudinally aligned dimples 120 may be spaced apart by a distance d (center to center) of about 500 μm to about 800 μm. The variable width or diameter of the microfluidic channel 114 may vary due to the dimples 120. The microfluidic channel 114 may have a shorter width w1 of about 400 μm to about 600 μm and a larger width w2 of about 600 μm to about 800 μm. Further discussion of embodiments of the dimples is provided in U.S. Patent Publication No. 2023 / 0105059, which is previously incorporated herein by reference.

[0041] return Figure 1, the microfluidic device 100 can have a third port or connector member 108 at the bottom portion of the mixing member 106. In some embodiments, the third connector member 108 can include a tip configured to be attached to the receiving container 60 via the vial adapter 70. In some embodiments, the third connector member 108 can have a sleeve in the form of a male Luer connector (not shown). The tip can have an outlet channel 125 that communicates with the second or bottom portion of the microfluidic channel 114. The tip can be received in the connector 74 of the vial adapter 70, and the sleeve can be threadedly connected to the outer surface of the connector 74 with a Luer connection. The third connector member 108 can be a male Luer connector that is configured to connect to the female Luer connector of the vial adapter 70. However, additionally or alternatively, the connector member 108 can be connected to the third container 60 using other types of connections, such as snap fit and / or press fit. The outlet channel 125 can provide a passage for the mixed composition from the mixing chamber 124 to the receiving container 60.

[0042] The microfluidic device 100 can be formed by polymer, metal and / or glass. In a preferred embodiment, the microfluidic device 100 can be formed as a single integral piece (e.g., by injection molding or 3D printing) comprising a first port 102, a second port 104, a mixing member 106, a tubular member 129 and / or a connector member 108. Alternatively, the microfluidic device 100 can be formed by two pieces (e.g., two halves) and fixed or fused together, each piece being a metal, a polymer or a glass. In order to increase the ease with which the fluid to be mixed flows through the microfluidic device 100, a low surface energy material can be used for at least a portion of the microfluidic device 100. For example, in some embodiments, the microfluidic device 100 can be formed by or coated with a low surface energy material such as ethylene tetrafluoroethylene (ETFE). Other low surface energy materials can also be used, e.g., fluoropolymer materials except ETFE. Alternatively, at least one path can be processed to reduce surface energy. Forming the sides of the microfluidic channel 114 of a low surface energy material can reduce the loss of components across the microfluidic channel 114 during use, thereby enabling the microfluidic device 100 to operate more efficiently. Although low surface energy materials can provide additional advantages in some embodiments, they are an optional feature of the present disclosure. In some embodiments, as discussed below, the microfluidic device 100 can additionally or alternatively be formed from an elastomer, such as silicone, rubber, and / or a thermoplastic elastomer.

[0043] Figure 3 A method 1000 of forming a microfluidic device 100 by injection molding is shown, and Figure 4An embodiment of a core pin 200 that can be used in method 1000 is shown. Method 1000 and core pin 200 can address shortcomings in the fabrication of three-dimensional internal components, such as the microfluidic channel 114 of the microfluidic device 100. Method 1000 can fabricate the microfluidic device 100 as a single, unitary piece by injection molding. Method 1000 can eliminate manufacturing limitations by utilizing an elastomeric material for at least one of the core pin 200 and / or the microfluidic device 100 to facilitate removal of the core pin 200 during fabrication of unique design geometries.

[0044] In step 1002, the core pin 200 may be inserted into a cavity (not shown) of a mold. The mold may be formed from two housing members that are releasably attached and form a cavity. Figure 4 As shown, the core pin 200 can have an elongated shaft 202 with a plurality of protrusions 204 on an outer surface of the elongated shaft 202. The protrusions 204 can have a spherical shape and be arranged along the elongated shaft 202 corresponding to the desired arrangement of the dimples 120. In some embodiments, the core pin 200 can be made of an elastomer, such as silicone, rubber, and / or a thermoplastic elastomer.

