Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
  • B01F33/30—Micromixers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/14—Details; Accessories therefor
  • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
  • A61J1/2096—Combination of a vial and a syringe for transferring or mixing their contents
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D43/00—Separating particles from liquids, or liquids from solids, otherwise than by sedimentation or filtration
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
  • B01F25/40—Static mixers
  • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
  • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
  • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
  • B01F25/4338—Mixers with a succession of converging-diverging cross-sections, i.e. undulating cross-section
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
  • B01F35/165—Making mixers or parts thereof
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C45/00—Injection moulding, i.e. forcing the required volume of moulding material through a nozzle into a closed mould; Apparatus therefor
  • B29C45/17—Component parts, details or accessories; Auxiliary operations
  • B29C45/40—Removing or ejecting moulded articles
  • B29C45/44—Removing or ejecting moulded articles for undercut articles
  • B29C45/4478—Removing or ejecting moulded articles for undercut articles using non-rigid undercut forming elements, e.g. elastic or resilient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/14—Details; Accessories therefor
  • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
  • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
  • A61J1/2068—Venting means
  • A61J1/2075—Venting means for external venting
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
  • B01F2101/22—Mixing of ingredients for pharmaceutical or medical compositions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
  • B01F2101/2305—Mixers of the two-component package type, i.e. where at least two components are separately stored, and are mixed in the moment of application
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C45/00—Injection moulding, i.e. forcing the required volume of moulding material through a nozzle into a closed mould; Apparatus therefor
  • B29C2045/0087—Injection moulding, i.e. forcing the required volume of moulding material through a nozzle into a closed mould; Apparatus therefor making hollow articles using a floating core movable in the mould cavity by fluid pressure and expelling molten excess material
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C33/00—Moulds or cores; Details thereof or accessories therefor
  • B29C33/44—Moulds or cores; Details thereof or accessories therefor with means for, or specially constructed to facilitate, the removal of articles, e.g. of undercut articles
  • B29C33/46—Moulds or cores; Details thereof or accessories therefor with means for, or specially constructed to facilitate, the removal of articles, e.g. of undercut articles using fluid pressure
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
  • B29L2031/00—Other particular articles
  • B29L2031/753—Medical equipment; Accessories therefor

Definitions

• RNA-LNP messenger RNA-lipid nanoparticle
• rnRNA messenger RNA
• CMC Chemical & Manufacturing Control
• rnRNA provided alone is not readily absorbed or delivered effectively to human immune cells and has unstable chemical and physical properties, therefore is not effective for use as a vaccine.
• absorption and stability of rnRNA can be increased to effective levels if it is encapsulated within lipid nanoparticle (LNP) vectors.
• Preparation of mRNA-LNP vaccines is achieved by mixing lipids dissolved ethanol with RNA in buffers, under closely controlled conditions. Such mixing is usually carried out in a laboratory using devices which are often inappropriate for high-scale distribution, due to their low durability, high cost, high complexity, low lot-to-lot consistency and/or high interbatch variation.
• mRNA-LNP vaccines are stored at extremely low temperatures (typically -20 to -80 degrees Celsius). This is a problem because low temperature distribution is expensive and logistically complex. Additionally, there is a risk of mRNA-LNP vaccines being wasted if, for example, the low-temperature environment at any stage in the distribution chain were to fail.
• Non-messenger RNA drugs such as RNAi, siRNA and other oligonucleotides can also be formed into lipid nanoparticle compositions (RNA-LNP).
• RNA-LNP drugs can be chemically modified to improve their stability and shelf life at room temperature (such chemical modification is not possible for mRNA-LNP technology which requires interaction with cellular proteins to function appropriately). Chemical modification of RNA-LNP can be difficult and expensive to achieve but is nonetheless often preferred to avoid the significant distribution costs associated with non-modified RNA-LNP drugs which must similarly be kept at very low temperatures, as well as the difficult ⁇ ' associated with managing drug efficacy over time due to the limited molecular half-life.
• a first aspect of the present disclosure is directed to a microfluidic device having at least one inlet channel: a microfluidic channel having a first portion fluidly connected to the at least one inlet channel; and at least one outlet channel fluidly connected to a second portion of the microfluidic channel, wherein the microfluidic channel has a plurality of dimples extending away from an axis of the microfluidic channel.
• 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.
• the plurality of dimples may be arranged circumferentially around the microfluidic channel. The plurality of dimples may be arranged in sets that longitudinally overlap.
