WO2009042829A1 - Fibres d'hydrogel bioactives - Google Patents

Fibres d'hydrogel bioactives Download PDF

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Publication number
WO2009042829A1
WO2009042829A1 PCT/US2008/077785 US2008077785W WO2009042829A1 WO 2009042829 A1 WO2009042829 A1 WO 2009042829A1 US 2008077785 W US2008077785 W US 2008077785W WO 2009042829 A1 WO2009042829 A1 WO 2009042829A1
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Prior art keywords
fibers
hydrogel
fiber
dextran
functionalized polymer
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PCT/US2008/077785
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English (en)
Inventor
Stephen Massia
Benjamin Bowen
Katherine Louie
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Stephen Massia
Benjamin Bowen
Katherine Louie
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Application filed by Stephen Massia, Benjamin Bowen, Katherine Louie filed Critical Stephen Massia
Publication of WO2009042829A1 publication Critical patent/WO2009042829A1/fr

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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
    • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
    • 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
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/225—Mixtures of macromolecular compounds
    • 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
    • A61L15/44—Medicaments
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/426—Immunomodulating agents, i.e. cytokines, interleukins, interferons

Definitions

  • the invention pertains to hydrogel fibers comprised of a carboxy-functioalized polymer (e.g. a polyacid, such as polyacrylic acid) and a hydroxy-functionalized polymer (e.g. a polysaccharide, such as dextran); articles made therewith; and uses of same.
  • a carboxy-functioalized polymer e.g. a polyacid, such as polyacrylic acid
  • a hydroxy-functionalized polymer e.g. a polysaccharide, such as dextran
  • articles made therewith e.g. a polysaccharide, such as dextran
  • the resultant fibers which can be nano- and micro- fibers having diameters ranging from hundreds of nanometers to microns, can then be applied to various surfaces to create diverse topographies, including mesh-like and bristly fibrous coatings.
  • the articles thus formed can be used inter alia for medical applications where fine control over cell adhesion properties is desired,
  • Hydrogel fibers of small diameter are generally known, often constituted of polymeric material and made by electrospinning techniques. Articles having utility in medical applications can be comprised of such fibers when the materials of construction are biocompatible. Nonetheless, there remains a need for further refinement of small diameter hydrogel technology to e.g., enable different surface topographies, modulate cell adhesion characteristics, and to create other bioactive surface properties heretofore unavailable. Summary of the Invention
  • the invention is directed to hydrogel fibers having small diameter (nanometers to microns), preferably of short fiber length (nanometers to millimeters) and comprised of a cross-linked carboxy-functionalized polymer and a hydroxy-functionalized polymer, such as polyacrylic acid (PAA) and a polysaccharide, such as dextran, respectively.
  • PAA polyacrylic acid
  • the invention is further directed to a method of making said hydrogel fibers; articles comprised of same; and the uses of said articles in various medical and biological contexts.
  • FIG. 1 (a)-(i) are SEM images of electrospun dextran/PAA fibers of the invention.
  • the fibers were electrospun using different polymer concentrations, resulting in smaller and larger diameter fibers.
  • FIG. 2 shows a fibrous surface coating of the invention.
  • the image shown is a confocal image of fluorescent fiber "bristles" attached to a poly-L-lysine coated surface.
  • the fibers used were, on average, a few microns in diameter.
  • FIG. 3(a) and 3(b) show an endothelial cell culture on dextran/PAA fibers in accordance with the invention.
  • bovine endothelial cells actin cytoskeleton stained with rhodamine-phalloidin were cultured on fluorescent dextran/PAA fibers (range of 690nm to 2.7 microns, average of about 1.5 microns in diameter) for 1 week. Endothelial cells are able to spread and proliferate on fiber-coated surfaces.
  • FIG. 3(b) is a montage of confocal slices;
  • FIG. 3 (a) is an overlay image of all confocal slices of FIG. 3(b).
  • FIG. 4 is a graph showing the results of the ethanolamine passivation of fibers in accordance with the invention.
  • FIG. 5 is a graph of fluorescence intensity fibers added to a surface (micrograms of fiber). In the slope between about 100 and 250 micrograms the fiber attached in a bristle configuration to the surface.
  • FIG. 6 is a graph of protein adsorption on fibers of the invention.
  • FIG. 7 is a graph of protein adsorption on fibers immobilized onto an adhesive (e.g. PLL) surfaces and non-adhesive (e.g. dextran monolayer) surface.
  • an adhesive e.g. PLL
  • non-adhesive e.g. dextran monolayer
  • FIG. 8(a)-(f) show cell adhesion resistance of fibrous surface coatings with micro- scale fibers and high density or low density fiber coatings.
  • hydrogel micro- and nano- fibers are fabricated and used to create selectively bioactive fibrous biomaterials. Electrospinning is preferably used to generate fibers preferably comprised of polysaccharide (e.g. dextran) and polyacrylic acid (PAA) ranging from hundreds of nanometers to microns in diameter.
  • the dry fibers are preferably cross-linked, making them stable as individual fiber hydrogels in aqueous solution.
  • the long, continuous fibers can be further processed into short fiber "bristles” and attached as such to various surfaces to form articles useful in medical and biological settings.
