WO2023044055A1 - Biodegradable and bioactive fibers, scaffolds, and methods of use thereof - Google Patents
Biodegradable and bioactive fibers, scaffolds, and methods of use thereof Download PDFInfo
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- WO2023044055A1 WO2023044055A1 PCT/US2022/043877 US2022043877W WO2023044055A1 WO 2023044055 A1 WO2023044055 A1 WO 2023044055A1 US 2022043877 W US2022043877 W US 2022043877W WO 2023044055 A1 WO2023044055 A1 WO 2023044055A1
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- WIPO (PCT)
- Prior art keywords
- pullulan
- polymeric fiber
- agent
- reservoir
- scaffold
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Classifications
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/28—Polysaccharides or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/0241—Containing particulates characterized by their shape and/or structure
- A61K8/027—Fibers; Fibrils
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
Definitions
- biodegradable nonwoven fibers comprising the same, methods of making the same, and methods of use thereof.
- the composition and methods disclosed herein provide, among other things, means to treat skin-associated conditions.
- the solution comprises water.
- the solution further comprises a crosslinking agent.
- the crosslinking agent covalently cross-links the pullulan.
- the solution comprises about 1 % (w/v) to about 20% (w/v) of the crosslinking agent.
- the cross-linking agent comprises citric acid, citric acid anhydride, or the combination thereof.
- the solution further comprises a therapeutic agent.
- the therapeutic agent is an anti-microbial agent, an anti-fungal agent, an anti-acne agent, an anti-inflammatory agent, an anti-aging agent, or a wound healing agent.
- the therapeutic agent is formulated in a formulation that maintains the stability of the therapeutic agent.
- the at least one flow of gas comprises a plurality of flows of gas that converge and form a combined gas flow in the first direction.
- a total gas flow rate of the plurality of converging flows of gas is controllable to change a distance from the reservoir at which the focused fiber deposition stream of the at least one micron or nanometer dimension polymeric fiber has the tightest focus.
- the focused fiber deposition stream has a substantially tangential orientation to the target surface during fiber collection.
- the method further comprises at least partially blocking flow of gas from upstream of the reservoir to reduce an effect of airflow upstream of the plurality of gas flow sources on focusing of the fiber deposition stream of the at least one micron or nanometer dimension polymeric fiber.
- the orifice is about 0.5 mm to about 2 mm in diameter.
- the present invention provides a method for forming a non-woven polymeric fiber scaffold comprising pullulan.
- the method includes rotating a reservoir holding a solution comprising about 20% w/v pullulan and between about 1 % w/v and 20% w/v citric acid about a rotation axis to eject at least one jet of pullulan from at least one orifice defined by an outer sidewall of the reservoir; directing at least one flow of gas through a portion of the reservoir radially inward of the outer sidewall, the at least one flow of gas directed from an upstream first end of the reservoir to a downstream second end of the reservoir during rotation of the reservoir and ejection of the at least one jet of the pullulan to form at least one polymeric fiber comprising pullulan, the at least one flow of gas entraining the at least one polymeric fiber comprising pullulan and forming a focused pullulan fiber deposition stream of the at least one poly
- the polymeric fiber is formed from a solution comprising pullulan, wherein the solution further comprises a cross-linking agent that covalently crosslinks the pullulan.
- the fiber scaffold comprises an intra-fiber linkage, an inter-fiber linkage, or the combination thereof.
- each polymeric fiber independently has a diameter in a range of about 200 nm to 10 pm.
- the fiber scaffold further comprises a therapeutic agent.
- the therapeutic agent is a fatty acid, a surfactants, a ceramides, or a metal.
- the therapeutic agent is an anti-microbial agent, an anti-fungal agent, an anti-acne agent, an anti-inflammatory agent, an anti-aging agent, or a wound healing agent.
- the therapeutic agent is formulated in a formulation that maintains the stability of the therapeutic agent.
- the polymeric fiber is formed from a solution comprising the pullulan, wherein the solution further comprises the therapeutic agent.
- the therapeutic agent comprises an anti-inflammatory agent.
- the anti-inflammatory agent comprises a phytoestrogen.
- the phytoestrogen comprises a genistein.
- the therapeutic agent comprises a wound-healing agent.
- the therapeutic agent comprises an anti-aging agent.
- the anti-aging agent is genistein.
- the anti-aging agent comprises a genistein.
- the present invention also provides a method for treating a subject having a skin disorder or condition.
- the method includes providing a polymeric fiber scaffold of the invention; and disposing the polymeric fiber scaffold on, over, or in an area of skin affected by the disorder or the condition, thereby treating the subject.
- the method further comprises keeping the polymeric fiber scaffold disposed on, over or in the skin area during treatment.
- the method promotes wound healing of the subject.
- the method reduces inflammation of the subject.
- the method promotes tissue regeneration in the subject.
- the method delays aging of skin in the subject.
- FIG. 1 is a schematic depicting an exemplary embodiment of the present invention.
- FIG. 2A is a schematic depicting an exemplary embodiment of the present invention.
- a polymer e.g., a pullulan
- a bioactive agent such as genistein, used a therapeutic agent, may be optionally incorporated into the nonwoven fabrics.
- the nanofiber is made through a one-step synthesis using rotary jet spinning.
- FIG. 2B is a schematic depicting the structure of a pullulan polymer.
- FIG. 2C is a schematic depicting the structure of geneistein.
- FIG. 2D is a schematic of the activation of genistin to genistein.
- FIGs. 3A-3B are table, images and graphs depicting pullulan nanofiber scaffold topology characterization.
- FIG. 3A is a table depicting the parameters used to make the nanofibers and scaffolds of the invention.
- FIG. 3B includes image of the nanofibers and scaffolds, and the scanning electron microscope images of the nanofibers.
- FIG. 3C is a graph depicting the distribution of the diameters of nanofibers.
- FIG. 4 is an image depicting the Fourier-transform infrared spectroscopy (FTIR) analysis of pullulan.
- FTIR Fourier-transform infrared spectroscopy
- FIG. 5 is a schematic depicting the mechanisms of biopolymer crosslinking.
- FIG. 6 includes schematics depicting exemplary mechanism of pullulan crosslinking with citric acid.
- the exemplary mechanism allows for the one-step in situ crosslinking of pullulan nanofibers.
- FIGs. 7A-7C include table, images, and graphs depicting characterization of citric acid crosslinked pullulan nanofibers.
- FIG. 7A is a table depicting the parameters used to make the nanofibers and scaffolds.
- FIG. 7B includes phase-contrast microscopic images of nanofibers and scaffolds prepared using difference concentration of citric acid (CA).
- FIG. 7C includes graphs depicting the distribution of the diameters of the nanofibers synthesized with different concentration of citric acid (CA).
- the present invention is based, at least in part, on the fabrication of polymeric fibers, e.g., micron, submicron or nanometer dimension polymeric fibers comprising one or more water soluble polymers, e.g., pullulan, and non-woven polymeric scaffolds comprising the polymeric fibers that are bio-degradable.
- polymeric fibers e.g., micron, submicron or nanometer dimension polymeric fibers comprising one or more water soluble polymers, e.g., pullulan, and non-woven polymeric scaffolds comprising the polymeric fibers that are bio-degradable.
- novel biodegradable nanofibers and scaffolds comprising the same, methods for making the same, and methods for using the same in treating cutaneous disorders.
- the nanofibers and scaffolds comprising the same further comprise an active ingredient that can be used for treating various cutaneous disorders or conditions.
- the polymeric fibers, e.g., pullulan fibers, according to the present invention possess several superior properties.
- the pullulan fibers are biodegraded and, thus, are environment friendly.
- Methods to produce the fibers and scaffolds are also straightforward and cost-effective.
- the polymer monomers e.g., pullulan
- the polymer monomers can be dissolved in cold water and a water solution of pullulan can be used to fabricate the fiber and the scaffold, thus eliminating the need for volatile solvents.
- the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
- One of ordinary skill in the art will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
- the term “substantially” may therefore be used in some embodiments herein to capture potential lack of completeness inherent in many biological and chemical phenomena.
- weight/volume percentages (w/v%) associated with the fibers and scaffolds of the invention mean that the related fibers and scaffolds are prepared using a solution containing such amounts expressed as w/v%.
- “pullulan (20 wt/v%) nanofibers” means that the fibers are prepared using a solution containing 20 wt/v% pullulan.
- “pullulan / citric acid (20 wt/v% / 5 wt/v%) nanofibers” means that the fibers are prepared using a solution containing 20 wt/v% pullulan and 5 wt/v% citric acid.
- the present invention provides polymeric fibers, e.g., pullulan fibers, and non-woven polymeric fiber scaffolds comprising a plurality of polymeric fibers that can be used in treating cutaneous disorders.
- polymeric fibers e.g., pullulan fibers
- non-woven polymeric fiber scaffolds comprising a plurality of polymeric fibers that can be used in treating cutaneous disorders.
- fiber and polymeric fiber are used interchangeably herein, and both terms refer to polymeric fibers having micron, submicron, and nanometer dimensions.
- scaffold refers to a structure comprising a plurality of polymeric fibers that provides structure to a tissue and allows an active ingredient to be released therefrom to the tissue.
- the polymeric fiber scaffolds of the invention may further include an additional therapeutic agent, such as an anti-inflammatory or anti-aging agent.
- an additional therapeutic agent such as an anti-inflammatory or anti-aging agent.
- the polymeric fibers may be contacted with additional agents which will allow the agents to, for example, coat (fully or partially) the fibers.
- the polymer solution is contacted with the additional agent during the fabrication of the polymeric fibers which allows the agents to be incorporated into the polymeric fibers themselves.
- the additional therapeutic agent is an anti-inflammatory agent, e.g., genistein.
- the additional therapeutic agent is an anti-aging agent, e.g., genistein.
- the additional agent is an anti-acne agent.
- the additional therapeutic agent is an anti-fungal agent.
- the additional therapeutic agent is an anti-microbial, agent
- the scaffolds of the invention may be used for a variety of cutaneous applications, for example, a cutaneous covering or a sheet mask that covers and delivers a therapeutic agent, e.g., an anti-inflammatory agent to an area of skin that needs treatment.
- a therapeutic agent e.g., an anti-inflammatory agent to an area of skin that needs treatment.
- the scaffolds of the invention may also be combined with other substances, such as, therapeutic agents (such as an anti-inflammatory, anti-acne, anti-fungal, anti-microboal or anti-aging agent) during or after fabrication of the polymeric fibers and scaffolds in order to deliver such substances to the site of application of the polymeric fiber scaffolds.
- therapeutic agents such as an anti-inflammatory, anti-acne, anti-fungal, anti-microboal or anti-aging agent
- Suitable devices and methods of use of such devices for fabricating the polymeric fiber (micron, submicron or nanometer dimension polymeric fiber) scaffolds of the present invention are described in U.S. Patent Nos. 9,410,267 and 9,738,046, and U.S. Patent Publication Nos. 2013/0312638, 2015/0354094, and 2020/0376170, the entire contents of each of which are incorporated herein by reference.
- Exemplary fiber formation devices do not employ a nozzle for ejecting the liquid material, a spinneret or rotating reservoir containing and ejecting the liquid material, or an electrostatic voltage potential for forming the fibers.
- the exemplary devices described herein are simplified as they do not employ a spinneret or an electrostatic voltage potential.
- the lack of a nozzle for ejecting the liquid material in exemplary devices avoids the issue of clogging of the nozzle.
- suitable devices for fabricating the polymeric fiber scaffolds of the invention which may, in some embodiments, be configured in a desired shape, may include a reservoir for holding a polymer, the reservoir including one or more orifices for ejecting the polymer during fiber formation, and a collection device, e.g., a mandrel, for accepting the formed polymeric fiber, wherein at least one of the reservoir and the collection device employs rotational motion during fiber formation, and the device is free of an electrical field, e.g., a high voltage electrical field.
- RJS rotary jet spinning
- the device may include a rotary motion generator for imparting a rotational motion to the reservoir and, in some exemplary embodiments, to the collection device.
- a flexible air foil is attached to a shaft of the motor above the reservoir to facilitate fiber collection and solvent evaporation.
- Rotational speeds of the reservoir in exemplary embodiments may range from about 1 ,000 rpm-60,000 rpm, about 1 ,000 rpm-50,000 rpm, about 1 ,000 rpm to about 40,000 rpm, about 1 ,000 rpm-30,000 rpm, about 1,000 rpm to about 20,000 rpm, about 1,000 rpm- 10,000 rpm, about 5,000 rpm-60,000 rpm, about 5,000 rpm-50,000 rpm, about 5,000 rpm to about 40,000 rpm, about 5,000 rpm-30,000 rpm, about 5,000 rpm-20,000 rpm, about 5,000 rpm to about 15,000 rpm, about 5,000 rpm- 10,000 rpm, about 10,000 rpm-60,000 rpm, about 10,000 rpm-50,000 rpm, about 10,000 rpm to about 40,000 rpm, about 10,000 rpm-30,000 rpm, about 10,000 rpm-20,000 rpm, about 10,000 rpm-50,000 rpm, about
- rotational speeds of the reservoir of about 50,000 rpm-400,000 rpm are intended to be encompassed by the invention.
