Threads of hyaluronic acid, methods of making thereof and uses thereof

0001Cross-reference of related applications This application claims the benefit of US Patent Provisional Application No. 61 / 190,866 filed on September 2, 2008, pursuant to 35 USC 119 (e).

0002Field The present invention generally relates to threads of hyaluronic acid and / or derivatives thereof, methods of making them, and uses thereof, such as aesthetic applications (eg, dermal fillers), surgery (eg, sutures), drug delivery. For use in negative pressure wound therapy, wet wound bandages, etc.

0003background Hyaluronic acid is a repeating disaccharide unit in which β-DN-acetylglucoamine and β-D-glucuronic acid, which are the main components of the extracellular matrix, are alternately bound (that is, (-4GlcUAβl-3GlcNAcβl-)._n) Is a linear polysaccharide (ie, non-sulfated glycosaminoglycan) found, for example, in connective tissue, epithelial tissue, and nervous tissue. Natural hylauronic acid is highly biocompatible due to its lack of species and organ specificity and is therefore used as a biomaterial in tissue engineering and as a common ingredient in various dermal fillers. Often.

0004Various chemically modified hyaluronic acids (eg, cross-linked, ion-modified, esterified) to address the major problems associated with natural hyaluronic acid, which has low in vivo stability due to rapid enzymatic degradation and hydrolysis. Etc.) are synthesized. Currently, hyaluronic acid or a crosslinked version thereof is used in various gel forms, for example, as a dermal filler, an anti-adhesion material, and the like.

0005However, the use of hyaluronic acid or its crosslinked version of the gel is fraught with considerable problems. First, the force required to administer a gel of hyaluronic acid or a cross-linked version thereof is non-linear, causing the early "lumps" reported by many physicians when injecting hyaluronic acid or a cross-linked version thereof. Become. Second, hyaluronic acid gels have little mechanical strength, making it very difficult to accurately administer such gels to specific locations. In addition, the use of gels is problematic in many applications (eg, treatment of fine wrinkles), as the gel occupies the least resistant space.

0006Therefore, what is needed is a new physical form of hyaluronic acid or a cross-linked version thereof that can be uniformly administered to a particular location regardless of tissue resistance. Such new forms may have specific uses, for example, in aesthetic and surgical applications, drug delivery, wound therapy, and wound bandages.

0007Overview The present invention provides a thread of hyaluronic acid or a salt thereof, a hydrate or a solvate compound in one aspect and a thread of a crosslinked hyaluronic acid or a salt thereof, a hydrate or a solvate compound in the second aspect. Meet these and other needs by providing. In some embodiments, the thread is a combination of a thread of hyaluronic acid or a salt thereof, a hydrate, or a solvate compound and a thread of crosslinked hyaluronic acid or a salt thereof, a hydrate, or a solvate compound.

0008In the third aspect, a method for making a thread of hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is provided. Hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is mixed with water or a buffer to form a gel. The gel is extruded to form threads. The yarn is then dried to give a hyaluronic acid yarn.

0009In the fourth aspect, a method for making a thread of crosslinked hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is provided. Hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is mixed with water or a buffer and a cross-linking agent to form a gel. The gel is extruded to form threads. The yarn is then dried to give a crosslinked hyaluronic acid yarn.

0010In a fifth aspect, a method of treating wrinkles is provided in a subject in need of treatment of wrinkles. A thread of hyaluronic acid or a salt thereof, a hydrate or a solvate compound, or a thread of crosslinked hyaluronic acid or a salt thereof, a hydrate or a solvate compound, or a combination thereof is attached to the proximal end side of the needle. The end of the needle is inserted through the skin surface of the subject into the dermis adjacent to or within the wrinkles. A needle is passed through the subject's dermis at the base of the wrinkle. The needle then exits the subject's skin surface and is pulled end-to-end until it is removed from the subject's skin so that the thread is pulled into the position previously occupied by the needle. The excess thread is cut from the needle at the skin surface of the subject.