  • the invention is to a hydrogel fiber comprised of a polysaccharide and polyacrylic acid.
  • the polysaccharide is dextran.
  • the fiber can be produced by e.g. electrospinning the polysaccharide and PAA.
  • the polysaccharide-PAA fiber is cross-linked by methods known in the art, preferably by thermal esterification techniques.
  • the hydrogel fiber consists essentially of a polysaccharide (such as dextran) and PAA.
  • the hydrogel fibers of the invention can be immobilized onto various substrates, forming nano- and microtextured coatings, or bonded to each other to create slab-like fibrous, porous hydrogel membranes.
  • the individual polymer components of the fibers are accepted as biocompatible materials; as a result, the fibers have utility in a variety of biomaterials applications.
  • One embodiment of the invention is directed to a substrate having a surface wherein the surface comprises a plurality of electrospun hydrogel fibers having diameters of less than one micron; the hydrogel fibers are comprised of a carboxy-functionalized polymer and a hydroxy-functionalized polymer wherein the electrospun hydrogel fibers are cross-linked and fragmented.
  • the fragmented hydrogel fibers are attached to a surface in a bristle configuration, but when the carboxy-functionalized polymer is polyacrylic acid and the hydroxy-functionalized polymer is a polysaccharide (e.g. dextran)., the fibers may be attached to the surface in a bristle, mesh, or other configuration.
  • the electrospun fibers are fragmented into a length less than about 3mm. More preferably, they have a diameter of between about 10 nanometers to about 10,000 nanometers; the electrospun hydrogel fibers preferably have been cross-linked by e.g. thermal esterification; and the length of the fibers is preferred as between about 100 nanometers and about 2mm.
  • the hydrogel fibers of the invention can be chemically modified to exhibit minimal protein adsorption or cell adhesion properties. This property is useful in applications in which biofouling is unwanted (e.g. implants, controlled release devices, biofiltration).
  • the fibers can be used to control cell adhesion, providing a protective barrier from cellular infiltration into or onto the underlying material.
  • the fibers can prevent biofouling from disrupting the function of a material / implant / device used in vivo or in vitro or ex vivo.
  • the hydrogel fibers of the invention can be used in ameliorating, including preventing, the rejection of implanted material by the host body.
  • the surface coatings of the hydrogel fibers are applied to implanted materials to render same effectively invisible to the immune system, thereby minimizing or even circumventing detrimental immune responses and consequent rejection for implants, which include but are not limited to: stents, catheters, grafts, pacemakers, electrodes, organ transplants, bone screws and the like.
  • the hydrogel fibers of the invention can be custom- modified with various bioactive components (e.g. peptides, proteins, polysaccharides, enzymes, etc). Combining specific bioactivity with the fibers, preferably when they are in a mesh configuration, results in a biomimetic of native extracellular matrix (ECM; or ECM-mimetic).
  • ECM extracellular matrix
  • Specific tissue environments can thus be custom-generated for various applications, including the promotion of cell type- selective interactions, differentiation of progenitor cells, immobilization of enzymes, and the induction of specific receptor-Hgand interactions. Other applications include in situ regeneration of tissue and progenitor cell recruitment into vascular grafts.
  • the hydrogel fibers of the invention can be adapted for and used in controlled release applications.
  • the fibers themselves can be loaded with substances (drugs, bioactive compounds) and either injected or implanted without eliciting an inflammatory response. Release characteristics can be modified by controlling the rate of degradation, for example, by using different fiber morphologies, controlling the degree of cross-linking, or other chemical-related methods.
  • the hydrogel fibers of the invention can be used to facilitate wound healing, by e.g., being used as a bioactive wound dressing.
  • the wound dressing of the invention comprises hydrogel fibers that mimic the extracellular matrix environment of dermal wounds, in combination with bioactive molecules.
  • the wound dressing can release a multitude of bioactive agents in a temporally and spatially specific, event-driven manner to promote optimal tissue regeneration and repair of chronic wounds.
  • the wound dressing of the invention provides tissue-like structure in the wound and has chemical and physical properties that support the reservoir/carrier functionality for locally delivery of wound healing bioactive molecules.
  • the wound dressing can effectively treat a wide variety of wounds, including chronic wounds such as, but not limited to, venous ulcers, arterial ulcers, diabetic ulcers, pressure ulcers, vasculitis and the like.
  • inventive hydrogel fibers take advantage of the increased surface area created by the fibrous surface coatings, as opposed to that of a flat surface.
  • fibrous surface coatings can significantly increase the available surface area for specific binding of the target molecule, resulting in a more sensitive sensor.
  • Filtration is another application contemplated by the invention, either to remove components or specifically isolate certain molecules (similar to HPLC or dialysis device), with increased surface area increasing contact area either static or under flow.
  • Fiber Composition [0021] Specific preferred practices will now be described.
  • a first aspect of the invention contemplates a hydrogel fiber of small diameter, e.g. less than 10 microns; preferably between about 10 nanometers (ran) and about 100,000 run; more preferably between about 20 ran to about 10,000 nm.
  • the fiber is comprised of at least one carboxy-functionalized polymer and at least one hydroxy- functionalized polymer.