[0045] In step 1004, one or more materials may be injected into the cavity in liquid form and around the core pin 200. In some embodiments, the one or more materials may include an elastomer, such as silicone, rubber, and / or a thermoplastic elastomer. The one or more materials may be melted as they are injected to conform to the core pin 200 within the cavity.

[0046] In step 1006, a component including a microfluidic channel having a plurality of dimples can be formed from one or more materials. The component can be formed by cooling the one or more materials. The one or more materials can be cross-linked and / or vulcanized to form a component, such as the microfluidic device 100. The one or more materials can be formed into a microfluidic channel 114 along the axis 202, wherein the dimples 120 are formed around the protrusions 204 to form the desired obstacle geometry.

[0047] In step 1006, the injection molded part, such as the microfluidic device 100, can be removed from the cavity of the mold. The core pin 200 can be removed from the microfluidic channel 114 of the microfluidic device 100. The flexibility of the elastomeric material of the microfluidic device 100 and / or the core pin 200 can allow the core pin 200 to be withdrawn from the microfluidic device 100 without stripping the dimple 120 from the microfluidic channel 114. In some embodiments, the core pin 200 can be removed from the microfluidic device 100 using an air ejector system in the mold assembly that applies pressure to release the core pin 200 from the microfluidic device 100.

[0048] Figure 5A second embodiment of a microfluidic device 200 is shown that can be implemented in system 10. Microfluidic device 200 can include a first inlet channel 210 configured to receive a first substance or component and a second channel 212 that can be configured to receive a second substance or component. In some embodiments, the first substance can be an aqueous solution and the second substance can be a lipid solution, as discussed with reference to system and microfluidic device 100, which discussion is expressly incorporated herein by reference in its entirety.

[0049] The microfluidic device 200 may include a microfluidic channel 215 having a first portion that is connected to a first inlet channel 210 and a second channel 212. The microfluidic channel 215 may be configured to mix a first substance and a second substance and / or separate the formed nanoparticles by size. The microfluidic channel 215 may have a plurality of obstacles 220 that are arranged to guide a plurality of specific chaotic flow streams in the microfluidic channel 215. The flow stream may be generated by the variable arrangement of the obstacles 220, forcing larger nanoparticles along one or more first fluid paths and forcing smaller nanoparticles along one or more second fluid paths. The plurality of obstacles 220 may include a first group of obstacles 220a that are longitudinally arranged along the first fluid path of the microfluidic channel 215. The plurality of obstacles 220 may include a second group of obstacles 220b that are longitudinally arranged along the first and second paths of the microfluidic channel 215. The plurality of obstacles 220 may include a third group of obstacles 220b that are longitudinally arranged along the third and second paths of the microfluidic channel 215.

[0050] In some embodiments, the first group of obstacles 220a may be separated by a first distance, and the second group of obstacles 220b may be separated by a second distance, wherein the first distance is different from the second distance. The third group of obstacles 220c may be separated by a third distance, wherein the third distance may be the same as the second distance. In some embodiments, the first group of obstacles 220a may have a first width or diameter, and the second group of obstacles 220b may have a second width or diameter, wherein the first width or diameter is different from the second width or diameter. The third group of obstacles 220c may have a third width or diameter, wherein the third width or diameter may be the same as the third distance. In some embodiments, the first group of obstacles 220a may have a first depth, and the second group of obstacles 220b may have a second depth, wherein the first depth is different from the second depth. The third group of obstacles 220c may have a third depth, wherein the third depth may be the same as the third depth. Thus, the obstacle geometry of obstacles 220 can generally force larger nanoparticles along one or more fluid paths and force smaller nanoparticles along one or more different fluid paths.

[0051] like Figure 5As further shown, a first set of obstacles 220a can be arranged along a centerline or axis of channel 214 on a central portion and configured to direct nanoparticles to a first outlet channel 225a. A second set of obstacles 220b can be arranged on a first lateral portion of channel 214 and configured to direct nanoparticles to a second outlet channel 225b. A second set of obstacles 220b can be arranged on a second lateral portion of channel 214 and configured to direct nanoparticles to a third outlet channel 225c. The second set of obstacles 220b and the third set of obstacles 220c can be on opposite lateral sides of the first set of obstacles 220a.