0011In yet other aspects, for example, dermal fillers, anti-adhesion materials, wound dressings including negative pressure wound bandages, sutures, etc., hyaluronic acid or salts thereof, hydrates, or solvate compounds, or Methods are provided that use crosslinked hyaluronic acid or a salt thereof, a hydrate, or a thread of a solvate compound, or a combination thereof. For example, in surgery, opthamology, wound closure, drug delivery, etc., hyaluronic acid or a salt thereof, a hydrate, or a thread of a solvate compound, or a crosslinked hyaluronic acid or a salt thereof, a hydrate, or a solvent. Further provided are methods of using solvated yarns, or combinations thereof. [Invention 1001] A thread consisting of hyaluronic acid or a salt thereof, a hydrate, or a solvate compound. [Invention 1002] A thread composed of crosslinked hyaluronic acid or a salt thereof, a hydrate, or a solvate compound. [Invention 1003] A thread composed of a combination of a thread made of hyaluronic acid or a salt thereof, a hydrate or a solvate compound and a thread made of crosslinked hyaluronic acid or a salt thereof, a hydrate or a solvate compound. [Invention 1004] A wound bandage comprising any of the threads 1001 to 1003 of the present invention. [Invention 1005] A wound bandage of the present invention 1004, wherein the thread contains collagen. [Invention 1006] A wound bandage comprising at least one woven mesh consisting of any of the threads 1001-1003 of the present invention. [Invention 1007] A wound bandage of the present invention 1006, comprising 2 to about 10 layers of woven mesh. [Invention 1008] A wound bandage of the present invention 1006, wherein the woven mesh contains the same thread. [Invention 1009] A wound bandage of the present invention 1006, wherein the woven mesh contains different threads. [Invention 1010] Anti-adhesion material containing any of the threads of the present invention 1001 to 1003. [Invention 1011] Anti-adhesion material comprising at least one woven mesh consisting of any of the threads of the present invention 1001-1003. [Invention 1012] A pad that fits the wound position, an airtight seal that is detachably attached to the pad, a negative pressure source that communicates fluidly with the pad, and any thread of the present invention 1001 to 1003 that is attached to the wound contact surface of the pad. Wound bandages, including. [Invention 1013] The wound bandage of the present invention 1012, comprising at least one layer of woven mesh consisting of threads. [Invention 1014] A method of treating a wound in a subject comprising attaching the wound bandage of the present invention 1004 to the wound of the subject in need of wound healing. [Invention 1015] A method of treating a wound in a subject comprising attaching the wound bandage of the present invention 1012 to the wound of the subject in need of wound healing. [Invention 1016] A dermal filler comprising any of the threads of the present invention 1001 to 1003. [Invention 1017] A method of using the dermal filler of the present invention 1016 in cosmetic applications. [Invention 1018] A suture made of any of the threads 1001 to 1003 of the present invention. [Invention 1019] A method of using the suture of the present invention 1018 in a surgical application. [Invention 1020] A method of using any of the threads of the present invention 1001-1003 in surgical applications, eye surgery, wound closure, drug delivery, and intra-articular injection. [Invention 1021] How to treat wrinkles in a subject, including the following steps: A step of attaching any of the threads 1001 to 1003 of the present invention to the needle; The process of passing the end of the needle through the skin surface of the subject and inserting it into the dermis of the subject adjacent to the wrinkles; The process of traversing the subject's dermis beneath the wrinkles with a needle; The process of pushing the needle out of the subject's skin surface; and The process of cutting a thread from a needle on the surface of the subject's skin. [Invention 1022] The step of mixing hyaluronic acid or a salt thereof, a hydrate, or a solvate compound with water or a buffer solution to form a gel; The process of extruding the gel into threads; A method for producing a yarn of the present invention 1001, which comprises a step of drying the hyaluronic acid yarn. [Invention 1023] The method of 1022 of the present invention further comprising the step of mixing a therapeutic agent and / or a diagnostic agent, hyaluronic acid, water or a buffer to form a gel. [1024 of the present invention] The step of mixing hyaluronic acid or a salt thereof, a hydrate, or a solvate compound with water or a buffer solution and a cross-linking agent to form a gel; The process of extruding the gel into threads; A method for producing a thread of the present invention 1002, which comprises a step of drying a thread of crosslinked hyaluronic acid. [Invention 1025] The present invention further comprises the step of mixing a therapeutic agent and / or a diagnostic agent with hyaluronic acid or a salt thereof, a hydrate, or a solvate compound with water or a buffer solution and a cross-linking agent to form a gel. the method of.