  • Carboxy-functionalized polymers and molecules serviceable in the invention include, without limitation, polyacrylic acid (PAA), carboxy-methyl dextran (CM-dex), poly(methacrylic acid), polysaccharides such as hyaluronic acid, multi-carboxylic acid molecules such as citric acid, succinate, and malate, peptides and proteins with multiple carboxy-functionality and other like polymers having carboxylic acid (-COOH) functionality .
  • Hydroxy-fiinctionalized polymers are those having -OH groups therein, including without limitation, polysaccharides (such as dextran), polyvinyl alcohol (PVA) and other like polymers.
  • PVA polyvinyl alcohol
  • the hydroxy-functionalized polymer is dextran of M w of between 5K to 2MM Dalt ⁇ ns, preferably about 7OK Daltons; and the carboxy-functionalized polymer is polyacrylic acid of M w between about 5K to about 2MM Daltons, preferably about 9OK Daltons.
  • the ratio of dextran:PAA can be varied between about 0:10 and about 10:0, with a ratio of about 10:4 being preferable.
  • higher or lower molecular weight formulations of these polymers can also be used within the limits of the change in morphology of electrospun fibers that result; i.e.
  • the dextran/P AA fibers can be made fluorescent by substituting about 0.5wt% of dextran with about 70 Kilodalton (K; g/mol) of fluorescein isothiocyanate dextran (FITC-dextran) prior to electrospinning.
  • the invention contemplates a method of making hydrogel fibers comprising: (a) electrospinning an admixture of a carboxy-functionalized polymer and a hydroxy-functionalized polymer, as herein defined, under conditions effective to form fibers from same, said fibers having diameters less than about 10 microns; (b) optionally cross-linking the fibers of step (a), by e.g. thermal esterification, to render them stable in aqueous solution; and (c) fragmenting the cross-linked fibers step (b), by e.g. mechanical shearing, including sonication, into lengths less than 3mm, preferably less than 2 mm, more preferably between about 100 nm and 1 mm.
  • the resulting fibers can be used to form articles of manufacture by, e.g. step (d) attaching said fibers (in a flat configuration, bristle configuration, or both), onto a surface (e.g. a positively charged surface or other suitable substrate) to form an article of manufacture or a component of same.
  • step (d) attaching said fibers (in a flat configuration, bristle configuration, or both), onto a surface (e.g. a positively charged surface or other suitable substrate) to form an article of manufacture or a component of same.
  • the invention in another aspect, relates to an article of manufacture comprising a plurality of electrospun hydrogel fibers having diameters of less than one micron, said hydrogel fibers comprised of a carboxy-functionalized polymer and a hydroxy- functionalized polymer, said electrospun hydrogel fibers being cross-linked and fragmented into a length less than about 3mm, said fragmented hydrogel fibers being attached to a surface in a bristle configuration.
  • said electrospun hydrogel fibers have a diameter of between about 2 nanometers to about 10,000 nanometers; said carboxy-functionalized polymer is polyacrylic acid, said hyroxy-functionalized polymer is dextran; and said electrospun hydrogel fibers have been cross-linked by thermal esterification; the length of said fibers preferably between about 100 nanometers and about 2mm.
  • a preferred use setting for this article is a medical device.
  • a substrate having a surface, said surface comprising a plurality of hydrogel fibers attached thereto.
  • said fibers are comprised of a carboxy-functionalized polymer and a hydroxy-functionalized polymer.
  • said carboxy-functionalized polymer is polyacrylic acid or carboxy-methyl dextran; said hydroxy-functionalized polymer is dextran or polyvinyl alcohol; and said fibers are cross-linked, preferably by thermal esterification.
  • the surface of the substrate can comprise the hydrogel fibers in various configuration, with bristle and mesh configurations preferred, provided preferably that when the fibers are comprised of PAA and a polysaccharide (e.g. dextran), the configuration can be bristle or mesh; and when other carboxy-functionalized polymers and hydroxy-functionalized polymers comprise the fiber, the configuration is preferably bristle.
  • said fibers may be attached in a bristle, mesh, or other configuration.
  • One practice of the invention relates to a device for biological or medical use comprising the substrate aforesaid, e.g. said device can comprise a filter, a membrane, a tissue graft, wound dressing, or an implant, e.g. for controlled release of drug substances.
  • the device can also comprise fibers that have been modified to exhibit decreased cell adhesion, or that have been modified with one or more peptides, proteins, polysaccharides or enzymes.
  • the bioactive agents are also utilized with same, such as growth factors, cytokines, bioactive peptides, or combinations thereof.
  • the wound dressing is formulated into a moisturizing dressing, an absorptive dressing or a wound filler.
  • the wound dressing contemplated by the invention can be used to treat, without limitation, venous ulcers, arterial ulcers, diabetic ulcers, pressure ulcers, vasculitis and the like.
  • Implants contemplated by the invention include without limitation, stents, catheters, pacemakers, electrodes, bone screws and the like.
  • Fibers can be generated to the diameters specified by methods known in the art, all of which are contemplated by the invention.
  • the fibers are electrospun using commercially available technology and techniques as known to the artisan. See e.g. Zong, XH; Kim, K; Fang, DF; Ran, SF; Hsiao, BS; Chu, B. 2002. Structure and Process Relationship of Electrospun Bioabsorbable Nanofiber Membranes. POLYMER 43 (16): 4403-4412, incorporated herein by reference.