• a second aspect of the disclosure is directed to a microfluidic device having: a plurality of inlet channels; a microfluidic channel having a first portion fluidly connected to the plurality of inlet channels; and a plurality of outlet channels fluidly connected to a second portion of the microfluidic channel, wherein the microfluidic channel has a plurality of dimples extending away from an axis of the microfluidic channel.
• FIG. 3 illustrates an exemplary method of manufacturing the microfluidic device of FIGS. 1 and 2.
• FIG. 4 illustrates an exemplary' core pin used in the method of FIG. 3.
• FIG. 5 illustrates a second embodiment of the microfluidic device of FIG. 1.
• a microfluidic device for connecting one or more fluid containers for mixing first and second substances to produce a pharmaceutical complex.
• the microfluidic device may include a first port or connector member configured to connect to a first container, a second port or connector member configured to connect to a second container, and a third port or connector member configured to connect to a recipient container.
• the microfluidic device may further include a microfluidic channel extending from a first portion in fluid communication with the first port and the second port to a second portion in communication with 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 alignment and structure based on their chemical makeup, charge, and/or shape.
• Each syringe body 22, 42 may have a syringe barrel extending from a proximal end to a distal end along a longitudinal direction. 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 along the longitudinal direction to define a chamber. The chamber may be configured to receive, store, and/or mix the substance for dispensing through a distal opening of the syringe tip.
• the first plunger rod 24 may have a first flange 25 at a proximal end
• the second plunger rod 44 may have a second flange 45 at a proximal end.
• the syringe tip of the first syringe body 22 may include a first connector 26 for engagement with an external device, such as a syringe needle, a container, and/or the microfluidic device 100.
• the syringe tip of the second syringe body 42 may include a second connector 46 for engagement with the same or different external device, such as a syringe needle, a container, and/or the microfluidic device 100.
• Each connector 26, 46 may further include a male Luer connector including the syringe tip and a threaded sleeve around the tip.
• the flange 25, 45 may be actuated either by being pulled to create a negative pressure to pull a substance into the chamber and/or being pushed to create a positive pressure to push the substance out of the chamber.
• At least part of the first syringe 20 and the second syringe 40 may be integrally or releasably connected to enable joint handling and/or actuation of the first syringe 20 and the second syringe 40.
• the system may further have 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, such that the first syringe 20 and the second syringe 40 may be handled together.
• Each of the first and second lumens may be closed or be formed by C-shaped walls configured to snap around the respective syringe body 22, 42.
• the barrel holder may fix the syringe bodies 22, 42 in a substantially parallel arrangement.
• the system may further include a plunger clip configured to translate the plunger rods 24, 44 through the syringe bodies 22, 42 together to push and/or pull the material with the same longitudinal translation.
• the plunger clip may be configured to attach to the flanges 25, 26, such as having a groove configured to releasably receive the flanges 25, 26.
• Embodiments of the barrel holder and/or the plunger clip are further discussed in U.S. Pat. Nos. 5,104,375, 6,840,921, and 8,240,511, the entire disclosures of which are incorporated herein by reference.
• the recipient container 60 may be a fixed volume container, such as a vial attachable to the microfluidic device 100 with a vial adapter 70.
• the vial 60 may include a vial bottle 62 enclosing a chamber and having a crown and a neck.
• the chamber may be sealed by a drug vial seal at the crow n attached circumferentially by an aluminum band.
• the vial adapter 70 may have a transverse top wall 72, a connector 74 extending upwardly from the top wall 72, and a skirt 76 extending downwardly from the top wall 72.
• the connector 74 may be a female Luer connector including an external screw thread for screw 7 thread engagement by a male Luer lock connector, such as that of the microfluidic device 100.
• the skirt 76 may be for telescopic mounting over the crow n and/or the neck of the vial 60.
• the skirt 76 may surround a cannula (not shown) extending downw ardly from the top w all 72 and be configured to puncture the vial stopper.
• the cannula may have a lumen in fluid communication with the chamber of the vial bottle 62 when puncturing the vial stopper.
• the vial adapter 70 may be vented in order to draw air into the container 60 and to ease drawing the fluid through the system. Further discussion of embodiments of the container 60 and/or the vial adapters 70 is provided in U.S. Pat. Nos. 8,753,325 and 9,943,463, the entire disclosures of which are expressly incorporated herein by reference.