0012<figref num="1">The whole picture of the thread attached to the base end of a needle is shown.</figref><figref num="2A">The enlarged view of the thread inserted in the inner diameter of a needle is shown.</figref><figref num="2B">An enlarged view of the base end of a solid needle in which a part of the thread overlaps with the needle is shown.</figref><figref num="3A">Shows fine facial wrinkles in the periorbital region of humans.</figref><figref num="3B">Indicates a needle and thread inserted into the wrinkled dermis on the medial edge.</figref><figref num="3C">Indicates a needle that is adjusted to traverse under the wrinkles.</figref><figref num="3D">Indicates a needle protruding from the outer edge of the wrinkle.</figref><figref num="3E">The needle that pulled the thread to the position that the needle occupied earlier under the wrinkle is shown.</figref><figref num="3F">Indicates a thread transplanted under a wrinkle, where the excess thread has been cut.</figref><figref num="4A">A top-to-bottom diagram of a man with typical androgenetic alopecia is shown.</figref><figref num="4B">Indicates where hair growth is desirable, taking into account the hairline.</figref><figref num="4C">Indicates a curved needle with a thread attached, inserted into one of the imaginary lines where hair growth is desirable.</figref><figref num="4D">It crosses an imaginary line and shows a needle coming out of the skin.</figref><figref num="4E">The state in which the needle is pulled toward the end side and the thread is pulled in a desired position is shown.</figref><figref num="4F">Shows the scissors used to cut the excess thread.</figref><figref num="5A">A cross-sectional view of a fold or wrinkle is shown.</figref><figref num="5B">Shows a thread transplanted under a wrinkle that has not yet been hydrated.</figref><figref num="5C">Shows a thread transplanted under the wrinkles that has been completely hydrated and the surface appearance of the wrinkles has been flattened.</figref><figref num="6A">Shows the human pancreas with a tumor.</figref><figref num="6B">Indicates a curved needle to which a thread is attached.</figref><figref num="6C">Shows a curved needle that traverses a tumor in the pancreas.</figref><figref num="6D">The final result of repeated transplantation of threads is shown.</figref><figref num="7A">Shown are multiple concentric coil layers of thread molded to be human papillae.</figref><figref num="7B">The implant of FIG. 7A is shown in cross section.</figref><figref num="7C">Shows how coiled thread grafts are used for papilla reconstruction.</figref><figref num="8">Shows how needles and threads are used to place the thread in a particular linear position and promote nerve or blood vessel regrowth at a particular line.</figref>

0013Detailed explanation Definition "Buffer solution" includes 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, L- (+)-tartaric acid, D- (-)-tartaric acid, ACES, ADA, acetic acid, ammonium acetate, ammonium hydrogencarbonate, ammonium citrate, ammonium formate, ammonium oxalate, ammonium phosphate, sodium ammonium phosphate, ammonium sulfate, ammonium tartrate, BES, BICINE, BIS-TRIS, hydrogen carbonate, Boric acid, CAPS, CHES, calcium acetate, calcium carbonate, calcium citrate, citrate, citric acid, diethanolamine, EPP, disodium ethylenediamine tetraacetate, formic acid solution, Gly-Gly-Gly, Gly-Gly, glycine, HEPES, imidazole, lithium acetate, lithium citrate, MES, MOPS, magnesium acetate, magnesium citrate, magnesium formate, magnesium phosphate, oxalic acid, PIPES, phosphate buffered saline, phosphate buffered saline, piperazin D-tartaric acid Potassium, potassium acetate, potassium hydrogen carbonate, potassium carbonate, potassium chloride, potassium citrate, potassium formate, potassium oxalate, potassium phosphate, potassium phthalate, sodium tartrate, potassium tetraborate, potassium tetraoxalate defhydrate , Propionic acid solution, STE buffer solution, 5,Sodium 5-diethylbarbiturate, sodium acetate, sodium hydrogencarbonate, sodium hydrogen tartrate monohydrate, sodium carbonate, sodium citrate, sodium formate, sodium oxalate, sodium phosphate, sodium pyrophosphate, sodium tartrate, tetraho Sodium acid, TAPS, TES, TNT, TRIS-glycine, TRIS-acetic acid, TRIS buffered saline, TRIS-HCl, TRIS phosphate-EDTA, trisine, triethanolamine, triethylamine, triethylammonate acetate, triethylammonium phosphate, acetic acid Includes trimethylammonium, trimethylammonium phosphate, Trizma® acetate, Trizma® base, Trizma® carbonate, Trizma® hydrochloride or Trizma® maleate However, it is not limited to this.