  • electrospinning is performed using water as solvent; or using water a the primary solvent in the electrospinning solution in concert with other solvents, such as DMSO, DMF, ethanol and the like.
  • Water when present can optionally have dissolved therein anionic or cationic salts, such as sodium chloride, calcium chloride, potassium chloride and the like, and/or dissolved proteins or peptides, and/or dissolved small molecules, such as fluorescent dye molecules and the like.
  • Electrospinning can be performed using polymer solution concentrations of between about 0.4 to about 1.2 grains of polymer dissolved in 1 ml of solvent.
  • a low humidity environment is preferred for the electrospirming, e.g 0% to about 30% humidity.
  • Voltage applied to the electrospinning solution is between about 15KV to about 30KV.
  • Solution flow rates are between about 1 ⁇ L/min to about 50 ⁇ L/min from the capillary tip.
  • a metal capillary of about 0.01 inch to about 0.05 inch in diameter is used to extrude the polymer solution.
  • the electrospinning is performed with the target located about 5 cm to about 20 cm from the capillary tip.
  • an aqueous solution is prepared by dissolving a mixture of dextran and PAA polymers in deionized water.
  • concentration of total polymer can vary between about 0.6 to about 1.0 gram per 1 mL water.
  • the ratio of dextran:PAA can also be varied between about 0:10 and about 10:0, with a ratio of about 10:4 being more preferred.
  • Electrospinning can be performed at a flow rate of between about 7-15 ⁇ L/min, using a high-voltage power supply to apply 25kV to a metal capillary tip (0.02 inch to 0.03 inch inner diameter). The electrospun fibers that result are collected on a grounded metal target located between about 10-20 cm from the tip.
  • fiber diameter is controlled primarily by varying initial polymer solution concentration, with lower concentrations generating smaller diameter nanofibers (tens to hundreds of nanometers) and higher concentrations generating larger diameter microfibers (e.g. microns).
  • Intrafiber Cross-Linking and Stability is controlled primarily by varying initial polymer solution concentration, with lower concentrations generating smaller diameter nanofibers (tens to hundreds of nanometers) and higher concentrations generating larger diameter microfibers (e.g. microns).
  • the dextran/PAA fibers can be cross-linked using techniques known in the art.
  • cross-linking is performed using a thermal dehydration reaction based on the procedure in Chen, H; Hsieh, YL. 2004.
  • Ultrafme Hydrogel Fibers With Dual Temperature and pH Responsive Swelling Behaviors JOURNAL OF POLYMER SCIENCE PART A- POLYMER CHEMISTRY 42 (24); 6331-6339, incorporated herein by reference.
  • the dried fibers resulting from, e.g., electrospinning are placed in a vacuum oven for between about 1 minute to about 1 month, preferably between about 15 minutes and about 1 week, more preferably between about 1 hour to about 2 hours, at between about 120° C and 300° C, preferably between about 140° C to about 210° C, more preferably about 18O 0 C.
  • This induces thermal esterification between the hydroxyl groups (-OH) of the dextran and the carboxylic acid groups (-COOH) of poly(acrylic acid); i.e. an ester bond is formed between these groups.
  • the degree of cross- linking is controlled by varying the 'mer' ratio of dextran to polyacrylic acid.
  • fibers with a higher degree of cross-linking are more stable when immersed in water, while those with lower degrees of cross-linking are less stable.
  • dextran/PAA fibers created using about a 10:1 mer ratio result in a low degree of cross-linking, and will initially swell when immersed in water, then dissolve within a short time.
  • fiber stability is affected by mechanisms that cleave ester bonds, including hydrolysis, strong acids or bases, or esterase enzymes.
  • the fibers are fabricated into short fiber segments or "bristles.”
  • the long electrospun fibers are fragmented into pieces less than about 3mm, to more preferably ranging between about lOOnm to about 2mm millimeters in length, more preferably between about lOOnm and about lmm.
  • the length is less than about 0.1 ⁇ m (10 5 nm). While any form of mechanical shearing can be used, such as forcing the fiber through a narrow-gauged syringe, sonication is preferred.
  • the dry fibers are removed from the metal collector after electrospinmng, cross-linked via thermal esterification, and immersed in deionized water.
  • a sonicator probe is inserted into the fiber solution at a setting of 4 for about 10 seconds, which mechanically shears the long fibers into short fragments.
  • the fragmented fibers, or “bristles,” that result are stable between the temperatures of about 4° to about 37° C, at pH ⁇ 7, and can be stored in deionized water (DI) (typically at 4 0 C) until ready for use.
  • DI deionized water
  • the fibers of the invention can be attached to various surfaces as known in the art.
  • the fibers fragmented they may be attached in a single layer, e.g. having a "mesh" configuration wherein the fibers are attached to lie flat on the surface; in a "bristle” or “bristly” configuration wherein they protrude upwards from the surface; or they can be attached in multiple layers on a surface, to form a multiplayer coating of attached fiber fragments.
  • the fibers are not fragmented, they may be attached to a surface in a single layer, or in multiple layers.
  • the fibers have a net negative charge, as e.g.