- devices employing rotational motion may be rotated at a speed greater than about 50, 000 rpm, greater than about 55,000 rpm, greater than about 60,000 rpm, greater than about 65,000 rpm, greater than about 70,000 rpm, greater than about 75,000 rpm, greater than about 80,000 rpm, greater than about 85,000 rpm, greater than about 90,000 rpm, greater than about 95,000 rpm, greater than about 100,000 rpm, greater than about 105,000 rpm, greater than about 110,000 rpm, greater than about 115,000 rpm, greater than about
- Rotational speeds of the collection device in exemplary embodiments may range from about 1,000 to about 10,000 rpm. Ranges and values intermediate to the above recited range and values are also contemplated to be part of the invention.
- Exemplary devices employing rotational motion may be rotated for a time sufficient to form a desired polymeric fiber, such as, for example, about 1 minute to about 100 minutes, about 1 minute to about 60 minutes, about 10 minutes to about 60 minutes, about 30 minutes to about 60 minutes, about 1 minute to about 30 minutes, about 20 minutes to about 50 minutes, about 5 minutes to about 20 minutes, about 5 minutes to about 30 minutes, or about 15 minutes to about 30 minutes, about 5-100 minutes, about 10-100 minutes, about 20-100 minutes, about 30-100 minutes, or about 1, 2, 3, 4, 5, 6,
- the reservoir may not be rotated, but may be pressurized to eject the polymer material from the reservoir through one or more orifices.
- a mechanical pressurizer may be applied to one or more surfaces of the reservoir to decrease the volume of the reservoir, and thereby eject the material from the reservoir.
- a fluid pressure may be introduced into the reservoir to pressurize the internal volume of the reservoir, and thereby eject the material from the reservoir.
- An exemplary reservoir may have a volume ranging from about one nanoliter to about 1 milliliter, about one nanoliter to about 5 milliliters, about 1 nanoliter to about 100 milliliters, or about one microliter to about 100 milliliters, for holding the liquid material.
- Some exemplary volumes include, but are not limited to, about one nanoliter to about 1 milliliter, about one nanoliter to about 5 milliliters, about 1 nanoliter to about 100 milliliters, one microliter to about 100 microliters, about 1 milliliter to about 20 milliliters, about 20 milliliters to about 40 milliliters, about 40 milliliters to about 60 milliliters, about 60 milliliters to about 80 milliliters, about 80 milliliters to about 100 milliliters, but are not limited to these exemplary ranges. Exemplary volumes intermediate to the recited volumes are also part of the invention.
- the volume of the reservoir is less than about 5, less than about 4, less than about 3, less than about 2, or less than about 1 milliliter.
- the physical size of a polymer and the desired number of polymers that will form a fiber dictate the smallest volume of the reservoir.
- the reservoir includes one or more orifices through which one or more jets of the fiberforming liquid (e.g., polymer solution) are forced to exit the reservoir by the motion of the reservoir during fiber formation.
- One or more exemplary orifices may be provided on any suitable side or surface of the reservoir including, but not limited to, a bottom surface of the reservoir that faces the collection device, a side surface of the reservoir, a top surface of the reservoir that faces in the opposite direction to the collection device, etc.
- Exemplary orifices may have any suitable cross- sectional geometry including, but not limited to, circular, oval, square, rectangular, etc.
- one or more nozzles may be provided associated with an exemplary orifice to provide control over one or more characteristics of the fiber-forming liquid exiting the reservoir through the orifice including, but not limited to, the flow rate, speed, direction, mass, shape and/or pressure of the fiber-forming liquid.
- the locations, cross-sectional geometries and arrangements of the orifices on the reservoir, and/or the locations, cross-sectional geometries and arrangements of the nozzles on the orifices may be configured based on the desired characteristics of the resulting fibers and/or based on one or more other factors including, but not limited to, viscosity of the fiber-forming liquid, the rate of solvent evaporation during fiber formation, etc.
- Exemplary orifice lengths that may be used in some exemplary embodiments range between about 0.001 m and about 0.05 m, e.g., 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045, 0.005, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, or 0.05.
- exemplary orifice lengths that may be used range between about 0.002 m and 0.01 m. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
- Exemplary orifice diameters that may be used in some exemplary embodiments range between about 0.1 pm and about 10 pm, about 50 pm to about 500 pm, about 200 pm to about 600 pm, about 200 pm to about 1,000 pm, about 500 pm to about 1,000 pm, about 200 pm to about 1,500 pm, about 200 pm to about 2,000 pm, about 500 pm to about 1,500 pm, or about 500 pm to about 2,000 pm, e.g., about 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1,000, 1,050, 1,100, 1,150, 1,200, 1,250, 1,300, 1,350, 1,400, 1,450, 1,500, 1,550, 1,600, 1,650, 1,700, 1,750, 1,800, 1,850, 1,900, 1,950, or about 2,000 pm. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
- a suitable device for the formation of a polymeric fibers includes a reservoir for holding a polymer, the reservoir including one or more orifices for ejecting the polymer during fiber formation, a collection device, e.g., a mandrel, and an air vessel for circulating a vortex of air around the formed fibers to wind the fibers into one or more threads.
- a collection device e.g., a mandrel
- an air vessel for circulating a vortex of air around the formed fibers to wind the fibers into one or more threads.
- a suitable device for the formation of a micron, submicron or nanometer dimension polymeric fiber includes a reservoir for holding a polymer, the reservoir including one or more orifices for ejecting the polymer during fiber formation, thereby forming a polymeric fiber, a collection device, e.g., a mandrel, one or more mechanical members disposed or formed on or in the vicinity of the reservoir for increasing an air flow or an air turbulence experienced by the polymer ejected from the reservoir, and a collection device for accepting the formed micron, submicron or nanometer dimension polymeric fiber.
- a collection device e.g., a mandrel, one or more mechanical members disposed or formed on or in the vicinity of the reservoir for increasing an air flow or an air turbulence experienced by the polymer ejected from the reservoir
- a collection device for accepting the formed micron, submicron or nanometer dimension polymeric fiber.
- a suitable device further comprises a component suitable for continuously feeding the polymer into the rotating reservoir (or a platform), such as a spout or syringe pump.
- An exemplary method to fabricate the scaffolds of the invention comprising a plurality of polymeric fibers may include imparting rotational motion to a reservoir holding a polymer, the rotational motion causing the polymer to be ejected from one or more orifices in the reservoir and collecting a plurality of formed polymeric fibers, e.g., on a collection surface, e.g., a surface of a mandrel, thereby forming a scaffold comprising a plurality of polymeric fibers.
- a polymer is fed into a reservoir as a fiber-forming liquid.
- the methods may further comprise dissolving the polymer in a solvent prior to feeding the solution into the reservoir.
- the methods include feeding a polymer into a rotating reservoir of a device of the invention and providing motion at a speed and for a time sufficient to form a plurality of polymeric fibers, and collecting the formed fibers, e.g., on a collection surface, e.g., a surface of a collection device, such as a mandrel having a desired shape, to form a scaffold comprising a plurality of polymeric fibers, e.g., a scaffold comprising a plurality of polymeric fibers having the desired shape.
- the methods include feeding a polymer solution into a rotating reservoir of a device of the invention and providing an amount of shear stress to the rotating polymer solution for a time sufficient to form a plurality of polymeric fibers, and collecting the formed fibers e.g., on a collection surface, e.g., a surface of a collection device, such as a mandrel having a desired shape, to form a scaffold comprising a plurality of polymeric fibers, e.g., a scaffold comprising a plurality of polymeric fibers having the desired shape.
- suitable devices for fabricating the polymeric fiber scaffolds of the invention which may, in some embodiments, be configured in a desired shape, include those described in International Patent Publication No. WO 2020/150207, the entire contents of which are incorporated herein by reference.
- Such devices which may be referred to as focused rotary jet spinning (fRJS) devices, are suitable for forming micron-scale diameter to nanometer-scale diameter polymer fibers by ejection of a fiber forming liquid from a spinning reservoir that employ gas (e.g., air) flows to focus and align the produced fibers in a fiber stream for controlled deposition.
- gas e.g., air
- suitable devices for fabricating the polymeric fiber scaffolds of the invention which may, in some embodiments, be configured in a desired shape, include those described in U.S. Patent Publication No. 2015/0354094, the entire contents of which are incorporated herein by reference.
- Such devices which may be referred to as immersed rotary jet spinning (iRJS) devices, are suitable for preparing polymeric fiber scaffolds from polymers that, e.g., require on-contact crosslinking, that cannot be readily dissolved at a high enough concentrations to provide sufficient viscosity for random entanglement and solvent evaporation to form polymeric fibers, and that require precipitation,
- Suitable iRJS devices include, a reservoir for holding a polymer and including a surface having one or more orifices for ejecting the polymer for fiber formation; a motion generator configured to impart rotational motion to the reservoir, the rotational motion of the reservoir causing ejection of the polymer through the one or more orifices; and a collection device holding a liquid, the collection device configured and positioned to accept the polymer ejected from the reservoir; wherein the reservoir and the collection device are positioned such that the one or more orifices of the reservoir are submerged in the liquid in the collection device during rotation of the reservoir to eject the polymer; and wherein the ejection of the polymer into the liquid in the collection device causes formation of one or more polymeric fibers.
- the device may include a second motion generator couplable to the collection device, the second motion generator configured to impart rotational motion to the liquid in the collection device.
- Suitable rotational speeds of the rotating reservoir and the collection device, suitable rotational times, suitable reservoir volumes, suitable orifice diameters, and suitable orifice lengths in the iRJS devices are the same as those of the RJS device described supra.
- Use of such devices for preparation of scaffolds comprising a plurality of polymeric fibers of the invention include using the motion generator to rotate the reservoir about an axis of rotation to cause ejection of the polymer in one or more jets; and collecting the one or more jets of the polymer in the liquid held in the collection device to cause formation of the plurality of polymeric fibers, thereby forming the scaffold.
- a suitable device for formation of the polymeric fiber scaffolds of the invention includes a reservoir for holding a polymer and including an outer surface having one or more orifices for ejecting the polymer for fiber formation; a first motion generator couplable to the reservoir, the first motion generator configured to impart rotational motion to the reservoir to cause ejection of the polymer through the one or more orifices; and a collection device holding a liquid, the collection device configured and positioned to accept the polymer ejected from the reservoir; a second motion generator couplable to the collection device, the second motion generator configured to impart rotational motion to the liquid in the collection device to generate a liquid vortex including an air gap; wherein the reservoir and the collection device are positioned such that the one or more orifices of the reservoir are positioned in the air gap of the liquid vortex in the collection device; and wherein the ejection of the polymer into the air gap and subsequently into the liquid of the liquid vortex in the collection device causes formation of one or more micron, submicron or
- Pullulan (chemical formula: (C18H30O15)n) is a natural linear polysaccharide produced primarily by the fungus Aureobasidium pullalaria, consisting of repeating matditriose subunits, alternating between one (1— >6) and two (1 — >4) glycosidic linkages (FIG. 1). Pullulan has high molecular weight. It does not form gel spontaneously when it is dissolved in water, but forms highly viscous solution. Pullulan is fully soluble in cold water, with solubility up to xx% (w/v). Pullulan can be produced at low cost and easy to produce. It is biodegradable. Pullulan is also a sustainable material, which is not derived from petrochemicals. Pullulan is globally available. Pullulan is nontoxic and biocompatible. Pullulan can resist high temperature. Pullulan is lowly permeable to oxygen. Pullulan is stable in a wide range of pH and temperature.
- pullulan is a desirable material for many industrial applications, such as used as slow release capsules or sublingual oral strips in pharmaceuticals, thickening agent in cosmetics, or thickening agent, color and/or flavor trapping agent in food.
- the crosslinking between the pullulan polymers can be ionic crosslinking, covalent crosslinking, or physical crosslinking, e.g., chemical crosslinking or annealing through heat and pressure.
- the crosslinking is covalent crosslinking.
- a crosslinking agent is added to the solution that comprises the pullulan polymer to crosslink the pullulan polymers.
- a crosslinking agent comprises two or more functional groups that react with the hydroxyl group on the pullulan to form covalent bond between the crosslinking agent and the pullulan polymer and crosslink the pullulan polymer. Chemical crosslinking of unmodified pullulan can occur through etherfication or esterification.
- the term “therapeutic agent” refers to an agent that treats, prevents, inhibits, ameliorates, or reduces the symptoms of one or more disorder or conditions, for example skin inflammatory reaction.
- a therapeutic agent also include an agent that improves a condition of a subject, e.g., improve the condition of aging skin.
- the therapeutic agent is selected from a group consisting of a metal, a small molecule, an organic compound, an inorganic compound, a polysaccharide, an oligopeptide, a polypeptide, an antibody, a nucleic acid, a recombinant virus, a vaccine, and a cell.
- an organic compound refers to a small molecule organic compound.
- a small molecule has a molecular weight that is less than 5000 Dalton, such as less than 4000 Dalton, 3000 Dalton, 2000 Dalton, or 1000 Dalton.