[0052] In some embodiments, the first width or diameter may be smaller than the second width or diameter and / or the third width or diameter. For example, the first width or diameter may be from about 50 μm to about 200 μm, and the second width or diameter and / or the third width or diameter may be from about 200 μm to about 500 μm. Additionally or alternatively, the first distance may be smaller than the second distance and / or the third distance. Additionally or alternatively, the third depth may be smaller than the second depth and / or the third depth. Thus, in some embodiments, the obstacle geometry of channel 214 may keep smaller particles in the center of channel 214 and be directed into the first outlet channel 225a, and force larger particles to the outer edge of channel 214 and be directed into the second outlet channel 225b. The obstacle geometry may separate particles by size to produce a high-quality, collectible yield of particles of the desired size.

[0053] The size and configuration of obstacles 220 can be designed based on the desired size and source of the nanoparticles. In some embodiments, the first width or diameter can be greater than the second width or diameter and / or the third width or diameter. Additionally or alternatively, the first distance can be greater than the second distance and / or the third distance. Additionally or alternatively, the third depth can be greater than the second depth and / or the third depth. In some embodiments, the third set of obstacles 220c can be different from the second set of obstacles 220b. In some embodiments, when two fluid paths are desired, the third set of obstacles 220c and / or the third outlet channel 225c can be omitted.

[0054] The microfluidic channel 215 can have a generally rectangular cross-section having a pair of long sides extending the width of the microfluidic channel 215 and a pair of short sides extending the height of the microfluidic channel 215. The obstacle 220 can extend to or from a flat bottom surface of the microfluidic channel 215. In some embodiments, the obstacle 220 can extend from multiple surfaces of the microfluidic channel 215, for example, the obstacle can extend to or from a flat bottom surface formed by a first long side and a flat top surface formed by a second long side of the generally rectangular cross-section.

[0055] In some embodiments, the obstacles 220 can be dimples extending from the microfluidic channel 215 , as further discussed with respect to the microfluidic device 100 , which discussion is expressly incorporated herein by reference. In some embodiments, the obstacles 220 can be protrusions extending into the microfluidic channel 215 .

[0056] As further shown, microfluidic device 200 can be in the form of a microfluidic chip or be included in a microfluidic chip. In some embodiments, the microfluidic chip can be formed by a two-piece housing engaged by one or more removable fasteners (such as screws, nuts, bolts, clamps, bands and / or pins). For example, microfluidic channel 114 can be formed in one or two parts of the two-piece housing. However, microfluidic channel 114 can be formed in a separate microfluidic structure or plate contained between the two-piece housing to seal the microfluidic structure therebetween. One or more inlet ports 102, 104 and / or one or more outlet ports 108 (as shown in relation to microfluidic device 100) can be formed in the housing. In some embodiments, microfluidic device 200 can be a single integral piece (e.g., formed by injection molding or 3D printing). Adapter 200 can be manufactured or formed similarly to microfluidic device 100, as expressly incorporated herein by reference.

[0057] The microfluidic channel 215 may be configured to mix the first substance and the second substance to form nanoparticles and separate the nanoparticles, such that the first inlet channel 210 and the second channel 212 may be directly connected to the microfluidic channel 215, as shown. Figure 5 As shown. However, in some embodiments, the nanoparticles may be formed by a second channel (such as microfluidic channel 114) that is fluidically connected to the microfluidic channel 215. Therefore, the system may include a first microfluidic channel (as shown with respect to microfluidic channel 114) having a first cross-section for mixing and a second microfluidic channel (as shown with respect to microfluidic channel 215) having a second cross-section for separating the formed nanoparticles. The inlet ports 210, 212 may be directly connected to the microfluidic channel 115, and the first microfluidic channel 115 and the second microfluidic channel 215 may be connected by a single connecting channel. For example, the first microfluidic channel 115 may have circumferentially arranged pits to mix the first substance and the second substance to form nanoparticles, and the second microfluidic channel 215 may have laterally arranged pits to separate the formed nanoparticles. The microfluidic channel 114 and the microfluidic channel 215 may be in the same chip or different chips. In some embodiments, when on different chips, the chip may have different inlets and / or outlets.