  • the fibers can be attached to a positively-charged surface, such as poly-L-lysine adsorbed onto tissue culture plastic or acid-etched glass.
  • a fiber solution in water typically from about 1 microgram to about 10 micrograms of dry fiber bristles hydrated in about 1 mL DI water, is added to a positively-charged surface, preferably poly-L-lysine-coated tissue culture plastic (PLL), and the fibers are allowed to settle overnight. After rinsing, the fibers remain attached.
  • PLL poly-L-lysine-coated tissue culture plastic
  • PBS 5 cell culture media DI water, high and low pH solutions of weak acids or bases
  • the attached fibers are very stable to vigorous rinsing. Mechanical shear such as scratching with a blunt probe removes adherent fibers.
  • Fiber density can be controlled by manipulating the concentration of fibers in solution.
  • Surface morphology can be controlled by allowing the fibers to dehydrate onto the surface, which results in a mesh morphology; or stay hydrated, which results in a bristly morphology.
  • the fibers can be aligned, e.g. they can be attached to a surface such that they lie parallel to each other. This is accomplished by flowing a solution of fiber bristles in water over a positively charged surface. The fibers attach, then lie down and attach in the direction of flow.
  • the fibers are passivated, as may be desired for various use settings, e.g. where non-specific protein fouling and cell adhesion is disfavored or can betolerated only in limited fashion. Suitable passivation techniques are known in the art.
  • electronegative -COOH groups are neutralized by attaching ethanolamine at these sites.
  • a solution of 3OmM EDC, SmM NHS, and 0.1M ethanolamine in 5OmM MES buffer is added to a fiber-coated surface and allowed to react overnight, then rinsed thoroughly.
  • bioactivity of the fibers is modified.
  • bioactive modification is performed similarly to passivation, i.e.instead of ethanolamine, a specific bioactive molecule containing an amine group (peptide, protein, enzyme, etc.) is added.
  • a specific bioactive molecule containing an amine group peptide, protein, enzyme, etc.
  • EDC N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide
  • NHS N-hydroxysuccinimide
  • the degree of modification can be controlled by varying the concentration of bioactive molecule, or decreasing or increasing the number of NHS- activated carboxyl groups.
  • Carboxyl groups can be totally eliminated by ethanolamine passivation, while additional carboxyl groups can be generated by incubating the fibers with bromoacetic acid (0.1 M to IM) and sodium hydroxide (2M NaOH) for a given time (1 minute to 24 hours).
  • IM bromoacetic acid
  • IM sodium hydroxide
  • the fibers are differentially modified from each other, or from the underlying surface.
  • one preferred method for differentially modifying fibers is sequentially attaching fibers in batches, while modifying each batch before the next batch is added.
  • fibers can be modified prior to attachment, and combinations of fibers with selected modifications can then be attached.
  • a preferred practice is to apply a dextran monolayer. This passivates the background surface (which was previously a positively charged adsorptive/adhesive surface).
  • the bioactive molecule can be included in the electrospinning solution (prior to electrospinning) and cross-linked into the fibers (e.g. as in making fluorescent fibers by incorporating FITC-dextran in the electrospinning solution).
  • this practice of the invention mediates the interfacial interaction between the body (cellular response/biological components) and underlying implanted material comprising fibers of the invention.
  • Implants in this regard ameliorate, including preventing, rejection of the implant by the host body.
  • mediation for this purpose invokes three properties: chemical, topographical, and mechanical.
  • these three properties are tunable and can be optimized to tailor the host body's response towards acceptance of the implanted material.
  • the fibrous surface coatings for implantable materials are constructed from nanofibers and microfibers of dextran and polyacrylic acid (PAA) polymers as herein described. They include dextran-PAA hydrogel fibers, or "bristles,” which are tunable in size between about 400nm to about 4 ⁇ m in diameter, and between about l ⁇ m to about lmm in length. Immobilizing these fibrous "bristles" onto the surface of an implantable material forms a coating that functions, e.g., as a camouflaging barrier or bridge.
  • PAA polyacrylic acid
  • fibers thereof when fibers thereof are implemented as a barrier coating on an implant, they are preferably customized to resist either or both protein adsorption and cell adhesion, which events typically instigate inflammatory responses leading to implant rejection.
  • the fibers can be modified to include chemical groups to which proteins minimally adhere. The experimental results demonstrate this protein-repellant nature (see Example 7).
  • Example 8 demonstrates the cell resistant nature for fibrous coatings applied at high surface density or constructed using micro-scale fiber diameters. Synergistically combining protein-resistant chemistry and cell-resistant topographies and coating densities can result in a surface coating that can be applied on an implant as a resilient barrier to the immune system. Camouflaged by this protein- and cell-resistant fibrous barrier, the underlying implanted material is able to effectively appear "invisible" to the immune system, evading recognition as a foreign body and ultimate rejection.
  • fibers of the invention can be implemented as a bridge coating so that they are customized to interact with the host body's cells to promote natural incorporation of the material.
  • the fibers are patterned with topographical and chemical cues derived from the native extracellular environment. This mimicry of the native environment can provide signals to the body's cells, inducing them to integrate the fiber-coated, implanted material within the body. Hvdrogel fibers in wounding dressing.