0014"Salt" refers to a salt of hyaluronic acid that has the desired activity of the parent compound. Such salts include: (1) acid-added salts formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid; or organic acids such as acetic acid, propionic acid. , Hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartrate acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid , Silica, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid , benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4 -Toluene sulfonic acid, camphor sulfonic acid, 4-methylbicyclo [2.2.2]-octa-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, laurylsulfate, Acid-added salts formed using gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc .; or (2) Acidic protons present in the salt parent compound are ammonium ions, metal ions, for example. Salts formed when substituted with alkali metal ions (eg sodium or potassium), alkaline earth ions (eg calcium or magnesium), or aluminum ions; or organic bases such as ethanolamine, diethanolamine, triethanol Coordinating bonds with, but not limited to, amines, N-methylglucamine, morpholin, piperidine, dimethylamine, diethylamine, etc. Also included are salts of amino acids such as arginate and salts of organic acids such as glucurmic acid or galactunoric acid.

0015Hyaluronic acid and its derivatives The present invention generally provides threads of hyaluronic acid or salts thereof, hydrates or solvate compounds, crosslinked hyaluronic acid or salts thereof, hydrates or threads of solvate compounds, and combinations thereof. In some embodiments, hyaluronic acid is isolated from an animal source. In another embodiment, hyaluronic acid is isolated from the fermented bacterial product.

0016In some embodiments, the life of the hyaluronic acid or salt, hydrate, or solvate compound yarn in vivo is from about 1 minute to about 1 month. In other embodiments, the life of the hyaluronic acid or salt, hydrate, or solvate compound yarn in vivo is from about 10 minutes to about 1 week. In yet another embodiment, the life of the hyaluronic acid or salt, hydrate, or solvate compound yarn in vivo is from about 1 hour to about 3 days.

0017In some embodiments, the life of the crosslinked hyaluronic acid or salt thereof, hydrate, or solvate compound in vivo is from about 1 week to about 24 months. In other embodiments, the life of the crosslinked hyaluronic acid or salt, hydrate, or solvate compound thereof in vivo is from about 1 month to about 12 months. In yet another embodiment, the life of the hyaluronic acid or salt, hydrate, or solvate compound yarn in vivo is from about 3 months to about 9 months.

0018In some embodiments, the hyaluronic acid or salt, hydrate, or solvate compound thereof is butanediol diglycidyl ether (BDDE), divinyl sulfone (DVS), or 1-ethyl-3- (3-dimethylamino) hydrochloride. It is crosslinked with propyl) carbodiimide (EDC). Those skilled in the art will appreciate that many other cross-linking agents can be used to cross-link hyaluronic acid or its salts, hydrates, or solvate compounds. Therefore, the above list of crosslinkers is not comprehensive but exemplary.

0019In some of the above embodiments, the degree of cross-linking of hyaluronic acid or a salt thereof, a hydrate, or a solvate compound with a cross-linking agent is from about 0.01% to about 20%. In another aspect of the above aspect, the degree of cross-linking between hyaluronic acid or a salt thereof, a hydrate, or a solvate compound and a cross-linking agent is about 0.1% to about 10%. In yet another aspect of the above embodiment, the degree of cross-linking between the hyaluronic acid or a salt thereof, a hydrate, or a solvate compound and the cross-linking agent is about 1% to about 8%.