• the recipient container 60 may be initially empty and be configured to receive material injected from the first and second containers 20, 40 and mixed in the microfluidic device 100. Once the first and second constituents are introduced into the microfluidic device 100, the resultant pharmaceutical complex may be stored within the recipient container 60.
• the first storage container 80 and/or the second storage container 82 may have similar structure as the recipient container 60, the discussion of w hich is expressly incorporated herein in its entirety.
• each of the first and second storage containers 80, 82 may be a fixed volume container, such as an enclosing a chamber and having a crown 84 and a neck 85.
• the chamber may be sealed by a drug vial seal 86 at the crown 84 attached circumferentially by an aluminum band.
• Each of the first and second storage containers 80, 82 may be attached to a vial adapter 70, as discussed with reference to the recipient container 60.
• the first substance of the first storage container 80 may be an aqueous solution.
• the aqueous solution may be any aqueous buffers which may be used for dissolving nucleic acids.
• the aqueous solution may be a solution of 20 mM Citrate and 300 mM NaCl and have a pH in the range of 3 to 6.
• the aqueous solution may be 20mM phosphate buffer solution (PBS) at pH 7.
• PBS phosphate buffer solution
• the aqueous solution may be a solution of 5mM to 25mM Sodium acetate buffer with pH range from 4 to 6.
• the second substance of the second storage container 82 may be a lipid solution having a composition comprising in whole, or in part, an organic solvent having a lipid or mixture of lipids.
• the lipid solution may include clinical grade lipids solubilized in an organic alcohol solution (e.g, ethanol).
• the lipid solution may be at least 25% alcoholic solution.
• the lipid solution may be at least 40% alcoholic solution.
• the lipid solution may be at least 60% alcoholic solution.
• the alcoholic solution is preferably an ethanolic solution.
• Providing the lipid in an increased concentration of alcohol may allow the lipid in alcoholic solution to withstand dilution by a reconstituting agent without affecting the quality of the resulting pharmaceutical complex.
• the lipids compositions in ethanol solution may be composed of an ionizable lipid or cationic lipids or synthetic lipids, structural lipids, a PEG-lipid or its derivative and cholesterol or its derivatives.
• the second substance may include other nanoparticle forming solutions.
• 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 a nucleic acid including gene editing complexes, a drug, a protein, oligonucleotides or the like.
• the nucleic acid may include RNA and/or DNA.
• the 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 (noncoding RNA), aptamers, ribozy mes, chimeric sequences, or derivatives of these groups.
• Gene editing complexes may include gRNA (guide RNA), cas 9 protein, mRNA or DNA encoding for cas 9 protein or the CRISPR-cas9 gRNA complex.
• the DNA may be in the form of antisense, plasmid DNA, parts of a plasmid DNA, pre-condensed DNA, product of a polymerase chain reaction (PCR), vectors (Pl, PAC, BAC, YAC, artificial chromosomes), expression cassettes, chimeric sequences, chromosomal DNA, or derivatives of these groups.
• the therapeutic agent may be stored in a dehydrated and/or lyophilized state and be reconstituted in the aqueous solution to form the first substance prior to being introduced into the microfluidic device 100.
• the first storage container 80 may hold the dehydrated therapeutic agent
• the first container 20 may hold the aqueous solution.
• the aqueous solution may 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 may then be introduced into the first container 20 to be introduced into the adapter.
• the first substance (with the therapeutic agent in the lyophilized state or as a solution) and the second substance may be adapted for transportation and medium-term or long-term storage at room temperature.
• the system and microfluidic device 100 disclosed herein may enable the obstacles associated with storing and transporting RNA-LNP complexes at prohibitively low temperatures to be mitigated.
• the microfluidic device 100 may be easy to use at the point of care.
• the first substance and the second substance may be mixed with the microfluidic device 100 as discussed herein.
• the mixing may generate liposomal formations that entrap the therapeutic agent coincident with formation of the liposomes.
• An electrostatic interaction between the negatively charged therapeutic agent (e g., nucleic acid) and positively charged cationic lipid may bring about the encapsulation, forming the pharmaceutical complex.
• the pharmaceutical complex may be monodispersed Lipid Nano Particles (LNP).
• the system and microfluidic device 100 may be used to form a ready -to-inject RNA-LNP (for instance, mRNA-LNP) complex by mixing the constituents of the aqueous solution including RNA and the lipid solution.