  • the hydrogel fibers of the invention can be used as a bioactive wound dressing, including for the treatment of chronic, non-healing wounds. Chronic non-healing wounds often involve progressive tissue loss and a disruption of the normal process of healing.
  • the wound dressing of the invention can provide a provisional tissue structure that initiates accelerated wound healing.
  • the highly tunable mechanical properties of the hydrogel fibers of the invention, topography, bioactivity, and biodegradation rates, are suitable for wound healing inasmuch as (1) they permit a fine degree of control over ranges emulating that of native cellular and tissue environments; (2) the innate nature of the fiber material is non-fouling, providing an inert background for adding back specific bioactive functionality; and (3) the fibers can be applied as a surface coating or comprise the scaffold itself.
  • the wound dressing of the invention comprises hydrogel fibers that mimic the extracellular matrix environment of dermal wounds in combination with bioactive molecules. These can include various growth factors, cytokines, and bioactive peptide fragments that are released in a temporally and spatially specific, event-driven manner to promote optimal tissue regeneration and repair of chronic wounds.
  • the hydrogel fibers can also serve as a reservoir or carrier for bioactive molecules that facilitate tissue regeneration and wound healing.
  • the hydrogel fibers can also add back tissue-like structure in the wound and have chemical and physical properties that support the reservoir/carrier functionality for locally delivery of wound healing bioactive molecules.
  • biodegradation rates of the hydrogel fibers can be tailored to control specific time release of bioactive agents, thus creating a smart wound healing system.
  • the hydrogel fibers for this practice are dextran-polyacrylic acid (Dex-PAA) fibers ranging from about 200 nm to about 3000 nm diameter.
  • the wound dressing in accordance with the invention can be formulated into various wound care modalities, including but not limited to, 1) moisturizing dressings; 2) adsorptive dressing; and 3) wound fillers.
  • FIG l(a) and FIG l(b) and FIG l(c) are the SEMs of the fibers resulting from the 0.7g/mL concentration taken at 100Ox, 2000x, and 10,000x, respectively.
  • FIG l(d) and FIG l(e) are the SEMs of the fibers resulting from the 0.75g/mL concentration, both taken at 10,000x.
  • FIG 2 shows a fluorescent confocal image wherein 0.5% FITC-dextran was mixed in a 0.8 g/mL dex/PAA solution prior to electrospinning, thermally cross linked, then attached to a PLL-coated surface; fiber concentration was about 200 micrograms/mL.
  • fibers attached in a relatively flat or sticking up (“end-on” or "bristle”) morphology As shown in the perspective confocal image of FIG 2, fibers attached in a relatively flat or sticking up (“end-on” or "bristle”) morphology.
  • BECs Bovine endothelial cells
  • FITC- fibers darker area of FIG 3 (a)
  • FIG 3 (a) A confocal fluorescence image, FIG 3 (a) was then taken using a water-dip lens at 64x.
  • endothelial cells were able to spread and proliferate on the fiber-coated surfaces.
  • FIG 3(b) is a montage comprised of the same fluorescence confocal slices used to generate FIG 3 (a). From left to right then top to bottom, slices are shown from the bottom of the surface to the top. As shown in the images of FIG 3(b), the cell is growing on top of and intermingling with the fibers.
  • FIG 4 is a graph of the results. As shown in FIG 4, absorbance readings showed that minimal toluidene blue was bound to fibers treated with ethanolamine versus untreated control fibers. This indicated that the carboxy groups of the fibers were successfully passivated.
  • Fiber Immobilization Density An increasing amount of FITC-labeled fibers were added for immobilization to poly-L-lysine (PLL) coated wells of a 24-well plate (2 cm 2 surface area/well).
  • PLL poly-L-lysine
  • fiber solutions were made in DI water in concentrations ranging from 5 to 360 ⁇ g per mL. 1 mL of fiber solution was added per well and incubated overnight, then rinsed 3x with water. Fluorescence was measured at ex/em wavelengths of 485/535nm. As shown in FIG 5, the amount of immobilized fiber increases linearly from zero to approximately lOO ⁇ g, and transitioning to a more logarithmic trend towards 360 ⁇ g.
  • the fibers attached to the PLL surface either sticking up (end-on or bristle configuration) or relatively flat.
  • the ratio between these morphologies differed depending on the packing density at each fiber concentration. As concentration increased, the number of "end-on” fibers increased.
  • the total immobilization amount increased up to a saturation point at which fibers are sterically hindering other fibers from the reaching the surface.
  • FIG 7 graphs FITC-BSA protein adsorption levels on PLL and dextran monolayer surface treatments, with and without immobilized dextran/PAA fibers.
  • fibers were immobilized onto either PLL ⁇ an adhesive) or onto dextran monolayer (a non-adhesive) background surface coating. As shown FIG 7, immobilized fibers did no increase protein absorption levels as opposed to the levels measured on the background surface. On an adhesive PLL surface, immobilized fibers actually decreased protein adsorption levels. On a generally non-adhesive surface ⁇ dextran monolayer), immobilized fibers exhibited adsorption levels comparable to that of the dextran monolayer.
  • the fibers of the invention are protein-repellant, and capable of reducing overall protein adsorption when immobilized onto a protein-adhesive background substrate.