- a therapeutic agent according to the present invention can be used for any treatment for a condition, such as inflammatory, e.g., psoriasis, eczema, atopic dermatitis, aging, infection, wound, or tissue damage.
- a therapeutic agent may be an anti-inflammatory agent, an anti-acne agent, an anti-fungal agent, an anti-aging agent, an antimicrobial agent, a wound healing agent, or a tissue regeneration agent.
- the therapeutic agent of the invention is an agent that treats a disorder or a condition of skin.
- Exemplary therapeutic agents include, but are not limited to methotrexate, cyclosporine, steroids, biologies such as TNF inhibitor, interleukin inhibitors, and immunomodulators.
- Genistein is an isoflavone abundant in soybeans. Genistein may inhibit chronic low grade skin inflammation by several mechanisms. Without wishing to be bound by any theory, it is hypothesized that genistein may inhibit the expression of NF-kB, IL-ip, IE-6, and RANKL. Genistein may also inhibit TNF-a induced endothelial inflammation. Genistein is a suitable natural compound for the treatment of chronic inflammatory skin conditions sue to its antiinflammatory and antioxidant properties, low adverse event profile and low cost of production. Genistein can be incorporated directly into the spinning solution and be released from the scaffold onto the area of treatment, such as an area of skin.
- Glycosylated genistein has unfavorable skin penetration because of its hydrophilicity and water solubility.
- genistein In its aglycone form, genistein is a hydrophobic molecule that is partially soluble in water and is soluble in methanol and ethanol.
- Aglycone genistein has a favorable partition coefficient (logP) of about 2.98, which lies within the effective range of skin penetration.
- logP partition coefficient
- free genistein which has low solubility in cold water, can be in the same solution with pullulan so pullulan and genistein can be co-spun to form the pullulan/genistein scaffold.
- solution is broadly defined to include the colloid suspension of aglycone genistein in water. It is contemplated one of the several advantages of the invention that free aglycone (active) genistein is attached to the pullulan scaffold to enhance the stability thereof.
- Genistein is also an agent that has beneficial effects on skin aging, especially in its free (active) aglycone form. When applied topically, genistein has anti-oxidant, anti-inflammatory, photoprotective effects.
- the agent is an anti-microbial selected from the group consisting of iodine, silver sulfadiazine, chlorhexidine, acetic acid, mafenide, mupirocin, ketoconazole, silver nitrate, betadine, benzyl peroxide, sodium hypochlorite, and miconazole.
- the therapeutic agent e.g., genistein
- the therapeutic agent e.g., genistein
- the therapeutic agent may be attached to the scaffold through Van der Waals force.
- the therapeutic agent may be attached to the scaffold via a chemical bond, such as an ionic bond, a hydrogen bond, or a covalent bond.
- the therapeutic agent is directly attached to the scaffold.
- the therapeutic agent may be formulated in a formulation first and the formulation containing the therapeutic agent may be attached to the scaffold via any mechanism.
- the formulation of the therapeutic agent can serve various purpose, such as increasing the stability of the therapeutic agent, e.g., genistein, or controlling the release of the therapeutic agent.
- the formulation is a liposome formulation.
- the attachment of the therapeutic agent to the scaffold is reversible.
- the therapeutic agent is released from the scaffold when the pullulan/therapeutic agent scaffold is applied to treat a disorder or condition, e.g., when the scaffold is applied to an area of skin to treat a cutaneous disorder or condition.
- treating when it is used in the context of treating a disease, disorder or condition in a subject, is defined as the application or administration of a therapeutic agent to a patient, said patient having a disease, a symptom of disease or a predisposition toward a disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease, the symptoms of disease or the predisposition toward disease.
- treating can include suppressing, inhibiting, preventing, treating, or a combination thereof.
- treatment delaying or preventing the onset of such a disease or disorder, reversing, alleviating, ameliorating, inhibiting, slowing down or stopping the progression, aggravation or deterioration the progression or severity of a condition associated with such a disease or disorder.
- the symptoms of a disease or disorder are alleviated by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%.
- the solvent used during fabrication of the pullulan or the pullulan therapeutic agent, e.g., genistein, fibers and scaffolds of the invention comprises water.
- the solvent comprises a solvent selected from the group consisting of an organic solvent, e.g., alcohols, benzene, toluene, esters, ethers, ketones, etc, and inorganic solvents, e.g., ammonia, hydrogen fluoride, sulfuric acid, etc.
- each pullulan or pulluan/therapeutic agent, e.g., genistein, fiber in the scaffold independently has a diameter of about 200 nm to 10 pm, e.g., about 250 nm to 400 nm, about 300 nm to 400 nm, about 350 nm to 400 nm, about 360 nm to 400 nm, about 370 nm to 400 nm, about 375 nm to 400 nm, about 380 nm to 400 nm, about 385 nm to 400 nm, about 390 nm to 400 nm, about 395 nm to 400 nm, about 300 nm, about 325 nm, about 350 nm, about 360 nm, about 370 nm, about 375 nm, about 380 nm, about 385 nm, about 390 nm, about 395 nm, or about 400 nm. Ranges and values intermediate to the above recited
- each pullulan or pulluan/therapeutic agent, e.g., genistein, fiber in the scaffold independently has a diameter of about 0.01 nm to 500 pm, about 0.5 to 10 pm, e.g., about 1 to 10 pm, about 1.5 to 10 pm, about 2.0 to 10 pm, about 2.5 to 10 pm, about 3.0 to 10 pm, about 3.5 to 10 pm, about 4.0 to 10 pm, about 4.5 to 10 pm, about 5.0 to 10 pm, about 5.5 to 10 pm, about 6.0 to 10 pm, about 6.5 to 10 pm, about 7.0 to 10 pm, about 7.5 to 10 pm, about 8.0 to 10 pm, about 8.5 o
- each pullulan or pulluan/therapeutic agent, e.g., genistein, fiber in the scaffold independently has a diameter of about 0.5 to 6.0 pm, e.g., about 1.0 to 6.0 pm, about 1.5 to 6.0 pm, about 2.0 to 6.0 pm, about 2.5 to 6.0 pm, about 3.0 to 6.0 pm, about 3.5 to 6.0 pm, about 4.0 to 6.0 pm, about 4.5 to 6.0 pm, about 5.0 to 6.0 pm, or about 5.5 to 6.0 pm.
- the scaffold formed has a porosity greater than about 40%, e.g., a porosity of about 60% to about 80%, about 65% to about 80%, about 70% to about 80%, e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or about 80%. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
- the thickness of the pullulan or pulluan / therapeutic agent, e.g., genistein, fibrous scaffolds of the invention can be controlled.
- the thickness of the scaffold can be controlled by the amount of the carrier or the polymer solution used.
- the thickness of the scaffold can be controlled by the rotation speed.
- the thickness of the scaffold ranges from about 0.1 mm to 5 mm, e.g.
- the scaffolds of the invention may be used in a broad range of applications, including, but not limited to, use in treatment of inflammation, wound healing, drug delivery, cosmetics, and personal care.
- Bioactive and biodegradable nanofibers for topical dressings have been designed.
- a polymer e.g., pullulan
- a therapeutic agent e.g., genistein
- the nanofibers form a scaffold (nanotextile as shown in FIG. 1), which optionally contains the therapeutic agent (therapeutic molecules in FIG. 1).
- Pullulan has been used for fabricating the nanofiber scaffold.
- therapeutic agent was added to the scaffold.
- genistein was selected as the therapeutic agent. As shown in FIG. 2 and described in this example, pullulan or pullulan / genistein nanofibers have been fabricated.
- FIG. 3A provides images depicting the topological characterization of exemplary pullulan nanofibers fabricated.
- FIG. 3C is a graph depicting the distribution of the diameters of exemplary pullulan nanofibers.
- Exemplary pullulan nanofibers were subject to FTIR analysis to verify that the nanofibers contain pullulan molecules. As shown in FIG. 4, the FTIR analysis of nanofibers showed spectra characteristic of pullulan.
- crosslinking agent was added in the solution for fabricating the pullulan nanofibers.
- An exemplary crosslinking agent is citric acid.
- FIG. 5 depicts various mechanisms for crosslinking pullulan, including citric acid mediated crosslinking.
- FIG. 6 depicts an exemplary mechanism that crosslinking pullulan using citric acid.
- FIG. 7A includes images depicting the nanofibers formed using different concentration of citric acid.
- FIG. 7C includes graphs depicting the distribution of fiber diameters of the nanofibers formed from pullulan with different concentration of citric acid.
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Abstract
The present invention provides biodegradable fibers, non-woven scaffolds comprising the same, methods of making the same, and methods of use thereof. The composition and methods disclosed herein provide, among other things, packaging means, e.g., means to treat skin-associated conditions.
Description
BIODEGRADABLE AND BIOACTIVE FIBERS, SCAFFOLDS, AND METHODS OF USE
THEREOF
RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Application No. 63/245,217, filed on September 17, 2021, the entire contents of which are incorporated herein by reference.
This application is related to U.S. Provisional Application No. 63/245,219, filed on September 17, 2021, the entire contents of which are incorporated herein by reference.
GOVERNMENT SUPPORT
This invention was made with Government support under 1420570 awarded by the National Science Foundation. The Government has certain rights in the invention.
BACKGROUND OF THE INVENTION
Nonwoven fabrics are web-like fibrous, flat structures that are typically produced by the entanglement of individual fibers or filaments, via chemical, mechanical or thermal manufacturing processes. Nonwoven fabrics are widely used in various areas, such as healthcare, cosmetics, personal care, and household products.
Many commercial products, especially disposable products, such as disposable wipes and sheetmasks, use nonwoven fabrics that are not biodegradable. Disposal of such products remains problematic because the processing of the nonwoven fabrics usually leaves non-degraded particles, which can cause damages to the environment or infrastructure, such as sewage systems, beaches, landfills, and oceans.
Accordingly, there is a need in the art for biodegradable nonwoven fabrics.
SUMMARY OF THE INVENTION
Disclosed herein are biodegradable nonwoven fibers, scaffolds comprising the same, methods of making the same, and methods of use thereof. The composition and methods disclosed herein provide, among other things, means to treat skin-associated conditions.
Accordingly, in one aspect, the present invention provides a method for forming a non-woven polymeric fiber scaffold comprising pullulan. The method include rotating a reservoir holding a solution comprising pullulan about a rotation axis to eject at least one jet of pullulan from at least one
orifice defined by an outer sidewall of the reservoir; directing at least one flow of gas through a portion of the reservoir radially inward of the outer sidewall, the at least one flow of gas directed from an upstream first end of the reservoir to a downstream second end of the reservoir during rotation of the reservoir and ejection of the at least one jet of the pullulan to form at least one polymeric fiber comprising pullulan, the at least one flow of gas entraining the at least one polymeric fiber comprising pullulan and forming a focused pullulan fiber deposition stream of the at least one polymeric fiber comprising pullulan in a first direction, the first direction having an orientation of within 5 degrees of the rotation axis of the reservoir; and collecting the focused pullulan fiber deposition stream on a target surface which is a three-dimensional shape, thereby forming the non-woven polymeric fiber scaffold comprising pullulan.
In another aspect, the present invention provides a method of forming a non-woven polymeric fiber scaffold comprising pullulan> The method includes providing a solution comprising: pullulan; rotating the pullulan in solution about an axis of rotation to cause ejection of the pullulan solution in one or more jets; and collecting the one or more jets of the pullulan in a liquid to cause formation of one or more polymeric fibers comprising pullulan, thereby forming the non-woven polymeric fiber scaffold comprising pullulan.
In one aspect, the present invention provides a method of forming a non-woven polymeric fiber scaffold comprising pullulan. The method includes providing a solution comprising: pullulan; forming a plurality of polymeric fibers comprising pullulan by ejecting or flinging the solution from a reservoir; and collecting the plurality of polymeric fibers comprising pullulan on a collection surface, thereby forming the non-woven polymeric fiber scaffold comprising pullulan.
In one embodiment, the solution comprises between about 1 % (w/v) and about 60% (w/v) of pullulan.
In one embodiment, the solution comprises water.
In one embodiment, the solvent of the solution comprises water.
In one embodiment, the solution further comprises an additional solvent.
In one embodiment, the additional solvent is s acetone.
In one embodiment, the solution further comprises a crosslinking agent.
In one embodiment, the crosslinking agent covalently cross-links the pullulan.
In one embodiment, the crosslinking agent is selected from the group consisting of citric acid, glyoxal, glutaraldehyde, genipin, and STMP.
In one embodiment, the solution comprises about 1 % (w/v) to about 20% (w/v) of the crosslinking agent.
In one embodiment, the cross-linking agent comprises citric acid, citric acid anhydride, or the combination thereof.
In one embodiment, the solution further comprises a therapeutic agent.
In one embodiment, the therapeutic agent is a small molecule, a polysaccharide, a nucleic acid, a protein, a botanical extract, a fatty acid, a surfactants, a ceramides, or a metal.
In one embodiment, the therapeutic agent is an anti-microbial agent, an anti-fungal agent, an anti-acne agent, an anti-inflammatory agent, an anti-aging agent, or a wound healing agent.