0020In some of the aforementioned embodiments, the thread comprises one or more therapeutic or diagnostic agents. In another aspect of the above embodiment, the diagnostic agent is a soluble TB (tuberculosis) protein. In yet another aspect of the above embodiment, the therapeutic agent is an anesthetic, including, but not limited to, lidocaine, xylocaine, novocaine, benzocaine, prlocaine, ripivacaine, propofol, or a combination thereof. In yet another aspect of the above embodiment, the therapeutic agent is epinephrine, adrenaline, ephedrine, aminophylline, theophylline or a combination thereof. In yet another aspect of the above embodiment, the therapeutic agent is botulinum toxin. In yet another aspect of the above embodiment, the therapeutic agent is laminin-511. In yet another aspect of the above aspect, the therapeutic agent is glucosamine, which can be used, for example, in the treatment of osteoarthritis. In yet another aspect of the above embodiment, the therapeutic agent is an antioxidant, including, but not limited to, vitamin E or all-trans retinoic acid, such as retinol. In yet another aspect of the above aspect, the therapeutic agent comprises stem cells. In yet another aspect of the above embodiment, the therapeutic agent is insulin, growth factor, eg, NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), PDGF (platelet-derived growth factor), or purmorphamine ( Purmorphamine) Deferoxamine NGF (nerve growth factor), dexamethasone, ascorbic acid, 5-azacitidine, 4, 6-Disubstituted pyrrolopyrimidine, cardiogenol, cDNA, DNA, RNAi, BMP-4 (bone morphogenetic protein-4), BMP-2 (bone morphogenetic protein-2), antibiotics such as β-lactam, fluoro Anti-fibrotic agents, anti-scarring agents, including but not limited to quinolones, including quinolones, aminoglycosides or macrolides, hepatocellular proliferative factors or pyrphenidones, such as anti-TGF-b2 monoclonal antibodies (rhAnti-TGF-b2 mAb), Peptides such as GHK copper-binding peptides, tissue regenerating agents, steroids, fibronectin, cytokines, analgesics, such as Tapentadol HCl, achen agents (eg, morphine, codon, oxycodon, etc.), preservatives, α-interferon, β-Interferon or γ-Interferon, EPO, Glucagon, Calcitonin, Heparin, Interleukin-1, Interleukin-2, Philgrastim, Protein, HGH, Bone morphogenetic hormone, Atrial sodium diuretic factor, Factor VIII, Factor IX, or follicular stimulating hormone. In yet another aspect of the above aspect, the yarn contains a combination of a plurality of therapeutic or diagnostic agents. In some of these embodiments, different threads comprise different therapeutic or diagnostic agents. mAb), peptides such as GHK copper-binding peptides, tissue regenerating agents, steroids, fibronectin, cytokines, analgesics such as tapentadol HCl, achen agents (eg morphine, codon, oxycodone, etc.), preservatives, α -Interleukin, β-interferon, or γ-interferon, EPO, glucagon, calcitonin, heparin, interleukin-1, interleukin-2, filgrastim, protein, HGH, luteinizing hormone, atrial sodium diuretic factor, VIII Factor, factor IX, or follicular stimulating hormone. In yet another aspect of the above embodiment, the yarn contains a combination of a plurality of therapeutic or diagnostic agents. In some of these embodiments, different threads comprise different therapeutic or diagnostic agents. mAb), peptides such as GHK copper-binding peptides, tissue regenerating agents, steroids, fibronectin, cytokines, analgesics such as tapentadol HCl, achen agents (eg morphine, codon, oxycodone, etc.), preservatives, α -Interleukin, β-interferon, or γ-interferon, EPO, glucagon, calcitonin, heparin, interleukin-1, interleukin-2, filgrastim, protein, HGH, luteinizing hormone, atrial sodium diuretic factor, VIII Factor, factor IX, or follicular stimulating hormone. In yet another aspect of the above aspect, the yarn contains a combination of a plurality of therapeutic or diagnostic agents. In some of these embodiments, different threads comprise different therapeutic or diagnostic agents.

0021In some of the above embodiments, the final tensile strength of the yarn is from about 0 kpsi to about 250 kpsi. In another aspect of the above aspect, the final tensile strength of the yarn is from about 1 kpsi to about 125 kpsi. In yet another aspect of the above embodiment, the final tensile strength of the yarn is from about 5 kpsi to about 100 kpsi.

0022In some of the above embodiments, the axial tensile strength of the yarn is from about 0.01 lbs to about 10 lbs. In another aspect of the above aspect, the axial tensile strength of the yarn is from about 0.1 lbs to about 5 lbs. In yet another aspect of the above aspect, the axial tensile strength of the yarn is from about 0.5 lbs to about 2 lbs.

0023In some of the above embodiments, the cross-sectional area of the yarn is about 1^*10⁶in²~ About 1,000^*10⁶in²Is. In another aspect of the above aspect, the cross-sectional area of the yarn is about 10.^*10⁶in²~ About 500^*10⁶in²Is. In yet another aspect of the above aspect, the cross-sectional area of the yarn is about 50.^*10⁶in²~ About 250^*10⁶in²Is.

0024In some of the above embodiments, the diameter of the yarn is from about 0.0001 inches to about 0.100 inches. In another aspect of the above aspect, the diameter of the yarn is from about 0.001 inch to about 0.020 inch. In yet another aspect of the above aspect, the diameter of the yarn is from about 0.003 inch to about 0.010 inch.

0025In some of the above embodiments, the elasticity of the yarn is from about 1% to 200%. In another aspect of the above aspect, the elasticity of the yarn is from about 5% to about 100%. In yet another aspect of the above embodiment, the elasticity of the yarn is about 10% to 50%. As used herein, elasticity is the% elongation of a yarn while retaining the ability to return to the initial length of the yarn.

0026In some of the above embodiments, the molecular weight of the yarn is from about 0.1 MD to about 8 MD (MD is one million daltons). In another aspect of the above aspect, the molecular weight of the yarn is from about 0.5 MD to about 4 MD. In yet another aspect of the above embodiment, the molecular weight of the yarn is from about 1MD to about 2MD.