  • Implants that comprise protein-resistant fibers of the invention will also resist cell adhesion inasmuch as cells need surface adherent proteins to bind to a surface.
  • Particular cells that are repelled by protein-resistant fibers of the invention include, without limitation, immune cells involved in the inflammatory-rejection response of an implant material otherwise.
  • FIG. 8 (a)-(f) shows confocal fluorescence images wherein light areas indicate fibers, and lighter areas (central portion of FIG. 8 (a)-(c)) indicates cells.
  • High density fiber coatings are depicted in FIG 8 (a), (b) and (c).
  • Low density fiber coatings are depicted in FIG 8 (d), (e) and (f).
  • the diameters of the fibers varied as follows: In FIG 8 (a) and (d): from 475nm to 2.15 ⁇ m.
  • FIG 8 (c) wherein micro-scale fibers were immobilized at low density, even though cells were able to adhere to some degree, they did not easily traverse over the fibers, indicating effective resistance to cell adhesion by coatings comprised of micro-scale fiber diameters.
  • FIG 8 (d), (e) and (f) show that high density, fibrous mesh surface coatings effectively prevented cell adhesion as not cells are readily visible; these particular topographies acted as barriers to cell adhesion by effectively restricting access to the underlying substrate.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Materials Engineering (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dispersion Chemistry (AREA)
  • Transplantation (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne des fibres d'hydrogel d'un faible diamètre (de l'ordre du nanomètre ou du micron), de préférence d'une courte longueur de fibre (de l'ordre du nanomètre ou du millimètre), qui sont constituées d'un polymère réticulé à fonction carboxy et d'un polymère à fonction hydroxy, par exemple et respectivement, l'acide polyacrylique (PAA) et un polysaccharide tel que le dextrane. L'invention concerne encore des articles constitués desdites fibres, dont des articles à la surface desquels lesdites fibres sont fixées selon une configuration en brosse.
PCT/US2008/077785 2007-09-27 2008-09-26 Fibres d'hydrogel bioactives WO2009042829A1 (fr)

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WO2009126870A2 (fr) 2008-04-11 2009-10-15 Virginia Commonwealth Unversity Fibres de dextrane électrofilées et dispositifs formés à partir de celles-ci
WO2010135418A3 (fr) * 2009-05-21 2011-02-17 Boston Scientific Scimed, Inc. Dispositifs médicaux implantables utilisés pour administrer un agent thérapeutique
US8057535B2 (en) 2007-06-11 2011-11-15 Nano Vasc, Inc. Implantable medical device
WO2012084421A1 (fr) 2010-12-22 2012-06-28 Unilever Nv Production de fibres par filage
WO2012084441A1 (fr) 2010-12-22 2012-06-28 Unilever Nv Compositions sous la forme de fibres
WO2012084427A1 (fr) * 2010-12-22 2012-06-28 Unilever Nv Compositions comprenant une phase liquide non aqueuse structurée
WO2013092024A1 (fr) * 2011-12-21 2013-06-27 Unilever N.V. Compositions comprenant une phase grasse structurée
WO2013172788A1 (fr) * 2012-05-15 2013-11-21 Technion Research And Development Foundation Ltd Composites d'hydrogel renforcé de fibres et procédés de formation de composites d'hydrogel renforcé de fibres
WO2016025945A1 (fr) 2014-08-15 2016-02-18 The Johns Hopkins University Technology Ventures Matériau composite pour une restauration de tissu
US9555157B2 (en) 2013-11-12 2017-01-31 St. Teresa Medical, Inc. Method of inducing hemostasis in a wound
US20170182206A1 (en) * 2014-04-04 2017-06-29 Nanofiber Solutions, Inc. Electrospun biocompatible fiber compositions
CN107469127A (zh) * 2017-08-04 2017-12-15 北京化工大学常州先进材料研究院 天然多糖衍生物/天然高分子复合纤维医用伤口敷料的制备方法
CN108853564A (zh) * 2017-05-08 2018-11-23 常州药物研究所有限公司 止血用交联葡聚糖微粒及其制备方法
US10828387B2 (en) 2015-11-12 2020-11-10 St. Teresa Medical, Inc. Method of sealing a durotomy
US10898608B2 (en) 2017-02-02 2021-01-26 Nanofiber Solutions, Llc Methods of improving bone-soft tissue healing using electrospun fibers
US10953128B2 (en) 2017-11-02 2021-03-23 St. Teresa Medical, Inc. Fibrin sealant products
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GB2599209A (en) * 2020-07-29 2022-03-30 The Electrospinning Company Ltd Fibrous composite material
US11737990B2 (en) 2012-01-12 2023-08-29 Nfs Ip Holdings, Llc Nanofiber scaffolds for biological structures