In one embodiment, the therapeutic agent is formulated in a formulation that maintains the stability of the therapeutic agent.
In one embodiment, the first direction is substantially parallel to the rotation axis of the reservoir.
In one embodiment, the at least one flow of gas comprises a plurality of flows of gas that converge and form a combined gas flow in the first direction.
In one embodiment, a flow rate of at least some of the plurality of converging flows of gas relative to others of the plurality of converging flows of gas is controllable to achieve a balanced combined gas flow.
In one embodiment, a total gas flow rate of the plurality of converging flows of gas is controllable to change a distance from the reservoir at which the focused fiber deposition stream of the at least one micron or nanometer dimension polymeric fiber has the tightest focus.
In one embodiment, the plurality of gas flows comprises three gas flows.
In one embodiment, the focused fiber deposition stream has a substantially tangential orientation to the target surface during fiber collection.
In one embodiment, the method further comprises rotating the target for deposition on more than one side of the three dimensional shape.
In one embodiment, the target is rotating at a speed up to 20,000 rpms
In one embodiment, the method further comprises at least partially blocking flow of gas from upstream of the reservoir to reduce an effect of airflow upstream of the plurality of gas flow sources on focusing of the fiber deposition stream of the at least one micron or nanometer dimension polymeric fiber.
In one embodiment, the target surface is static or moved linearly during deposition of the fiber.
In one embodiment, the reservoir is rotated at a speed of about up to 20, 000 rpm.
In one embodiment, the orifice is about 0.5 mm to about 2 mm in diameter.
In one aspect, the present invention provides a method for forming a non-woven polymeric fiber scaffold comprising pullulan. The method includes rotating a reservoir holding a solution comprising about 20% w/v pullulan and between about 1 % w/v and 20% w/v citric acid about a rotation axis to eject at least one jet of pullulan from at least one orifice defined by an outer sidewall of the reservoir; directing at least one flow of gas through a portion of the reservoir radially inward of the outer sidewall, the at least one flow of gas directed from an upstream first end of the reservoir to a downstream second end of the reservoir during rotation of the reservoir and ejection of the at least one jet of the pullulan to form at least one polymeric fiber comprising pullulan, the at least one flow of gas entraining the at least one polymeric fiber comprising pullulan and forming a focused pullulan fiber deposition stream of the at least one polymeric fiber comprising pullulan in a first direction, the first direction having an orientation of within 5 degrees of the rotation axis of the reservoir; and collecting the focused pullulan fiber deposition stream on a target surface which is a three-dimensional shape.
The present invention also provides a non-woven polymeric fiber scaffold comprising pullulan produced according to any of the methods of the invention.
In one aspect, the present invention provides a non-woven polymeric fiber scaffold comprising: a plurality of polymeric fibers, each polymeric fiber independently comprising pullulan.
In one embodiment, a solution forming the plurality of polymeric fibers comprises between about 1 w/v% and 60 w/v% pullulan.
In one embodiment, the pullulan is crosslinked.
In one embodiment, the pullulan is covalently crosslinked.
In one embodiment, is not covalently crosslinked.
In one embodiment, the pullulan is crosslinked via ionic bond, hydrogen bond, Van der Waals force
In one embodiment, the polymeric fiber is formed from a solution comprising pullulan, wherein the solution further comprises a cross-linking agent that covalently crosslinks the pullulan.
In one embodiment, the solution comprises between about 1 % w/v and 20 % w/v the crosslinking agent.
In one embodiment, the crosslinking agent comprises a citric acid anhydride or a citric acid.
In one embodiment, the fiber scaffold comprises an intra-fiber linkage, an inter-fiber linkage, or the combination thereof.
In one embodiment, each polymeric fiber independently has a diameter in a range of about 200 nm to 10 pm.
In one embodiment, the fiber scaffold further comprises a therapeutic agent.
In one embodiment, the therapeutic agent is a fatty acid, a surfactants, a ceramides, or a metal.
In one embodiment, the therapeutic agent is an anti-microbial agent, an anti-fungal agent, an anti-acne agent, an anti-inflammatory agent, an anti-aging agent, or a wound healing agent.
In one embodiment, the therapeutic agent is formulated in a formulation that maintains the stability of the therapeutic agent.
In one embodiment, the polymeric fiber is formed from a solution comprising the pullulan, wherein the solution further comprises the therapeutic agent.
In one embodiment, the therapeutic agent comprises an anti-inflammatory agent.
In one embodiment, the anti-inflammatory agent comprises a phytoestrogen.
In one embodiment, the phytoestrogen comprises a genistein.
In one embodiment, the therapeutic agent comprises a wound-healing agent.
In one embodiment, the therapeutic agent comprises an anti-aging agent.
In one embodiment, the anti-aging agent is genistein.
In one embodiment, the anti-aging agent comprises a genistein.
The present invention also provides a method for treating a subject having a skin disorder or condition. The method includes providing a polymeric fiber scaffold of the invention; and disposing the polymeric fiber scaffold on, over, or in an area of skin affected by the disorder or the condition, thereby treating the subject.
In one embodiment, the method further comprises keeping the polymeric fiber scaffold disposed on, over or in the skin area during treatment.
In one embodiment, the method promotes wound healing of the subject.
In one embodiment, the method reduces inflammation of the subject.
In one embodiment, the method promotes tissue regeneration in the subject.
In one embodiment, the method delays aging of skin in the subject.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic depicting an exemplary embodiment of the present invention.
FIG. 2A is a schematic depicting an exemplary embodiment of the present invention. As shown in FIG. 2A, a polymer, e.g., a pullulan, is used as backbone for making biodegradable and
biocompatible nanofibers and fiber scaffolds. A bioactive agent, such as genistein, used a therapeutic agent, may be optionally incorporated into the nonwoven fabrics. The nanofiber is made through a one-step synthesis using rotary jet spinning.
FIG. 2B is a schematic depicting the structure of a pullulan polymer.
FIG. 2C is a schematic depicting the structure of geneistein.
FIG. 2D is a schematic of the activation of genistin to genistein.
FIGs. 3A-3B are table, images and graphs depicting pullulan nanofiber scaffold topology characterization. FIG. 3A is a table depicting the parameters used to make the nanofibers and scaffolds of the invention. FIG. 3B includes image of the nanofibers and scaffolds, and the scanning electron microscope images of the nanofibers. FIG. 3C is a graph depicting the distribution of the diameters of nanofibers.
FIG. 4 is an image depicting the Fourier-transform infrared spectroscopy (FTIR) analysis of pullulan. The FTIR of nanfibers shows spectra characteristic of pullulan.
FIG. 5 is a schematic depicting the mechanisms of biopolymer crosslinking.
FIG. 6 includes schematics depicting exemplary mechanism of pullulan crosslinking with citric acid. The exemplary mechanism allows for the one-step in situ crosslinking of pullulan nanofibers.
FIGs. 7A-7C include table, images, and graphs depicting characterization of citric acid crosslinked pullulan nanofibers. FIG. 7A is a table depicting the parameters used to make the nanofibers and scaffolds. FIG. 7B includes phase-contrast microscopic images of nanofibers and scaffolds prepared using difference concentration of citric acid (CA). FIG. 7C includes graphs depicting the distribution of the diameters of the nanofibers synthesized with different concentration of citric acid (CA).
DETAILED DESCRIPTION
The present invention is based, at least in part, on the fabrication of polymeric fibers, e.g., micron, submicron or nanometer dimension polymeric fibers comprising one or more water soluble polymers, e.g., pullulan, and non-woven polymeric scaffolds comprising the polymeric fibers that are bio-degradable. Accordingly, disclosed herein are novel biodegradable nanofibers and scaffolds comprising the same, methods for making the same, and methods for using the same in treating cutaneous disorders. In one embodiment, the nanofibers and scaffolds comprising the same further comprise an active ingredient that can be used for treating various cutaneous disorders or conditions.
The polymeric fibers, e.g., pullulan fibers, according to the present invention possess several superior properties. For example, the pullulan fibers are biodegraded and, thus, are environment friendly. Methods to produce the fibers and scaffolds are also straightforward and cost-effective. For example, the polymer monomers, e.g., pullulan, can be dissolved in cold water and a water solution of pullulan can be used to fabricate the fiber and the scaffold, thus eliminating the need for volatile solvents.
I. Definition
In order that the present invention may be more readily understood, certain terms are first defined.
Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition.
The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural (i.e., one or more), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising, “having,” “including,” and “containing” are to be construed as open- ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value recited or falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited.
The term “about” or “approximately” means within 5%, or more preferably within 1%, of a given value or range.
As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the art will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” may therefore be used in some embodiments herein to capture potential lack of completeness inherent in many biological and chemical phenomena.
In the following brief descriptions and throughout the specification, weight/volume percentages (w/v%) associated with the fibers and scaffolds of the invention mean that the related fibers and scaffolds are prepared using a solution containing such amounts expressed as w/v%. For example, “pullulan (20 wt/v%) nanofibers” means that the fibers are prepared using a solution
containing 20 wt/v% pullulan. “pullulan / citric acid (20 wt/v% / 5 wt/v%) nanofibers” means that the fibers are prepared using a solution containing 20 wt/v% pullulan and 5 wt/v% citric acid.
It should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this invention.
II. Compositions and Methods of the Invention
The present invention provides polymeric fibers, e.g., pullulan fibers, and non-woven polymeric fiber scaffolds comprising a plurality of polymeric fibers that can be used in treating cutaneous disorders. The term “fiber” and “polymeric fiber” are used interchangeably herein, and both terms refer to polymeric fibers having micron, submicron, and nanometer dimensions.
The term “scaffold” as used herein refers to a structure comprising a plurality of polymeric fibers that provides structure to a tissue and allows an active ingredient to be released therefrom to the tissue.
The polymeric fiber scaffolds of the invention may further include an additional therapeutic agent, such as an anti-inflammatory or anti-aging agent. For example, the polymeric fibers may be contacted with additional agents which will allow the agents to, for example, coat (fully or partially) the fibers. In one embodiment, the polymer solution is contacted with the additional agent during the fabrication of the polymeric fibers which allows the agents to be incorporated into the polymeric fibers themselves.
In one embodiment, the additional therapeutic agent is an anti-inflammatory agent, e.g., genistein. In another embodiment, the additional therapeutic agent is an anti-aging agent, e.g., genistein. In another embodiment, the additional agent is an anti-acne agent. In another embodiment, the additional therapeutic agent is an anti-fungal agent. In another embodiment, the additional therapeutic agent is an anti-microbial, agent
The scaffolds of the invention may be used for a variety of cutaneous applications, for example, a cutaneous covering or a sheet mask that covers and delivers a therapeutic agent, e.g., an anti-inflammatory agent to an area of skin that needs treatment. The scaffolds of the invention may also be combined with other substances, such as, therapeutic agents (such as an anti-inflammatory, anti-acne, anti-fungal, anti-microboal or anti-aging agent) during or after fabrication of the polymeric fibers and scaffolds in order to deliver such substances to the site of application of the polymeric fiber scaffolds.
1. Devices and Methods for the Fabrication of the Polymeric Fiber Scaffolds of the
Invention
Suitable devices and methods of use of such devices for fabricating the polymeric fiber (micron, submicron or nanometer dimension polymeric fiber) scaffolds of the present invention are described in U.S. Patent Nos. 9,410,267 and 9,738,046, and U.S. Patent Publication Nos. 2013/0312638, 2015/0354094, and 2020/0376170, the entire contents of each of which are incorporated herein by reference. Exemplary fiber formation devices do not employ a nozzle for ejecting the liquid material, a spinneret or rotating reservoir containing and ejecting the liquid material, or an electrostatic voltage potential for forming the fibers. The exemplary devices described herein are simplified as they do not employ a spinneret or an electrostatic voltage potential. In addition, the lack of a nozzle for ejecting the liquid material in exemplary devices avoids the issue of clogging of the nozzle.
For example, as described in U.S. Patent No. 9,410,267 and U.S. Patent Publication No. 2013/0312638 , in some embodiments, suitable devices for fabricating the polymeric fiber scaffolds of the invention which may, in some embodiments, be configured in a desired shape, may include a reservoir for holding a polymer, the reservoir including one or more orifices for ejecting the polymer during fiber formation, and a collection device, e.g., a mandrel, for accepting the formed polymeric fiber, wherein at least one of the reservoir and the collection device employs rotational motion during fiber formation, and the device is free of an electrical field, e.g., a high voltage electrical field. Such devices may be referred to as rotary jet spinning (RJS) devices.
The device may include a rotary motion generator for imparting a rotational motion to the reservoir and, in some exemplary embodiments, to the collection device. In some embodiments, a flexible air foil is attached to a shaft of the motor above the reservoir to facilitate fiber collection and solvent evaporation.