0027In some of the above embodiments, the continuous chain length of the yarn is from about 10 nm to about 250 nm. In another aspect of the above embodiment, the continuous chain length of the yarn is from about 10 nm to about 125 nm. In yet another aspect of the above embodiment, the continuous chain length of the yarn is from about 10 nm to about 75 nm.

0028In some of the above embodiments, when the yarn is completely hydrated, the cross-sectional area of the yarn expands from about 0% to about 10,000%. In another aspect of the above embodiment, when the yarn is completely hydrated, the cross-sectional area of the yarn expands from about 0% to about 2,500%. In yet another aspect of the above embodiment, when the yarn is completely hydrated, the cross-sectional area of the yarn expands from about 0% to about 900%.

0029In some of the above embodiments, the yarn stretches from about 0% to about 1,000% when fully hydrated. In another aspect of the above aspect, the yarn stretches from about 0% to about 100% when fully hydrated. In yet another aspect of the above embodiment, the yarn stretches from about 0% to about 30% when fully hydrated.

0030In some of the above embodiments, the yarn is completely hydrated after being immersed in an aquatic environment for about 1 second to about 24 hours. In another aspect of the above aspect, the yarn is completely hydrated after being immersed in an aqueous environment for about 1 second to about 1 hour. In yet another aspect of the above embodiment, the yarn is completely hydrated after being immersed in an aqueous environment for about 1 second to about 5 minutes.

0031In some embodiments, the yarn is crosslinked and has a final tensile strength of about 50 kpsi to about 75 kpsi, a diameter of 0.005 inch to about 0.015 inch, and when fully hydrated, the thickness or diameter of the yarn is It swells from about 50% to about 100% and has a thread life of about 6 months in vivo.

0032In some embodiments, a string can be formed from the thread. In other embodiments, the cord can be formed from the yarn. In still other embodiments, the woven mesh can be formed from the yarn. In yet another embodiment, the woven mesh can be formed from the above-mentioned string or cord.

0033In some embodiments, the three-dimensional structure can be constructed by weaving, wrapping, winding, or layering the threads. In other embodiments, the three-dimensional structure can be constructed by weaving, wrapping, wrapping, or layering the strings. In still other embodiments, the three-dimensional structure can be constructed by weaving, wrapping, wrapping, or layering the cord. In still other embodiments, the three-dimensional structure can be constructed by weaving, wrapping, wrapping, or layering the mesh.

0034In some embodiments, a three-dimensional cylindrical implant made of any thread is provided. An exemplary use of such a graft is for papillary reconstruction. In some embodiments, the threads used to make the cylindrical implant are crosslinked and contain chondrocyte adhesion compounds. In another embodiment, a plurality of concentric coils of yarn give a cylindrical shape.

0035Threads of hyaluronic acid and / or its derivatives may contain one or more chiral centers and may therefore be present as stereoisomers, such as enantiomers or diastereomers. In general, of all stereoisomers (ie, possible compounds of the illustrated compounds), including sterically pure forms (eg, enantiomerically pure forms or diastereoisomerically pure forms). All enantiomers and stereoisomers) and mixtures of enantiomers and stereoisomers are within the scope of the invention.

0036Threads of hyaluronic acid and / or its derivatives may be present in several tautomeric forms and mixtures thereof, all within the scope of the present invention. The hyaluronic acid and / or derivative threads may be present in a non-solvate form or in a solvate form, including a hydrated form. In general, the hydrated and solvated forms are within the scope of the present invention. Thus, all physical forms of hyaluronic acid and / or its derivatives threads are equivalent for the intended use of the present invention and are intended to be within the scope of the present invention.

0037How to make threads of hyaluronic acid and its derivatives The present invention also provides a method for producing a thread of the above-mentioned hyaluronic acid and its derivative. In some embodiments, a method of making a thread of hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is provided. Hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is mixed with water or a buffer to form a gel. The gel is then extruded to form a thread of gel. For example, the gel can be extruded by placing the gel in a syringe with a nozzle, pressurizing the syringe so that the gel is extruded from the nozzle, and moving the syringe linearly. Nozzle features such as tapering, length and diameter, syringe pressure, and linear movement speed can be adjusted to produce threads of different sizes and mechanical strengths. Another method of making a thread of gel is by rotating the gel, i.e. rotating it like a dough, or by placing the gel in a mold. Yet another method of making a thread of gel is to stretch the gel into a thread under the influence of gravity or by using centrifugal force. Yet another method of making gel threads is by placing the gel between charged parallel glass plates and shearing. Yet another method of making a thread of gel is by enclosing the gel in a groove formed on the elastomer and then stretching the elastomer. Yet another method of making a thread of gel is to confine the gel in a permeable tubular structure capable of dehydrating the thread and, if necessary, adjusting environmental parameters such as temperature, pressure, and gas composition. This is a method by controlling the content of dehydration. Then, after preparation, the yarn of hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is dried.