• the complex may be formed by mixing the first substance including mRNA (or RNA) from the first container 20 and the second substance of the lipid solution from the second container 40.
• the first and second storage containers 80, 82 may be the same or different sizes based on the intended mixture. Any reference to two storage containers 80, 82 herein should therefore be construed as including three or more storage containers 80, 82. It will be appreciated that if more than two constituents are to be mixed then more than two containers may be provided, each of which may contain at least one constituent. Furthermore, any number of constituents can be provided in an unmixed state within a single container. In some embodiments, the first container 20 and the second container 40 may be prefilled with the respective substance, for example embodied as prefdled syringes, such that the first and second storage containers 80, 82 may be omitted.
• the microfluidic device 100 may 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 may be connected to a first upper portion of a mixing member 106.
• a third port or connector member 108 may be connected at a second bottom portion of the mixing member 106.
• the first port 102 may be configured to be received by the first syringe connector 26 and have an external thread 103 configured to threadably engage the internal threads of the first connector 26.
• the second port 104 may be configured to be received by the second connector 46 and have an external thread 105 around the second tubular member 108 configured to threadably engage the internal threads of the second syringe connector 46.
• the ports 102, 104 may be a female Luer connector, and the connectors 26, 46 of the containers 20, 40 may be a male Luer connector.
• the ports 102, 104 may, additionally or alternatively, connect to the containers 20, 40 with other types of connections such as a snap-fit, friction-fit and/or a press-fit.
• the first port 102 may define a first inlet channel 110
• the second connector member 104 may define a second inlet channel 112.
• the first inlet channel 110 may be configured to receive the tip of the first syringe 20 to place the chamber of the first syringe body 22 in fluid communication with the first inlet channel 110
• the second inlet channel 112 may be configured to receive the tip of the second syringe 40 to place the chamber of the second syringe body 42 in fluid communication with the second connector channel 112.
• the first port 102 and the second port 104 may extend substantially parallel to each other to facilitate joint actuation of the syringes 20, 40.
• the first inlet channel 110 and the second inlet channel 112 may extend at an angle to the mixing member 106.
• the angle may be at least 90 degrees, and in some embodiments, may be between about 120 degrees to about 160 degrees.
• the mixing member 106, the first port 102, and the second port 104 may form a Y-shaped portion of the microfluidic device 100.
• the mixing body 106 may define a microfluidic channel 114.
• FIG. 2 illustrates an embodiment of the microfluidic channel 114.
• the microfluidic channel 114 may include a pathway extending along a longitudinal axis of the mixing body 106.
• the pathway 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 a longitudinal axis of the microfluidic body 106, and the dimples 120 may extend radially outwardly from the microfluidic channel 114 and be recessed in the mixing body 106.
• the pathway of the 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 obstacle geometry configuration defined by the dimples 120 may create a purposefully chaotic flow inducing eddies and turbulence to mix substances of the fluids to improve mixing and generate consistently sized pharmaceutical complexes
• the dimples 120 may be continuously disposed around a perimeter and along a longitudinal axis of the microfluidic channel 114 in a three- dimensional manner.
• the dimples 120 may be formed surrounding (e.g., above, below, to the sides, circumferentially around, etc.) the microfluidic channel 114, allowing the full use of the microfluidic channel 114 to perform the mixing.
• the dimples 120 may be formed along an entire length of the microfluidic channel 114. The configuration may increase the efficiency over two-dimensional channels and provides a predictable fluid flow through the microfluidic channel 114.
• the size, shape, orientation, location, and pattern of this fluid obstacle geometry configuration may be tuned to allow for specific chaotic mixing that yields a predictive pattern of flow.
• the dimples 120 may be arranged circumferentially around the microfluidic channel 114 in sets that are longitudinally staggered or angularly offset, such that longitudinally adjacent dimples 120 are not aligned along their central axes.
• the sets may be formed by a first set of dimples 120a and a second set of dimples 120b that are rotationally offset and alternate along the longitudinal axis of the microfluidic channel 114.
• the staggering allows for the adjacent dimples 120 to longitudinally approximated and/or overlap increasing the density of the dimples 120.
• the microfluidic device 100 may have the third port or connector member 108 at the bottom portion of the mixing member 106.
• the third connector member 108 may include a tip configured to attach to the recipient container 60 via the vial adapter 70.
• the third connector member 108 may have a sleeve be in the form of a male Luer connector (not shown).