Rotational speeds of the reservoir in exemplary embodiments may range from about 1 ,000 rpm-60,000 rpm, about 1 ,000 rpm-50,000 rpm, about 1 ,000 rpm to about 40,000 rpm, about 1 ,000 rpm-30,000 rpm, about 1,000 rpm to about 20,000 rpm, about 1,000 rpm- 10,000 rpm, about 5,000 rpm-60,000 rpm, about 5,000 rpm-50,000 rpm, about 5,000 rpm to about 40,000 rpm, about 5,000 rpm-30,000 rpm, about 5,000 rpm-20,000 rpm, about 5,000 rpm to about 15,000 rpm, about 5,000 rpm- 10,000 rpm, about 10,000 rpm-60,000 rpm, about 10,000 rpm-50,000 rpm, about 10,000 rpm to about 40,000 rpm, about 10,000 rpm-30,000 rpm, about 10,000 rpm-20,000 rpm, about 10,000 rpm to about 15,000 rpm, about 20,000 rpm-60,000 rpm, about 20,000 rpm-50,000 rpm, about 20,000 rpm to about 40,000 rpm, about 20,000 rpm-30,000 rpm, or about 50,000 rpm to about 400,000 rpm, e.g., about 1,000, 1,500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, 8,000, 8,500, 9,000, 9,500,10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000,
14.500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000,
20.500, 21,000, 21,500, 22,000, 22,500, 23,000, 23,500, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,000, 46,000, 47,000, 48,000, 49,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, 100,000, 105,000, 110,000, 115,000, 120,000, 125,000, 130,000, 135,000, 140,000, 145,000, 150,000 rpm, about 200,000 rpm, 250,000 rpm, 300,000 rpm, 350,000 rpm, or 400,000 rpm. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
In certain embodiments, rotational speeds of the reservoir of about 50,000 rpm-400,000 rpm are intended to be encompassed by the invention. In one embodiment, devices employing rotational motion may be rotated at a speed greater than about 50, 000 rpm, greater than about 55,000 rpm, greater than about 60,000 rpm, greater than about 65,000 rpm, greater than about 70,000 rpm, greater than about 75,000 rpm, greater than about 80,000 rpm, greater than about 85,000 rpm, greater than about 90,000 rpm, greater than about 95,000 rpm, greater than about 100,000 rpm, greater than about 105,000 rpm, greater than about 110,000 rpm, greater than about 115,000 rpm, greater than about
120,000 rpm, greater than about 125,000 rpm, greater than about 130,000 rpm, greater than about
135,000 rpm, greater than about 140,000 rpm, greater than about 145,000 rpm, greater than about
150,000 rpm, greater than about 160,000 rpm, greater than about 165,000 rpm, greater than about
170,000 rpm, greater than about 175,000 rpm, greater than about 180,000 rpm, greater than about
185,000 rpm, greater than about 190,000 rpm, greater than about 195,000 rpm, greater than about
200,000 rpm, greater than about 250,000 rpm, greater than about 300,000 rpm, greater than about
350,000 rpm, or greater than about 400,000 rpm. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
Rotational speeds of the collection device in exemplary embodiments may range from about 1,000 to about 10,000 rpm. Ranges and values intermediate to the above recited range and values are also contemplated to be part of the invention.
Exemplary devices employing rotational motion may be rotated for a time sufficient to form a desired polymeric fiber, such as, for example, about 1 minute to about 100 minutes, about 1 minute to about 60 minutes, about 10 minutes to about 60 minutes, about 30 minutes to about 60 minutes, about 1 minute to about 30 minutes, about 20 minutes to about 50 minutes, about 5 minutes to about 20 minutes, about 5 minutes to about 30 minutes, or about 15 minutes to about 30 minutes, about 5-100 minutes, about 10-100 minutes, about 20-100 minutes, about 30-100 minutes, or about 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,
35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,
62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,
89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 minutes, or more. Times and ranges intermediate to the above-recited values are also intended to be part of this invention.
In some embodiments, the reservoir may not be rotated, but may be pressurized to eject the polymer material from the reservoir through one or more orifices. For example, a mechanical pressurizer may be applied to one or more surfaces of the reservoir to decrease the volume of the reservoir, and thereby eject the material from the reservoir. In another exemplary embodiment, a fluid pressure may be introduced into the reservoir to pressurize the internal volume of the reservoir, and thereby eject the material from the reservoir.
An exemplary reservoir may have a volume ranging from about one nanoliter to about 1 milliliter, about one nanoliter to about 5 milliliters, about 1 nanoliter to about 100 milliliters, or about one microliter to about 100 milliliters, for holding the liquid material. Some exemplary volumes include, but are not limited to, about one nanoliter to about 1 milliliter, about one nanoliter to about 5 milliliters, about 1 nanoliter to about 100 milliliters, one microliter to about 100 microliters, about 1 milliliter to about 20 milliliters, about 20 milliliters to about 40 milliliters, about 40 milliliters to about 60 milliliters, about 60 milliliters to about 80 milliliters, about 80 milliliters to about 100 milliliters, but are not limited to these exemplary ranges. Exemplary volumes intermediate to the recited volumes are also part of the invention. In certain embodiment, the volume of the reservoir is less than about 5, less than about 4, less than about 3, less than about 2, or less than about 1 milliliter. In other embodiments, the physical size of a polymer and the desired number of polymers that will form a fiber dictate the smallest volume of the reservoir.
The reservoir includes one or more orifices through which one or more jets of the fiberforming liquid (e.g., polymer solution) are forced to exit the reservoir by the motion of the reservoir during fiber formation. One or more exemplary orifices may be provided on any suitable side or surface of the reservoir including, but not limited to, a bottom surface of the reservoir that faces the collection device, a side surface of the reservoir, a top surface of the reservoir that faces in the opposite direction to the collection device, etc. Exemplary orifices may have any suitable cross- sectional geometry including, but not limited to, circular, oval, square, rectangular, etc. In an exemplary embodiment, one or more nozzles may be provided associated with an exemplary orifice to provide control over one or more characteristics of the fiber-forming liquid exiting the reservoir through the orifice including, but not limited to, the flow rate, speed, direction, mass, shape and/or pressure of the fiber-forming liquid. The locations, cross-sectional geometries and arrangements of the orifices on the reservoir, and/or the locations, cross-sectional geometries and arrangements of the nozzles on the orifices, may be configured based on the desired characteristics of the resulting fibers and/or based on one or more other factors including, but not limited to, viscosity of the fiber-forming liquid, the rate of solvent evaporation during fiber formation, etc.
Exemplary orifice lengths that may be used in some exemplary embodiments range between about 0.001 m and about 0.05 m, e.g., 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045, 0.005, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, or 0.05. In some embodiments, exemplary orifice lengths that may be used range between about 0.002 m and 0.01 m. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
Exemplary orifice diameters that may be used in some exemplary embodiments range between about 0.1 pm and about 10 pm, about 50 pm to about 500 pm, about 200 pm to about 600 pm, about 200 pm to about 1,000 pm, about 500 pm to about 1,000 pm, about 200 pm to about 1,500 pm, about 200 pm to about 2,000 pm, about 500 pm to about 1,500 pm, or about 500 pm to about 2,000 pm, e.g., about 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1,000, 1,050, 1,100, 1,150, 1,200, 1,250, 1,300, 1,350, 1,400, 1,450, 1,500, 1,550, 1,600, 1,650, 1,700, 1,750, 1,800, 1,850, 1,900, 1,950, or about 2,000 pm. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
In other embodiments, a suitable device for the formation of a polymeric fibers includes a reservoir for holding a polymer, the reservoir including one or more orifices for ejecting the polymer during fiber formation, a collection device, e.g., a mandrel, and an air vessel for circulating a vortex of air around the formed fibers to wind the fibers into one or more threads.
In yet other embodiments, a suitable device for the formation of a micron, submicron or nanometer dimension polymeric fiber includes a reservoir for holding a polymer, the reservoir including one or more orifices for ejecting the polymer during fiber formation, thereby forming a polymeric fiber, a collection device, e.g., a mandrel, one or more mechanical members disposed or formed on or in the vicinity of the reservoir for increasing an air flow or an air turbulence experienced by the polymer ejected from the reservoir, and a collection device for accepting the formed micron, submicron or nanometer dimension polymeric fiber.
In one embodiment, a suitable device further comprises a component suitable for continuously feeding the polymer into the rotating reservoir (or a platform), such as a spout or syringe pump.
An exemplary method to fabricate the scaffolds of the invention comprising a plurality of polymeric fibers (which may be configured in a desired shape) may include imparting rotational motion to a reservoir holding a polymer, the rotational motion causing the polymer to be ejected from one or more orifices in the reservoir and collecting a plurality of formed polymeric fibers, e.g., on a collection surface, e.g., a surface of a mandrel, thereby forming a scaffold comprising a plurality of polymeric fibers.
In one embodiment, a polymer is fed into a reservoir as a fiber-forming liquid. In this embodiment, the methods may further comprise dissolving the polymer in a solvent prior to feeding the solution into the reservoir.
In one embodiment, the methods include feeding a polymer into a rotating reservoir of a device of the invention and providing motion at a speed and for a time sufficient to form a plurality of polymeric fibers, and collecting the formed fibers, e.g., on a collection surface, e.g., a surface of a collection device, such as a mandrel having a desired shape, to form a scaffold comprising a plurality of polymeric fibers, e.g., a scaffold comprising a plurality of polymeric fibers having the desired shape.
In another embodiment, the methods include feeding a polymer solution into a rotating reservoir of a device of the invention and providing an amount of shear stress to the rotating polymer solution for a time sufficient to form a plurality of polymeric fibers, and collecting the formed fibers e.g., on a collection surface, e.g., a surface of a collection device, such as a mandrel having a desired shape, to form a scaffold comprising a plurality of polymeric fibers, e.g., a scaffold comprising a plurality of polymeric fibers having the desired shape.
In another embodiment, suitable devices for fabricating the polymeric fiber scaffolds of the invention which may, in some embodiments, be configured in a desired shape, include those described in International Patent Publication No. WO 2020/150207, the entire contents of which are incorporated herein by reference. Such devices, which may be referred to as focused rotary jet spinning (fRJS) devices, are suitable for forming micron-scale diameter to nanometer-scale diameter polymer fibers by ejection of a fiber forming liquid from a spinning reservoir that employ gas (e.g., air) flows to focus and align the produced fibers in a fiber stream for controlled deposition.
In another embodiment, suitable devices for fabricating the polymeric fiber scaffolds of the invention which may, in some embodiments, be configured in a desired shape, include those described in U.S. Patent Publication No. 2015/0354094, the entire contents of which are incorporated herein by reference. Such devices, which may be referred to as immersed rotary jet spinning (iRJS) devices, are suitable for preparing polymeric fiber scaffolds from polymers that, e.g., require on-contact crosslinking, that cannot be readily dissolved at a high enough concentrations to provide sufficient viscosity for random entanglement and solvent evaporation to form polymeric fibers, and that require precipitation,
Suitable iRJS devices include, a reservoir for holding a polymer and including a surface having one or more orifices for ejecting the polymer for fiber formation; a motion generator configured to impart rotational motion to the reservoir, the rotational motion of the reservoir causing ejection of the polymer through the one or more orifices; and a collection device holding a liquid, the collection device configured and positioned to accept the polymer ejected from the reservoir; wherein
the reservoir and the collection device are positioned such that the one or more orifices of the reservoir are submerged in the liquid in the collection device during rotation of the reservoir to eject the polymer; and wherein the ejection of the polymer into the liquid in the collection device causes formation of one or more polymeric fibers. In some embodiment, the device may include a second motion generator couplable to the collection device, the second motion generator configured to impart rotational motion to the liquid in the collection device.
Suitable rotational speeds of the rotating reservoir and the collection device, suitable rotational times, suitable reservoir volumes, suitable orifice diameters, and suitable orifice lengths in the iRJS devices are the same as those of the RJS device described supra.
Use of such devices for preparation of scaffolds comprising a plurality of polymeric fibers of the invention include using the motion generator to rotate the reservoir about an axis of rotation to cause ejection of the polymer in one or more jets; and collecting the one or more jets of the polymer in the liquid held in the collection device to cause formation of the plurality of polymeric fibers, thereby forming the scaffold.
In another embodiment, a suitable device for formation of the polymeric fiber scaffolds of the invention includes a reservoir for holding a polymer and including an outer surface having one or more orifices for ejecting the polymer for fiber formation; a first motion generator couplable to the reservoir, the first motion generator configured to impart rotational motion to the reservoir to cause ejection of the polymer through the one or more orifices; and a collection device holding a liquid, the collection device configured and positioned to accept the polymer ejected from the reservoir; a second motion generator couplable to the collection device, the second motion generator configured to impart rotational motion to the liquid in the collection device to generate a liquid vortex including an air gap; wherein the reservoir and the collection device are positioned such that the one or more orifices of the reservoir are positioned in the air gap of the liquid vortex in the collection device; and wherein the ejection of the polymer into the air gap and subsequently into the liquid of the liquid vortex in the collection device causes formation of one or more micron, submicron or nanometer dimension polymeric fibers.