0038In another embodiment, a method of making a thread of crosslinked hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is provided. Hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is mixed with water or a buffer and a cross-linking agent to form a gel. The gel is then extruded to form the threads. Alternatively, the yarn can be made by any of the methods described above. In general, the gel must be extruded or otherwise manipulated immediately after the cross-linking agent is added so that cross-linking occurs as the yarn dries. Then, after preparation, the yarn of crosslinked hyaluronic acid or a salt thereof, a hydrate, or a solvate compound is dried.

0039In some embodiments, the ratio of cross-linking agent to hyaluronic acid is from about 0.01% to about 10%. In other embodiments, the ratio of cross-linking agent to hyaluronic acid is from about 0.02% to about 5%. In yet another embodiment, the ratio of cross-linking agent to hyaluronic acid is from about 0.1% to about 3%.

0040In some of the aforementioned embodiments, one or more therapeutic or diagnostic agents are included in the gel forming step.

0041In some of the above embodiments, the gel has a concentration of hyaluronic acid from about 0.1% to about 10% by weight. In another aspect of the above embodiment, the gel has a concentration of hyaluronic acid of about 1% to about 7% by weight. In yet another aspect of the above embodiment, the gel has a concentration of hyaluronic acid of about 4% to about 6% by weight.

0042In some of the above embodiments, the polymer chains are further oriented along the axis of the yarn by stretching in the axial direction. In another aspect of the above aspect, the polymer chain is oriented along the axis of the yarn by gravity or centrifugal force. In yet another aspect of the above aspect, gravity is applied by suspending the thread vertically. In yet another aspect of the above embodiment, the polymer chain is oriented along the axis of the yarn by applying an electric potential along the length of the yarn. In yet another aspect of the above embodiment, the polymer chains are oriented along the axis of the yarn by a combination of the aforementioned methods.

0043In some of the above embodiments, the yarn is hydrated with water and then dried again. In another aspect of the above aspect, the hydration and drying steps are repeated multiple times. In yet another aspect of the above embodiment, the polymer chains of the yarn are stretched axially, by applying gravity or centrifugal force, by applying an electric potential along the length of the yarn, or by a combination thereof. Oriented along the axis. In yet another aspect of the above aspect, a therapeutic or diagnostic or cross-linking agent is applied to the yarn during the hydration step.

0044In some of the above embodiments, the gel is extruded onto a previously made thread to obtain a layered thread.

0045In another aspect of the above embodiment, after the drying step, the yarn is soaked in a drug or rinsed with a drug. In some of the aforementioned embodiments, the agent is a cross-linking agent, a therapeutic agent, or a diagnostic agent.

0046In another aspect of the above embodiment, the yarn is, for example, dried after the rinsing step and at the same time immersed in or rinsed with the agent. In some of the aforementioned embodiments, the agent is a cross-linking agent, a therapeutic agent, or a diagnostic agent.

0047In yet another aspect of the above aspect, the yarn is frozen and then thawed. In yet another aspect of the above embodiment, the yarn is frozen at least twice and then thawed.

0048In yet another aspect of the above embodiment, the dried yarn is irradiated to promote cross-linking. In some of the above embodiments, the hydrated yarn is irradiated to promote cross-linking.

0049In yet another aspect of the above embodiment, the dried or hydrated yarn is coated with a bioabsorbable biopolymer such as collagen, PEG, or PLGA to alter the properties of the yarn. Alternatively, the woven structure can be coated in one layer or in 3D in its entirety to create a woven or mesh that has different physical properties from the uncoated (free) woven mesh.