[0058] It will also be understood by those skilled in the art that modifications may be made to the example embodiments described herein without departing from the present invention. Structural features of the systems and devices described herein may be replaced with functionally equivalent parts or omitted entirely. Furthermore, it will be understood that features from the embodiments may be combined with one another without departing from the present disclosure.

Claims

1. A microfluidic device, comprising: at least one entryway; a microfluidic channel having a first portion fluidly connected to the at least one inlet channel; as well as at least one outlet channel fluidly connected to a second portion of the microfluidic channel, The microfluidic channel has a plurality of recesses extending away from an axis of the microfluidic channel.

2. The microfluidic device of claim 1, wherein the at least one inlet channel comprises a first inlet channel and a second inlet channel.

3. The microfluidic device of claim 1, wherein the at least one outlet channel comprises a first outlet channel and a second outlet channel. The microfluidic device of claim 1 , wherein the plurality of dimples are arranged circumferentially around the microfluidic channel. The microfluidic device of claim 4 , wherein the plurality of wells are arranged in longitudinally overlapping groups.

6. A microfluidic device according to claim 1, wherein the plurality of pits include a first group of pits arranged longitudinally along the microfluidic channel and a second group of pits arranged longitudinally along the microfluidic channel, the first group of pits and the second group of pits are laterally offset, and the first group of pits and the second group of pits are constructed to separate nanoparticles by size.

7. The microfluidic device of claim 6, wherein the first set of dimples has a first width or diameter, the second set of dimples has a second width or diameter of a second size, and the first width or diameter and the second width or diameter are different.

8. The microfluidic device of claim 7, wherein the first width or diameter is from about 50 μm to about 200 μm, and the second width or diameter is from about 200 μm to about 500 μm.

9. A microfluidic device according to claim 6, wherein the at least one outlet channel includes a first outlet channel and a second outlet channel, the first group of pits is arranged to guide nanoparticles of a first size to the first outlet channel, and the second group of pits is arranged to guide nanoparticles of a second size to the second outlet channel.

10. The microfluidic device of claim 9, wherein the at least one outlet channel comprises a third outlet channel, and the plurality of wells comprises a third group of wells arranged longitudinally along the microfluidic channel.

11. The microfluidic device of claim 10, wherein the third set of wells is configured to direct nanoparticles of the second size to the third outlet channel.

12. A microfluidic device, comprising: multiple entryways; a microfluidic channel having a first portion fluidly connected to the plurality of inlet channels; as well as a plurality of outlet channels fluidly connected to a second portion of the microfluidic channel, The microfluidic channel has a plurality of recesses extending away from an axis of the microfluidic channel.

13. The microfluidic device of claim 12, wherein the plurality of outlet channels comprises a first outlet channel, a second outlet channel, and a third outlet channel.

14. A microfluidic device according to claim 12, wherein the plurality of wells include a first group of wells arranged to guide nanoparticles of a first size to the first outlet channel, a second group of wells arranged to guide nanoparticles of a second size to the second outlet channel, and a third group of wells arranged to guide nanoparticles of the second size to the second outlet channel.

15. A method of manufacturing a microfluidic channel, the method comprising: injecting one or more elastomeric materials into a mold cavity surrounding a core pin, wherein the core pin has an elongated shaft with a plurality of protrusions extending from an axis of the core pin; forming a component including a microfluidic channel having a plurality of recesses from the one or more elastomeric materials; as well as Remove the core pin from the component.

16. The method of claim 15, further comprising removing the component and center core from the mold cavity before removing the core pin from the component.

17. The method of claim 15, wherein the one or more elastomeric materials can include silicone, rubber, and / or thermoplastic elastomers.

18. The method of claim 15, wherein removing the core pin from the component is performed using a compressed air jet system.

19. The method of claim 15, wherein removing the core pin from the component is performed by sliding the component off the core pin.

20. The method of claim 15, wherein the protrusions are spherical.

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