Use of such devices for preparation of scaffolds comprising a plurality of polymeric fibers include using the first motion generator to rotate the reservoir about an axis of rotation to cause ejection of the polymer in one or more jets; using the second motion generator to rotate the liquid in the collection device to generate the liquid vortex; and collecting the one or more jets of the polymer in the air gap of the liquid vortex and subsequently in the liquid of the liquid vortex of the collection device to cause formation of the plurality of polymeric fibers, thereby forming the scaffold
In another embodiment, suitable devices for fabricating the polymeric fiber scaffolds of the invention which may, in some embodiments, be configured in a desired shape, include those described
in U.S. Patent No. 9,738,046, the entire contents of which are incorporated herein by reference. Such devices may be referred to as pull-spinning devices which include a platform for supporting a deposit of a liquid polymer material. In an exemplary embodiment, the platform is stationary. In another exemplary embodiment, the platform is movable and/or moving. In an exemplary embodiment, the deposit may be a one-time deposit. In another exemplary embodiment, the deposit may be a continual or intermittently replenished deposit. The exemplary fiber formation device may include a component suitable for continuously feeding the liquid material onto the platform, such as a spout or syringe pump. The devices also include a rotating structure disposed vertically above the platform and spaced from the platform along a vertical axis, the rotating structure comprising: a central core rotatable about a rotational axis, and one or more blades affixed to the rotating core; wherein the rotating structure is configured and operable so that, upon rotation, the one or more blades contact a surface of the polymer to impart sufficient force in order to: decouple a portion of the polymer from contact with the one or more blades of the rotating structure, and fling the portion of the polymer away from the contact with the one or more blades and from the deposit of the polymer, thereby forming a polymeric fiber.
In another embodiment, suitable devices for fabricating the polymeric fiber scaffolds of the invention which may, in some embodiments, be configured in a desired shape, include a platform for supporting a stationary deposit of a polymer; and a jet nozzle disposed in the vicinity of the platform and spaced from the platform, the jet nozzle configured to generate a gas jet directed at the polymer so that the gas jet contacts a surface of the polymer to impart sufficient force in order to fling a portion of the polymer away from the contact with the gas jet and from the deposit of the polymer, thereby forming a polymeric fiber.
Use of such devices for preparation of scaffolds comprising a plurality of polymeric fibers include providing a stationary deposit of a liquid material comprising a polymer solution or a polymer melt; and making a contact with a surface of the liquid material in the stationary deposit to impart sufficient momentary force thereto in order to: decouple a portion of the liquid material from the deposit, and fling the portion of the liquid material away from the contact and from the deposit of the liquid material, wherein the force is applied substantially parallel to the surface of the liquid material by a rotating structure that penetrates the stationary deposit of the liquid material during its rotation, thereby forming a scaffold comprising a plurality of polymeric fibers.
2. Polymeric Fiber Scaffolds Comprising Pullulan and Therapeutic Agent
In one aspect, the present invention provides polymeric fiber scaffolds which include a plurality of polymeric fibers, each polymeric fiber independently comprising pullulan. In one embodiment, the scaffold further comprises one or more therapeutic agents. In one particular
embodiment, the pullulan and therapeutic agent are co-spun to form the scaffold (described below). The pullulan component can serve a depot for the therapeutic agent, while the therapeutic agent can be released from the scaffold to reach the area to be treated. In a particular embodiment, the therapeutic agent, e.g., genistein, is homogeneously distributed along the fibers (i.e., co-spinning of therapeutic agent, e.g., genistein, and pullulan results in an even districution of therapeutic agent, e.g., genistein, in the fibers and along the length of the fibers). Additionally, the scaffolds of the invention may contain additional bioactive molecules, e.g., phytoestrogens that enhance skin regeneration. Thus, the scaffolds of the invention are useful in methods of treatment of cutaneous conditions by providing covering to the area of skin to be treated and releasing the therapeutic agent therefrom.
Pullulan (chemical formula: (C18H30O15)n) is a natural linear polysaccharide produced primarily by the fungus Aureobasidium pullalaria, consisting of repeating matditriose subunits, alternating between one (1— >6) and two (1 — >4) glycosidic linkages (FIG. 1). Pullulan has high molecular weight. It does not form gel spontaneously when it is dissolved in water, but forms highly viscous solution. Pullulan is fully soluble in cold water, with solubility up to xx% (w/v). Pullulan can be produced at low cost and easy to produce. It is biodegradable. Pullulan is also a sustainable material, which is not derived from petrochemicals. Pullulan is globally available. Pullulan is nontoxic and biocompatible. Pullulan can resist high temperature. Pullulan is lowly permeable to oxygen. Pullulan is stable in a wide range of pH and temperature.
Due to its properties, e.g., the properties described above, pullulan is a desirable material for many industrial applications, such as used as slow release capsules or sublingual oral strips in pharmaceuticals, thickening agent in cosmetics, or thickening agent, color and/or flavor trapping agent in food.
Pullulan is highly soluble in water. Accordingly, it is important to modify pullulan to improve its mechanical properties. Pullulan is a polysaccharide biopolymer that is biodegradable and biocompatible and can be spun from water, eliminating the need for volatile solvents. To increase the mechanical properties of pullulan, the plurality of pullulan polymers are crosslinked to form fiber and scaffold of the present invention.
The crosslinking between the pullulan polymers can be ionic crosslinking, covalent crosslinking, or physical crosslinking, e.g., chemical crosslinking or annealing through heat and pressure. In one embodiment, the crosslinking is covalent crosslinking. To covalently crosslink the pullulan polymer, a crosslinking agent is added to the solution that comprises the pullulan polymer to crosslink the pullulan polymers. A crosslinking agent comprises two or more functional groups that react with the hydroxyl group on the pullulan to form covalent bond between the crosslinking agent and the pullulan polymer and crosslink the pullulan polymer. Chemical crosslinking of unmodified pullulan can occur through etherfication or esterification. Exemplary physical or chemical
crosslinking agents include, but are not limited to citric acid anhydride, glyoxal, gluteraldehyde, gneipin, citieic acid, STMP (trisodium trimetaphosphate), tripolyphosphate, Calcium chloride, Dextran sulfate, epichlorohydrin, diisocyanate, 4-butanediol diglycidyl ether, EGDE, l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide, transglutaminase
In one embodiment, the crosslinking agent comprises citric acid anhydride. Citric acid anhydride can be synthesized from citric acid as illustrated in FIG. 6.
As used herein, the term “therapeutic agent” refers to an agent that treats, prevents, inhibits, ameliorates, or reduces the symptoms of one or more disorder or conditions, for example skin inflammatory reaction. A therapeutic agent also include an agent that improves a condition of a subject, e.g., improve the condition of aging skin. In one embodiments, the therapeutic agent is selected from a group consisting of a metal, a small molecule, an organic compound, an inorganic compound, a polysaccharide, an oligopeptide, a polypeptide, an antibody, a nucleic acid, a recombinant virus, a vaccine, and a cell. As used herein, an organic compound refers to a small molecule organic compound. A small molecule has a molecular weight that is less than 5000 Dalton, such as less than 4000 Dalton, 3000 Dalton, 2000 Dalton, or 1000 Dalton.
A therapeutic agent according to the present invention can be used for any treatment for a condition, such as inflammatory, e.g., psoriasis, eczema, atopic dermatitis, aging, infection, wound, or tissue damage. Accordingly, a therapeutic agent may be an anti-inflammatory agent, an anti-acne agent, an anti-fungal agent, an anti-aging agent, an antimicrobial agent, a wound healing agent, or a tissue regeneration agent. In one embodiment, the therapeutic agent of the invention is an agent that treats a disorder or a condition of skin. Exemplary therapeutic agents include, but are not limited to methotrexate, cyclosporine, steroids, biologies such as TNF inhibitor, interleukin inhibitors, and immunomodulators.
In one particular embodiment, the therapeutic agent comprises genistein. The structure of genistein is illustrated in FIG. 2C. The term “genistein,” as used herein, refers to the free genistein as shown in FIG. 2C and its structural analog. As used herein, a genistein structural analog refers to a compound that has similar structure to that of the free genistein as shown in FIG. 2C. A genistein structural analog differs from the free genistein in one or more atoms or functions groups, which are replace with other atoms or functional groups. FIG. 2D is a schematic that illustrates an exemplary genistein structural analog, glycosylated genistein, and its activation to free (active) aglycone genistein. Genistin is the glycosylated form of genistein - both can be found in nature but the aglycone form has therapeutic benefits.
Genistein is an isoflavone abundant in soybeans. Genistein may inhibit chronic low grade skin inflammation by several mechanisms. Without wishing to be bound by any theory, it is hypothesized that genistein may inhibit the expression of NF-kB, IL-ip, IE-6, and RANKL.
Genistein may also inhibit TNF-a induced endothelial inflammation. Genistein is a suitable natural compound for the treatment of chronic inflammatory skin conditions sue to its antiinflammatory and antioxidant properties, low adverse event profile and low cost of production. Genistein can be incorporated directly into the spinning solution and be released from the scaffold onto the area of treatment, such as an area of skin.
Glycosylated genistein has unfavorable skin penetration because of its hydrophilicity and water solubility. In its aglycone form, genistein is a hydrophobic molecule that is partially soluble in water and is soluble in methanol and ethanol. Aglycone genistein has a favorable partition coefficient (logP) of about 2.98, which lies within the effective range of skin penetration. As described above, free genistein, which has low solubility in cold water, can be in the same solution with pullulan so pullulan and genistein can be co-spun to form the pullulan/genistein scaffold. As used herein, the term “solution” is broadly defined to include the colloid suspension of aglycone genistein in water. It is contemplated one of the several advantages of the invention that free aglycone (active) genistein is attached to the pullulan scaffold to enhance the stability thereof.
Genistein is also an agent that has beneficial effects on skin aging, especially in its free (active) aglycone form. When applied topically, genistein has anti-oxidant, anti-inflammatory, photoprotective effects.
In one embodiment, the agent is an anti-acne agent selected from the group consisting of salicylic acid, benzyl peroxide, aizelaic acid, willow bark, retinol, retinoids and retinoid-like drugs, phloretin, mandelic acid, witch hazel, tea tree, honey, cannabidiol, cannabis sativa, burdock, dapalene, dapsone, tretinoin, clindamycin, tazarotene, sulfur, hydrocortisone, erythromycin, resorcinol, glycolic acid, malic acid, and other BHAs and AHAs.
In one embodiment, the agent is an anti-fungal agent selected from the group consisting of miconazole nitrate, thyme, licorice, tea tree, lomatium, rosemary, burdock, echinacea, manuka, zinc pyrithione, sage, neem, honey, urea, and catnip, polymer anti-fungals, anole antifungals, allylamines, echinocandins, griseofulvin, flucytosine, ciclopirox, quinoline, potassium iodide, zinc pyrithione, azoles, e.g., Clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, miconazole, oxiconazole, sertaconazole, and sulconazole, alyylamines, e.g., neftifine, and terbinafine, Benzylamine, e.g., butte afi even, polyene, such as, nystatin, ciclopirox, and tolnaftate.
In one embodiment, the agent is an anti-microbial selected from the group consisting of iodine, silver sulfadiazine, chlorhexidine, acetic acid, mafenide, mupirocin, ketoconazole, silver nitrate, betadine, benzyl peroxide, sodium hypochlorite, and miconazole.
The therapeutic agent, e.g., genistein, can be attached to the scaffold by any mechanism. In one embodiment, for example, the therapeutic agent, e.g., genistein, can be attached to the scaffold via physical absorption. The therapeutic agent may be attached to the scaffold through Van der Waals
force. In another embodiment, the therapeutic agent may be attached to the scaffold via a chemical bond, such as an ionic bond, a hydrogen bond, or a covalent bond. In one embodiment, the therapeutic agent is directly attached to the scaffold. In another embodiment, the therapeutic agent may be formulated in a formulation first and the formulation containing the therapeutic agent may be attached to the scaffold via any mechanism. The formulation of the therapeutic agent can serve various purpose, such as increasing the stability of the therapeutic agent, e.g., genistein, or controlling the release of the therapeutic agent. In one embodiment, the formulation is a liposome formulation. Generally, the attachment of the therapeutic agent to the scaffold is reversible. The therapeutic agent is released from the scaffold when the pullulan/therapeutic agent scaffold is applied to treat a disorder or condition, e.g., when the scaffold is applied to an area of skin to treat a cutaneous disorder or condition.
As used herein, the term “treat,” “treating,” “treatment,” and the like, when it is used in the context of treating a disease, disorder or condition in a subject, is defined as the application or administration of a therapeutic agent to a patient, said patient having a disease, a symptom of disease or a predisposition toward a disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease, the symptoms of disease or the predisposition toward disease. Thus, treating can include suppressing, inhibiting, preventing, treating, or a combination thereof. Treating refers, inter alia, to increasing time to disease progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof. “Suppressing” or “inhibiting”, refers, inter alia, to delaying the onset of symptoms, preventing relapse to a disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, reducing the severity of symptoms, reducing the severity of an acute episode, reducing the number of symptoms, reducing the incidence of disease-related symptoms, reducing the latency of symptoms, ameliorating symptoms, reducing secondary symptoms, reducing secondary infections, prolonging patient survival, or a combination thereof. Symptoms may be any manifestation of a disease or pathological condition.