• the tip may have the outlet channel 125 in communication with a second or bottom portion of the microfluidic channel 114.
• the tip may be received in the connector 74 of the vial adapter 70 and the sleeve may be threadedly connected to an outer surface of the connector 74 in a Luer connection.
• the third connector member 108 may be a male Luer connector configured to connect to a female Luer connector of the vial adapter 70. However, the connector member 108 may, additionally or alternatively, connect to the third container 60 with other types of connections such as a snap-fit and/or a press-fit.
• the outlet channel 125 may provide passage of the mixed composition from the mixing chamber 124 to the recipient container 60.
• the microfluidic device 100 may be formed of a polymer, a metal, and/or a glass.
• the microfluidic device 100 may be formed in a single, unitary piece (for example through injection molding or 3D printing) including the first port 102, the second port 104, the mixing member 106, the tubular member 129, and/or the connector member 108.
• the microfluidic device 100 may be formed of two pieces (e.g, halves) and be secured or fused together, each of which can be a metal, a polymer, or a glass.
• low surface energy materials may be used for at least a portion of the microfluidic device 100.
• the microfluidic device 100 may be formed of or coated with a low surface energy material such as ethylene tetrafluoroethylene (ETFE).
• ETFE ethylene tetrafluoroethylene
• Other low surface energy materials may also be used, for example fluoropolymer materials other than ETFE.
• the at least one path may be treated to reduce the surface energy. Forming the sides of the microfluidic channels 114 of low surface energy materials can reduce loss of constituents across the microfluidic channel 114 during use and therefore may enable the microfluidic device 100 to operate more efficiently.
• the microfluidic device 100 may, additionally or alternatively, be formed of an elastomer, such as a silicone, a rubber, and/or a thermoplastic elastomer.
• the core pin 200 may be inserted into a cavity of a mold (not shown).
• the mold may be formed of two housing members releasably attached and forming the cavity.
• the core pin 200 may have an elongated shaft 202 having a plurality of protrusions 204 on an outer surface of the elongated shaft 202.
• the protrusions 204 may have a spherical shape and be arranged along the elongated shaft 202 corresponding to the desired arrangement of the dimples 120.
• the core pin 200 may be made of an elastomer, such as a silicone, a rubber, and/or a thermoplastic elastomer.
• one or more material may be injected in liquid form into the cavity and around the core pin 200.
• the one or more materials may include an elastomer, such as a silicone, a rubber, and/or a thermoplastic elastomer.
• the one or more materials may be molten when injected to conform around the core pin 200 inside of the cavity.
• a component may be formed including a microfluidic channel with a plurality of dimples from the one or more materials.
• the component may be formed by cooling the one or more materials.
• the one or more materials may crosslink and/or vulcanize to form the component, such as the microfluidic device 100.
• the one or more materials may form the microfluidic channels 114 along the shaft 202 with the dimples 120 being formed around the protrusions 204 to form the desired obstacle geometry.
• the injection molded component such as the microfluidic device 100
• the core pin 200 may be removed from the microfluidic channel 1 14 of the microfluidic device 100.
• the flexibility of the elastomeric material of the microfluidic device 100 and/or the core pin 200 may allow extraction of the core pin 200 from the microfluidic device 100 without stripping the dimples 120 from the microfluidic channel 114.
• the core pin 200 may be removed from the microfluidic device 100 with an air ejector system in the molding assembly that will apply pressure to release the core pine 200 from the microfluidic device 100.
• FIG. 5 illustrates a second embodiment of a microfluidic device 200 that may be implemented in the system 10.
• the microfluidic device 200 may include a first inlet channel 210 configured to a receive a first substance or constituent and a second channel 212 may be configured to receive a second substance or constituent.
• the first substance may be an aqueous solution and the second substance may be a lipid solutions, as discussed with reference to the system and the microfluidic device 100 as expressly incorporated herein by reference in its entirety.
• the microfluidic device 200 may include a microfluidic channel 215 having a first portion in communication with the first inlet channel 210 and the second channel 212.
• the microfluidic channel 215 may be configured to mix the first substance and the second substance and/or separate the formed nanoparticles by size.
• the microfluidic channel 215 may have a plurality of obstacles 220 arranged to direct multiple and specific chaotic flow streams in the microfluidic channel 215. The flow streams may be generated by a variable arrangement of the obstacles 220, forcing larger nanoparticles along one or more first fluid paths and smaller nanoparticles along one or more second fluid paths.