US11771807B2 (en) 2018-05-09 2023-10-03 The Johns Hopkins University Nanofiber-hydrogel composites for cell and tissue delivery
CN117138092A (zh) * 2023-09-08 2023-12-01 南京工业大学 一种负载生物相容相变微胶囊的控温保湿医用敷料的制备方法

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US8057535B2 (en) 2007-06-11 2011-11-15 Nano Vasc, Inc. Implantable medical device
WO2009126870A2 (fr) 2008-04-11 2009-10-15 Virginia Commonwealth Unversity Fibres de dextrane électrofilées et dispositifs formés à partir de celles-ci
US9399082B2 (en) 2008-04-11 2016-07-26 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Electrospun dextran fibers and devices formed therefrom
EP2276879A2 (fr) * 2008-04-11 2011-01-26 Virginia Commonwealth University Fibres de dextrane électrofilées et dispositifs formés à partir de celles-ci
EP2276879A4 (fr) * 2008-04-11 2013-04-24 Univ Virginia Commonwealth Fibres de dextrane électrofilées et dispositifs formés à partir de celles-ci
WO2010135418A3 (fr) * 2009-05-21 2011-02-17 Boston Scientific Scimed, Inc. Dispositifs médicaux implantables utilisés pour administrer un agent thérapeutique
WO2012084421A1 (fr) 2010-12-22 2012-06-28 Unilever Nv Production de fibres par filage
WO2012084441A1 (fr) 2010-12-22 2012-06-28 Unilever Nv Compositions sous la forme de fibres
WO2012084427A1 (fr) * 2010-12-22 2012-06-28 Unilever Nv Compositions comprenant une phase liquide non aqueuse structurée
WO2013092024A1 (fr) * 2011-12-21 2013-06-27 Unilever N.V. Compositions comprenant une phase grasse structurée
US11737990B2 (en) 2012-01-12 2023-08-29 Nfs Ip Holdings, Llc Nanofiber scaffolds for biological structures
US9950093B2 (en) 2012-05-15 2018-04-24 National University Of Singapore Fiber-reinforced hydrogel composites and methods of forming fiber-reinforced hydrogel composites
WO2013172788A1 (fr) * 2012-05-15 2013-11-21 Technion Research And Development Foundation Ltd Composites d'hydrogel renforcé de fibres et procédés de formation de composites d'hydrogel renforcé de fibres
CN104487103A (zh) * 2012-05-15 2015-04-01 泰克尼恩研究和发展基金有限公司 纤维增强水凝胶复合材料和形成纤维增强水凝胶复合材料的方法
US9555157B2 (en) 2013-11-12 2017-01-31 St. Teresa Medical, Inc. Method of inducing hemostasis in a wound
US20170182206A1 (en) * 2014-04-04 2017-06-29 Nanofiber Solutions, Inc. Electrospun biocompatible fiber compositions
US11684700B2 (en) 2014-08-15 2023-06-27 The Johns Hopkins University Composite material for tissue restoration
JP7478441B2 (ja) 2014-08-15 2024-05-07 ザ・ジョンズ・ホプキンス・ユニバーシティー 組織修復のための複合材料
JP2017527422A (ja) * 2014-08-15 2017-09-21 ザ・ジョンズ・ホプキンス・ユニバーシティー 組織修復のための複合材料
US10463768B2 (en) 2014-08-15 2019-11-05 The Johns Hopkins University Composite material for tissue restoration
JP2020189141A (ja) * 2014-08-15 2020-11-26 ザ・ジョンズ・ホプキンス・ユニバーシティー 組織修復のための複合材料
JP2022000210A (ja) * 2014-08-15 2022-01-04 ザ・ジョンズ・ホプキンス・ユニバーシティー 組織修復のための複合材料
US11707553B2 (en) 2014-08-15 2023-07-25 The Johns Hopkins University Composite material for tissue restoration
WO2016025945A1 (fr) 2014-08-15 2016-02-18 The Johns Hopkins University Technology Ventures Matériau composite pour une restauration de tissu
US10828387B2 (en) 2015-11-12 2020-11-10 St. Teresa Medical, Inc. Method of sealing a durotomy
US10898608B2 (en) 2017-02-02 2021-01-26 Nanofiber Solutions, Llc Methods of improving bone-soft tissue healing using electrospun fibers
US11806440B2 (en) 2017-02-02 2023-11-07 Nfs Ip Holdings, Llc Methods of improving bone-soft tissue healing using electrospun fibers
CN108853564A (zh) * 2017-05-08 2018-11-23 常州药物研究所有限公司 止血用交联葡聚糖微粒及其制备方法
CN108853564B (zh) * 2017-05-08 2021-04-06 常州药物研究所有限公司 止血用交联葡聚糖微粒及其制备方法
CN107469127A (zh) * 2017-08-04 2017-12-15 北京化工大学常州先进材料研究院 天然多糖衍生物/天然高分子复合纤维医用伤口敷料的制备方法
US10953128B2 (en) 2017-11-02 2021-03-23 St. Teresa Medical, Inc. Fibrin sealant products
US11771807B2 (en) 2018-05-09 2023-10-03 The Johns Hopkins University Nanofiber-hydrogel composites for cell and tissue delivery
GB2599209A (en) * 2020-07-29 2022-03-30 The Electrospinning Company Ltd Fibrous composite material
GB2599209B (en) * 2020-07-29 2024-06-05 The Electrospinning Company Ltd Fibrous composite material
CN112656988A (zh) * 2020-12-22 2021-04-16 重庆理工大学 水凝胶敷料及敷料贴
CN117138092A (zh) * 2023-09-08 2023-12-01 南京工业大学 一种负载生物相容相变微胶囊的控温保湿医用敷料的制备方法

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