By “treatment”, “prevention” or “amelioration” of a disease or disorder is meant delaying or preventing the onset of such a disease or disorder, reversing, alleviating, ameliorating, inhibiting, slowing down or stopping the progression, aggravation or deterioration the progression or severity of a condition associated with such a disease or disorder. In one embodiment, the symptoms of a disease or disorder are alleviated by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. Accordingly, as used herein, the term “treatment” or “treating” includes any administration of a therapeutic agent described herein and includes: (i) preventing the disease from occurring in a subject which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease; (ii) inhibiting the disease in an subject that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further
development of the pathology and/or symptomatology); or (iii) ameliorating the disease in a subject that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
Efficacy of treatment is determined in association with any known method for diagnosing the disorder. Alleviation of one or more symptoms of the disorder indicates that the compound confers a clinical benefit. Any of the therapeutic methods described to above can be applied to any suitable subject including, for example, mammals such as dogs, cats, cows, horses, rabbits, monkeys, and most preferably, humans.
As used herein, the term “condition” refers to both pathologic condition, e.g., a disease or disorder, and non-pathologic condition, such as condition caused by aging or exposure to elements, e.g., exposure to UV light. Accordingly, a therapeutic agent that treats a condition includes agent used in cosmetics or personal care, e.g., genistein, botanical extracts, or essential oils.
In one embodiment, a solution used to form the pullulan polymeric fibers and the scaffolds of the invention comprises about 1% to 60% w/v of pullulan (based on volume of the carrier during manufacturing of the fibers and scaffolds, i.e., w/v %), e.g., about 5% to 60%, about 5% to 55%, about 5% to 50%, about 5% to 35%, about 5% to 30%, about 5% to 25%, about 5% to 20%, about 5% to 15%, about 5% to 10%, about 10% to 60%, about 10% to 55%, about 10% to 50%, about 10% to 45%, about 10% to 40%, about 10% to 35%, about 10% to 30%, about 10% to 25%, about 10% to
20%, about 10% to 15%, about 15% to 60%, about 15% to 55%, about 15% to 50%, about 15% to
45%, about 15% to 40%, about 15% to 35%, about 15% to 30%, about 15% to 25%, about 15% to
20%, about 20% to 60%, about 20% to 55%, about 20% to 50%, about 20% to 45%, about 20% to
40%, about 20% to 35%, about 20% to 30%, about 20% to 25%, about 25% to 60%, about 25% to
55%, about 25% to 50%, about 25% to 45%, about 25% to 40%, about 25% to 35%, about 25% to
30%, about 30% to 60%, about 30% to 55%, about 30% to 50%, about 30% to 45%, about 30 to 40%, about 30 to 35%, about 35% to 60%, about 35% to 55%, about 35% to 50%, about 35% to 45%, about 35% to 40%, about 40% to 60%, about 40% to 55%, about 40% to 50%, about 40% to 45%, about 45% to 60%, about 45% to 55%, about 45% to 50%, about 50% to 60%, about 50% to 55%, about 55% to 60%, about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5%, about 55%, about 57.5%, or about 60% (w/v %). Preferably, the solution comprises about 5% to 30%, about 5% to 25%, about 5% to 15%, about 5% to 10%, about 10% to 30%, about 10% to 25%, about 10% to 20%, about 10% to 15%, about 15% to 30%, about 15% to 25%, about 15% to 20%, about 20% to 30%, about 20% to 30%, about 25 to 30%, about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 17.5%, or about 20% w/v % of pullulan. More preferably, the solution comprises about 5% to 15%, about 5% to 10%, about 10% to 15%, about 5%, about 10%, about 15%, about 20%, about 25%, or about 30% (w/v %) of pullulan. In
one embodiment, the solution comprises about 10% to 30% w/v % of pullulan. In one embodiment, the solution comprises about 10%, 20%, or 30% % w/v % of pullulan.
In one embodiment, a solution used to form the pullulan / therapeutic fibers and the scaffolds of the invention comprises both pullulan and therapeutic agent. The concentration of the therapeutic agent in the solution can vary depending on various factors, such as the solubility, stability, and the dosage of the therapeutic agent that is effective for treating a disorder or a condition.
In one embodiment, a solution used to form the pullulan / genistein fibers and the scaffolds comprises about 1% to 10% w/v % of genistein. In one embodiment, the solution comprises about 4% to 6% w/v % of genistein. In another embodiment, the solution comprises about 1% w/v % of genistein. In another embodiment, the solution comprises about 3% w/v % of genistein. In another embodiment, the solution comprises about 2% w/v % of genistein.
In one embodiment, a solution used to form the pullulan or the pullulan / therapeutic agent polymeric fibers and the scaffolds of the invention comprises a crosslinking agent. In one embodiment, the crosslinking agent comprises about 1% to 20% (based on volume of the carrier during manufacturing of the fibers and scaffolds, i.e., w/v %) of citric acid anhydride, e.g., about 5% to 20%, about 5% to 15%, about 5% to 10%, about 10% to 20%, about 10% to 15%, about 2.5%, about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 17.5%, or about 20% (w/v%) of citric acid anhydride.
The linkage formed through the covalent crosslinking include intra-fiber linkage, inter-fiber linkage, or both.
In one embodiment, the solvent used during fabrication of the pullulan or the pullulan therapeutic agent, e.g., genistein, fibers and scaffolds of the invention comprises water. Without wishing to be bound by any theory, it is one of several advantages of the present invention that the pullulan can be dissolve in water at room temperature and spun into fiber or scaffold. In one embodiment, the solvent comprises a solvent selected from the group consisting of an organic solvent, e.g., alcohols, benzene, toluene, esters, ethers, ketones, etc, and inorganic solvents, e.g., ammonia, hydrogen fluoride, sulfuric acid, etc.
Since the solvent dissipates completely upon formation e.g., solidification) of the fibers and scaffolds, the formed fibers and scaffolds of the invention, accordingly, contain pullulan and therapeutic agent at a pullulan/therapeutic agent weight ratio of about 1.5 -3:1, .e.g., about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 2.6:1, about 2.7:1, about 2.8:1, about 2.9:1, or about 3:1, preferably 1.8:1, about 1.9:1, about 2:1, about 2.1:1, or about 2.2:1, more preferably about 1.9:1, 2:1, or about 2.1:1. In one embodiment, the pullulan/therapeutic weight ratio is about 2:1.
Methods for forming polymeric fibers and scaffold comprising pullulan or pullulan and therapeutic agent, e.g., genistein, are described below.
In some embodiments, each pullulan or pulluan/therapeutic agent, e.g., genistein, fiber in the scaffold independently has a diameter of about 200 nm to 10 pm, e.g., about 250 nm to 400 nm, about 300 nm to 400 nm, about 350 nm to 400 nm, about 360 nm to 400 nm, about 370 nm to 400 nm, about 375 nm to 400 nm, about 380 nm to 400 nm, about 385 nm to 400 nm, about 390 nm to 400 nm, about 395 nm to 400 nm, about 300 nm, about 325 nm, about 350 nm, about 360 nm, about 370 nm, about 375 nm, about 380 nm, about 385 nm, about 390 nm, about 395 nm, or about 400 nm. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
In some embodiments, each pullulan or pulluan/therapeutic agent, e.g., genistein, fiber in the scaffold independently has a diameter of about 0.01 nm to 500 pm, about 0.5 to 10 pm, e.g., about 1 to 10 pm, about 1.5 to 10 pm, about 2.0 to 10 pm, about 2.5 to 10 pm, about 3.0 to 10 pm, about 3.5 to 10 pm, about 4.0 to 10 pm, about 4.5 to 10 pm, about 5.0 to 10 pm, about 5.5 to 10 pm, about 6.0 to 10 pm, about 6.5 to 10 pm, about 7.0 to 10 pm, about 7.5 to 10 pm, about 8.0 to 10 pm, about 8.5 o
10 pm, about 9.0 to 10 pm, or about 9.5 to 10 pm. In certain embodiments, each pullulan or pulluan/therapeutic agent, e.g., genistein, fiber in the scaffold independently has a diameter of about 0.5 to 6.0 pm, e.g., about 1.0 to 6.0 pm, about 1.5 to 6.0 pm, about 2.0 to 6.0 pm, about 2.5 to 6.0 pm, about 3.0 to 6.0 pm, about 3.5 to 6.0 pm, about 4.0 to 6.0 pm, about 4.5 to 6.0 pm, about 5.0 to 6.0 pm, or about 5.5 to 6.0 pm. In some embodiments, each pullulan or pulluan/therapeutic agent, e.g., genistein, fiber in the scaffold independently has a diameter of about 0.5 pm, about 0.75 pm, about 1.0 pm, about 1.25 pm, about 1.5 pm, about 1.75 pm, about 2.0 pm, about 2.25 pm, about 2.5 pm, about 2.75 pm, about 3.0 pm, about 3.25 pm, about 3.5 pm, about 3.75 pm, about 4.0 pm, about 4.25 pm, about 4.5 pm, about 4.75 pm, about 5.0 pm, about 5. 25 pm, about 5.5 pm, about 5.75 pm, about 6.0 pm, about 6.25 pm, about 6.5 pm, about 6.75 pm, about 7.0 pm, about 7.25 pm, about 7.5 pm, about 7.75 pm, about 8.0 pm, about 8.25 pm, about 8.5 pm, about 8.75 pm, about 9.0 pm, about 9.25 pm, about 9.5 pm, about 9.75 pm, or about 10 pm. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention. The scaffolds themselves may be of any desired size and shape and can be fabricated according to need and use. Methods for fabricating the polymeric fiber scaffold are described below.
In certain embodiments, the scaffold formed has a porosity greater than about 40%, e.g., a porosity of about 60% to about 80%, about 65% to about 80%, about 70% to about 80%, e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or about 80%. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
In some embodiments, the average pore diameter of the scaffold formed is about 6 pm to 20 pm, about 6 pm to 15 pm, about 6 pm to 12 pm, about 6 pm to 10 pm, about 6 pm to 8 pm, about 6 pm, about 8 pm, about 10 pm, about 12 pm, about 15 pm, or about 20 pm. Preferably, the average pore diameter is about 6 pm to 10 pm, about 6 pm to 8 pm, about 6 pm, about 8 pm, or about 10 pm. More preferably, the average pore diameter is about 6 pm to 8 pm, about 6 pm, or about 8 pm. In one embodiment, the average pore diameter is about 6 pm. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
The thickness of the pullulan or pulluan / therapeutic agent, e.g., genistein, fibrous scaffolds of the invention can be controlled. For example, if a rotary jet spinning (RJS) system is used to spin the fibers and to produce the scaffolds, the thickness of the scaffold can be controlled by the amount of the carrier or the polymer solution used. In another embodiment, the thickness of the scaffold can be controlled by the rotation speed. In some embodiments, the thickness of the scaffold ranges from about 0.1 mm to 5 mm, e.g. , about 0.2 mm to 4 mm, about 0.2 mm to 3 mm, about 0.2 mm to 2.5 mm, about 0.2mm to 2 mm, about 0.2 mm to 1.5 mm, about 0.2 mm to 1 mm, about 0.5 mm to 4 mm, about 0.5 mm to 3 mm, about 0.5 mm to 2.5 mm, about 0.5 mm to 2 mm, about 0.5 mm to 1.5 mm, about 0.5 mm to 1.0 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, or about 4 mm. Preferably, the thickness of the scaffold is from about about 0.2 mm to 3 mm, about 0.2 mm to 2.5 mm, about 0.2mm to 2 mm, about 0.2 mm to 1 mm, about 0.5 mm to 2 mm, about 0.5 mm to 1.0 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, or about 3 mm. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
3. Use of the Scaffolds of the Invention
The scaffolds of the invention may be used in a broad range of applications, including, but not limited to, use in treatment of inflammation, wound healing, drug delivery, cosmetics, and personal care.
Accordingly, in one aspect, the present invention provides methods of having a skin disorder or condition. The method includes providing a polymeric fiber scaffold of the invention and disposing the polymeric fiber scaffold on, over, or in an area of skin affected by the disorder or the condition, thereby treating the subject. Such use of the polymeric fiber scaffolds may be combined with other methods of treatment, debridement, repair, and contouring.
This invention is further illustrated by the following examples, which should not be construed as limiting. The entire contents of all references, patents and published patent applications cited throughout this application, as well as the Figures, are hereby incorporated herein by reference.
EXAMPLES
Example 1: Pullulan / Genistein Scaffolds
Bioactive and biodegradable nanofibers for topical dressings have been designed. As shown in FIG. 1, a polymer, e.g., pullulan, was crosslinked to form biodegradable nanofibers. Optionally, a therapeutic agent, e.g., genistein, was attached to the biodegradable nanofiber. The nanofibers form a scaffold (nanotextile as shown in FIG. 1), which optionally contains the therapeutic agent (therapeutic molecules in FIG. 1).
Pullulan has been used for fabricating the nanofiber scaffold. In some embodiment, therapeutic agent was added to the scaffold. In certain embodiments, genistein was selected as the therapeutic agent. As shown in FIG. 2 and described in this example, pullulan or pullulan / genistein nanofibers have been fabricated.