• the plurality of obstacles 220 may include a first set of obstacles 220a arranged longitudinally along a first fluid path of the microfluidic channel 215.
• the plurality of obstacles 220 may include a second set of obstacles 220b arranged longitudinally along a first second path of the microfluidic channel 215.
• the plurality of obstacles 220 may include a third set of obstacles 220b arranged longitudinally along a third second path of the microfluidic channel 215.
• the first set of obstacles 220a may be separated by a first distance and the second set of obstacles 220b may be separated by a second distance, where the first distance is different than the second distance.
• the third set of obstacles 220c may be separated by a third distance, where the third distance may be the same as the second distance.
• the first set of obstacles 220a may have a first width or diameter
• the second set of obstacles 220b may have a second width or diameter, where the first width or diameter is different than the second width or diameter.
• the third set of obstacles 220c may have a third width or diameter, where the third width or diameter may be the same as the third distance.
• the first set of obstacles 220a may have a first depth
• the second set of obstacles 220b may have a second depth, where the first depth is different than the second depth.
• the third set of obstacles 220c may have a third depth, where the third depth may be the same as the third depth.
• the obstacle geometry of the obstacles 220 may generally force larger nanoparticles along one or more fluid paths and smaller nanoparticles along one or more different fluid paths.
• the first width or diameter may be less than the second width or diameter and/or the third width or diameter.
• the first width or diameter may be about 50 pm to about 200 pm
• the second width or diameter and/or the third with or diameter may be about 200 pm to about 500 pm.
• the first distance may be less than the second distance and/or the third distance.
• the third depth may be less than the second depth and/or the third depth.
• the obstacle geometry of the channel 214 may keep smaller particles in the center of the channel 214 guided into the first outlet channel 225a and forcing larger particles to the outer edges of the channel 214 guided into the second outlet channels 225b.
• the obstacle geometry' may separate particles by size to generate a high-quality' collectable yield of particles of desired size.
• the size and configuration of the obstacles 220 may be designed based on the desired size and source of nanoparticles.
• the first width or diameter may be greater than the second width or diameter and/or the third width or diameter.
• the first distance may be greater than the second distance and/or the third distance.
• the third depth may be greater than the second depth and/or the third depth.
• the third set of obstacles 220c may be different than the second set of obstacles 220b.
• the third set of obstacles 220c and/or the third outlet channel 225c may be omitted when two fluid paths are desired.
• the obstacles 220 may be dimples extending from the microfluidic channel 215, as further discussed regarding the microfluidic device 100 as expressly incorporated herein by reference. In some embodiments, the obstacles 220 may be projections extending into the microfluidic channel 215.
• the microfluidic device 200 may be in the form of or be included in a microfluidic chip.
• the microfluidic chip may be formed by a two-piece housing joined by one or more removable fasteners, such as screws, nuts, bolts, clips, straps, and/or pins.
• the microfluidic channel 114 may be formed in or both of the components of the two-piece housing.
• the microfluidic channel 114 may be formed in a separate microfluidic structure or plate received 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 may be formed in the housing.
• the microfluidic device 200 may be a single, unitary piece (for example formed through injection molding or 3D printing).
• the adapter 200 may be made or formed similar to the microfluidic device 100, as expressly incorporated herein by reference.
• the microfluidic channel 215 may be configured to mix the first substance and the second substance to form the 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 illustrated in FIG. 5.
• the nanoparticles may be formed by a second channel, such as the microfluidic channel 114, fluidly connected to the microfluidic channel 215.
• the system may include a first microfluidic channel having a first cross-section for mixing (as illustrated with respect to the microfluidic channel 114) and a second microfluidic channel having a second cross-section for separating the formed nanoparticles (as illustrated with respect to the microfluidic channel 215).
• the inlet ports 210, 212 may be directly connected to the microfluidic channel 115, and the first microfluidic channel 1 15 and the second microfluidic channel 215 may be connected by a single connecting channel.
• the first microfluidic channel 115 may have circumferentially disposed dimples to mix the first and second substances to form the nanoparticles, and the second microfluidic 215 may have laterally disposed dimples 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 chips may have different inlets and/or outlets.

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• 2023
  • 2023-10-03 EP EP23801613.3A patent/EP4598652A2/de active Pending
  • 2023-10-03 KR KR1020257014966A patent/KR20250102032A/ko active Pending
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