Pullulan was dissolved in water at room temperature at 20% (w/v). Pullulan nanofibers were fabricated using focused rotary jet spinning (fRJS) method. The parameters for an exemplary fRJS method are shown in FIG. 3A. FIG. 3B provides images depicting the topological characterization of exemplary pullulan nanofibers fabricated. FIG. 3C is a graph depicting the distribution of the diameters of exemplary pullulan nanofibers.
Exemplary pullulan nanofibers were subject to FTIR analysis to verify that the nanofibers contain pullulan molecules. As shown in FIG. 4, the FTIR analysis of nanofibers showed spectra characteristic of pullulan.
To increase the mechanical strength of the pullulan nanofibers, crosslinking agent was added in the solution for fabricating the pullulan nanofibers. An exemplary crosslinking agent is citric acid. FIG. 5 depicts various mechanisms for crosslinking pullulan, including citric acid mediated crosslinking. FIG. 6 depicts an exemplary mechanism that crosslinking pullulan using citric acid.
In order to demonstrate that citric acid alone was able to catalyze the crosslinking reaction with pullulan while pullulan nanofibers were fabricated using fRJS system, citric acid was added to the solution for fabricating pullulan nanofibers to different concentration, e.g., 1%, 5%, 10%, or 20% (w/v). Pullulan nanofibers were fabricated using fRJS system with the parameters shown in FIG. 7A. Using the fRJS system, pullulan solution containing different concentration of citric acid resulted in nanofiber formation. FIG. 7B includes images depicting the nanofibers formed using different
concentration of citric acid. FIG. 7C includes graphs depicting the distribution of fiber diameters of the nanofibers formed from pullulan with different concentration of citric acid.
EQUIVALENTS
In describing exemplary embodiments, specific terminology is used for the sake of clarity. For purposes of description, each specific term is intended to at least include all technical and functional equivalents that operate in a similar manner to accomplish a similar purpose. Additionally, in some instances where a particular exemplary embodiment includes a plurality of system elements or method steps, those elements or steps may be replaced with a single element or step. Likewise, a single element or step may be replaced with a plurality of elements or steps that serve the same purpose. Further, where parameters for various properties are specified herein for exemplary embodiments, those parameters may be adjusted up or down by l/20th, l/10th, l/5th, l/3rd, Vi, etc., or by rounded-off approximations thereof, unless otherwise specified. Moreover, while exemplary embodiments have been shown and described with references to particular embodiments thereof, those of ordinary skill in the art will understand that various substitutions and alterations in form and details may be made therein without departing from the scope of the invention. Further still, other aspects, functions and advantages are also within the scope of the invention.
The contents of all references, including patents and patent applications, cited throughout this application are hereby incorporated herein by reference in their entirety. The appropriate components and methods of those references may be selected for the invention and embodiments thereof. Still further, the components and methods identified in the Background section are integral to this disclosure and can be used in conjunction with or substituted for components and methods described elsewhere in the disclosure within the scope of the invention.
As may be recognized by those of ordinary skill in the pertinent art based on the teachings herein, numerous changes and modifications may be made to the above -described and other embodiments of the present disclosure without departing from the spirit of the invention as defined in the appended claims. Accordingly, this detailed description of embodiments is to be taken in an illustrative, as opposed to a limiting, sense. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the described herein. Such equivalents are intended to be encompassed by the following claims.
Claims
1. A method for forming a non-woven polymeric fiber scaffold comprising pullulan, the method comprising: rotating a reservoir holding a solution comprising pullulan about a rotation axis to eject at least one jet of pullulan from at least one orifice defined by an outer sidewall of the reservoir; directing at least one flow of gas through a portion of the reservoir radially inward of the outer sidewall, the at least one flow of gas directed from an upstream first end of the reservoir to a downstream second end of the reservoir during rotation of the reservoir and ejection of the at least one jet of the pullulan to form at least one polymeric fiber comprising pullulan, the at least one flow of gas entraining the at least one polymeric fiber comprising pullulan and forming a focused pullulan fiber deposition stream of the at least one polymeric fiber comprising pullulan in a first direction, the first direction having an orientation of within 5 degrees of the rotation axis of the reservoir; and collecting the focused pullulan fiber deposition stream on a target surface which is a three- dimensional shape, thereby forming the non-woven polymeric fiber scaffold comprising pullulan.
2. A method of forming a non-woven polymeric fiber scaffold comprising pullulan, the method comprising: providing a solution comprising: pullulan; rotating the pullulan in solution about an axis of rotation to cause ejection of the pullulan solution in one or more jets; and collecting the one or more jets of the pullulan in a liquid to cause formation of one or more polymeric fibers comprising pullulan, thereby forming the non-woven polymeric fiber scaffold comprising pullulan.
3. A method of forming a non-woven polymeric fiber scaffold comprising pullulan, the method comprising: providing a solution comprising: pullulan; forming a plurality of polymeric fibers comprising pullulan by ejecting or flinging the solution from a reservoir; and collecting the plurality of polymeric fibers comprising pullulan on a collection surface, thereby forming the non-woven polymeric fiber scaffold comprising pullulan.
4. The method of claim 1 to 3, wherein the solution comprises between about 1% (w/v) and about 60% (w/v) of pullulan.
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5. The method of claim 4, wherein the solvent of the solution comprises water.
6. The method of claim 5, wherein the solvent of the solution comprises water.
7. The method of claim 6, wherein the solution further comprises an additional solvent.
8. The method of claim 7, wherein the additional solvent is s acetone.
9. The method of any one of claims 1-8, wherein the solution further comprises a crosslinking agent.
10. The method of claim 9, wherein the crosslinking agent covalently cross-links the pullulan.
11. The method of claim 10, wherein the crosslinking agent is selected from the group consisting of citric acid, glyoxal, glutaraldehyde, genipin, and STMP.
12. The method of claim 11, wherein the solution comprises about 1% (w/v) to about 20% (w/v) of the cross-linking agent.
13. The method of claim 11 or 12, wherein the cross-linking agent comprises citric acid, citric acid anhydride, or the combination thereof.
14. The method of any one of claims 1-13, wherein the solution further comprises a therapeutic agent.
15. The method of claim 14, wherein the therapeutic agent is a small molecule, a polysaccharide, a nucleic acid, a protein, a botanical extract, a fatty acid, a surfactants, a ceramides, or a metal.
16. The method of claim 14, wherein the therapeutic agent is an anti-microbial agent, an antifungal agent, an anti-acne agent, an anti-inflammatory agent, an anti-aging agent, or a wound healing agent.
17. The method of claim 15 or 16, wherein the therapeutic agent is formulated in a formulation that maintains the stability of the therapeutic agent.
18. The method of any one of claims 1-17, wherein the first direction is substantially parallel to the rotation axis of the reservoir.
19. The method of claim 18, wherein the at least one flow of gas comprises a plurality of flows of gas that converge and form a combined gas flow in the first direction.
20. The method of claim 19, wherein a flow rate of at least some of the plurality of converging flows of gas relative to others of the plurality of converging flows of gas is controllable to achieve a balanced combined gas flow.
21. The method of claim 18 or claim 19, wherein a total gas flow rate of the plurality of converging flows of gas is controllable to change a distance from the reservoir at which the focused fiber deposition stream of the at least one micron or nanometer dimension polymeric fiber has the tightest focus.
22. The method of any one of claims 18 to 21, wherein the plurality of gas flows comprises three gas flows.
23. The method of any one of claims 1, and 18-22, wherein the focused fiber deposition stream has a substantially tangential orientation to the target surface during fiber collection.
24. The method of any one of claims 1-17, further comprising rotating the target for deposition on more than one side of the three dimensional shape.
25. The method of claim 24, wherein the target is rotating at a speed up to 20,000 rpms
26. The method of any one of claims 1-17, further comprising at least partially blocking flow of gas from upstream of the reservoir to reduce an effect of airflow upstream of the plurality of gas flow sources on focusing of the fiber deposition stream of the at least one micron or nanometer dimension polymeric fiber.
27. The method of any one of claims 1-17, wherein the target surface is static or moved linearly during deposition of the fiber.
28. The method of any one of claims 1-17, wherein the reservoir is rotated at a speed of about up to 20, 000 rpm.
29. The method of any one of claims 1-18, wherein the orifice is about 0.5 mm to about 2 mm in diameter.
30. A method for forming a non-woven polymeric fiber scaffold comprising pullulan, the method comprising: rotating a reservoir holding a solution comprising about 20% w/v pullulan and between about 1% w/v and 20% w/v citric acid about a rotation axis to eject at least one jet of pullulan from at least one orifice defined by an outer sidewall of the reservoir; directing at least one flow of gas through a portion of the reservoir radially inward of the outer sidewall, the at least one flow of gas directed from an upstream first end of the reservoir to a downstream second end of the reservoir during rotation of the reservoir and ejection of the at least one jet of the pullulan to form at least one polymeric fiber comprising pullulan, the at least one flow of gas entraining the at least one polymeric fiber comprising pullulan and forming a focused pullulan fiber deposition stream of the at least one polymeric fiber comprising pullulan in a first direction, the first direction having an orientation of within 5 degrees of the rotation axis of the reservoir; and collecting the focused pullulan fiber deposition stream on a target surface which is a three- dimensional shape.
31. A non-woven polymeric fiber scaffold comprising pullulan produced according to the method of any one of claims 1 -30.
32. A non-woven polymeric fiber scaffold comprising: a plurality of polymeric fibers, each polymeric fiber independently comprising pullulan.
33. The polymeric fiber scaffold of claim 32, wherein a solution forming the plurality of polymeric fibers comprises between about 1 w/v% and 60 w/v% pullulan.
34. The polymeric fiber scaffold of any one of claims 31-33, wherein the pullulan is crosslinked.
35. The polymeric fiber scaffold of claim 34, wherein the pullulan is covalently crosslinked.
36. The polymeric fiber scaffold of claim 34, wherein the pullulan is not covalently crosslinked.
37. The polymeric fiber scaffold of claim 36, wherein the pullulan is crosslinked via ionic bond, hydrogen bond, Van der Waals force
38. The polymeric fiber scaffold of claim 35, wherein the polymeric fiber is formed from a solution comprising pullulan, wherein the solution further comprises a cross-linking agent that covalently crosslinks the pullulan.
39. The polymeric fiber scaffold of claim 38, wherein the solution comprises between about 1% w/v and 20 % w/v the crosslinking agent.
40. The polymeric fiber scaffold of claim 38 or 39, wherein the crosslinking agent comprises a citric acid anhydride or a citric acid.
41. The polymeric fiber scaffold of any one of claims 32-40, comprising an intra-fiber linkage, an inter-fiber linkage, or the combination thereof.
42. The polymeric fiber scaffold of any one of claims 32-41, wherein each polymeric fiber independently has a diameter in a range of about 200 nm to 10 pm.
43. The polymeric fiber scaffold of any one of claims 32-42, further comprising a therapeutic agent.
44. The polymeric fiber scaffold of claim 43, wherein the therapeutic agent is a fatty acid, a surfactants, a ceramides, or a metal.
45. The polymeric fiber scaffold of claim 44, wherein the therapeutic agent is an anti-microbial agent, an anti-fungal agent, an anti-acne agent, an anti-inflammatory agent, an anti-aging agent, or a wound healing agent.
46. The polymeric fiber scaffold of any one of claims 43-45, wherein the therapeutic agent is formulated in a formulation that maintains the stability of the therapeutic agent.
47. The polymeric fiber scaffold of any one of claims 43-46, wherein the polymeric fiber is formed from a solution comprising the pullulan, wherein the solution further comprises the therapeutic agent.
48. The polymeric fiber scaffold of any one of claims 43-47, wherein the therapeutic agent comprises an anti-inflammatory agent.
31
49. The polymeric fiber scaffold of claim 48, wherein the anti-inflammatory agent comprises a phytoestrogen.
50. The polymeric fiber scaffold of claim 49, wherein the phytoestrogen comprises a genistein.
51. The polymeric fiber scaffold of any one of claims 43-50, wherein the therapeutic agent comprises a wound-healing agent.
52. The polymeric fiber scaffold of any one of claims 43-51, wherein the therapeutic agent comprises an anti-aging agent.
53. The polymeric fiber scaffold of claim 52, wherein the anti-aging agent is genistein.
54. The polymeric fiber scaffold of claim 53, wherein the anti-aging agent comprises a genistein.
55. A method for treating a subject having a skin disorder or condition, the method comprising: providing the polymeric fiber scaffold of any one of claims 31-54; and disposing the polymeric fiber scaffold on, over, or in an area of skin affected by the disorder or the condition, thereby treating the subject.
56. The method of claim 55, wherein the method further comprises keeping the polymeric fiber scaffold disposed on, over or in the skin area during treatment.
57. The method of claim 55 or 56, wherein the method promotes wound healing of the subject.
58. The method of claim 55 or 56, wherien the method reduces inflammation of the subjection.
59. The method of claim 55 or 56, wherein the method promotes tissue regeneration in the subject.
60. The method of claim 55 or 56, wherein the method delays aging of skin in the subject.
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