0050Method of using hyaluronic acid and its derivative threads The threads, strings, cords, woven meshes, or three-dimensional structures described herein can be, for example, filling an aneurysm, obstructing blood flow to a tumor (ie, tumor obstruction), eyelid surgery (eg, enlargement or). Desensitization, ie, penile enlargement (for the treatment of premature leakage), intranasal (blood-brain barrier) delivery device for diagnostic and / or therapeutic agents, corneal transplantation for drug delivery, nasal or nasal reconstruction, lips Augmentation or reconstruction, facial augmentation or reconstruction, earlid enlargement or reconstruction, spinal cord transplantation (eg, spinal cord transplantation to support a bulging disk), root canal filling material (therapeutic agent is added) , Glottic insufficiency, laser photorefractive therapy (eg, hyaluronic acid thread / textile used as a cushion), scaffold material for organ regrowth, spinal therapy (BDNF and NGF) in Parkinson's disease (stereotactic delivery), therapeutic molecules Alternatively, it can be used in accurate delivery of diagnostic molecules, dental pulp transplantation, replacement pulp root canal treatment, molded root canal system, negative pressure wound therapy, anti-adhesion materials and wound bandages.

0051In some embodiments, the threads, strings, cords, woven meshes, or tertiary structures described herein are used as dermal fillers in a variety of aesthetic applications. In other embodiments, the threads, strings, cords, woven meshes, or tertiary structures described herein are used as sutures in a variety of surgical applications. In yet other embodiments, the threads, strings, cords, woven meshes, or tertiary structures described herein are used in ophthalmic surgery, drug delivery, and intra-articular injection.

0052In some embodiments, the threads, strings, cords, woven meshes, or tertiary structures described herein are used for wound bandages, including negative pressure wound bandages.

0053In some embodiments, the wound bandage remains in contact with the wound for at least 72 hours. In other embodiments, the negative pressure wound bandage remains in contact with the wound for at least 1 week. In yet another embodiment, the wound bandage remains in contact with the wound for at least 2 weeks. In yet another embodiment, the wound bandage remains in contact with the wound for at least 3 weeks. In yet another embodiment, the wound bandage remains in contact with the wound for at least 4 weeks. In the above embodiments, it should be understood that the granulation tissue does not retain these components, as the threads, strings, cords, woven meshes, or tertiary structures described herein are completely absorbed. In some of these embodiments, the wound bandage is about 1 cm to about 5 cm thick. Thus, in some of these embodiments, the wound bed can be closed without changing the bandage.

0054In some embodiments, the woven meshes described herein are used in wound bandages, including negative pressure wound bandages. In another embodiment, the bandage comprises 2 to about 10 layers of woven mesh.

0055In yet another embodiment, the woven mesh comprises the same yarn. In yet another embodiment, the woven mesh comprises different threads.

0056In some embodiments, the woven mesh is about 1 mm to about 2 mm thick when dried. In another embodiment, the woven mesh is about 2 mm to about 4 mm thick when dried.

0057In some embodiments, the pore size of the woven mesh is from about 1 mm to about 10 mm in width. In another aspect, the pore size of the woven mesh is from about 0.3 mm to about 0.6 mm in width. In yet another embodiment, the holes in the woven mesh are aligned. In yet another embodiment, the holes in the woven mesh are staggered. In yet another embodiment, the woven mesh is parallel to create holes of the desired size.

0058In some embodiments, the woven mesh is mechanically stable down to a decompression of about 75 mmHg. In another embodiment, the woven mesh is mechanically stable up to a decompression of about 150 mmHg.

0059In some embodiments, the woven mesh comprises collagen. In another embodiment, the bandage is attached to the polyurethane foam. In yet another embodiment, the polyurethane foam is an open cell foam. In yet another embodiment, the bandage is attached to a thin film. In yet another embodiment, the thin film is silicone or polyurethane. In yet another embodiment, the bandage is attached to a thin film with a water-soluble adhesive.

0060In some embodiments, the thread used for the bandage comprises a therapeutic or diagnostic agent.

0061In some embodiments, wounds, in particular open wounds (Zamierski U.S. Pat. Nos. 4,969,880, 5,100,396, 5,261,893, 5,527,293, and 6,071,267, and Argenta et al., U.S. Pat. No. Negative pressure wound bandages (Johnson et al., US Pat. No. 7,070,584, Kemp et al., US Pat. No. 5,256,418, Chateaulier) for use in decompression-induced healing of 5,636,643 and 5,645,081). et al., U.S. Pat. No. 5,449383, Bennet et al., U.S. Pat. No. 5,578,662, Yasukawa et al., U.S. Pat. Nos. 5,629,186 and 5,780,281 and U.S. Patent Application No. 08 / 951,832) are provided. Bandages are the threads described herein attached to a pad that fits the wound location, an airtight seal that is detachably attached to the pad, a negative pressure source that is in fluid communication with the pad, and the wound contact surface of the pad. , Strings, cords, woven meshes, or three-dimensional structures. Pads, seals, and decompression sources are performed as described in the prior art.

0062In other embodiments, the threads, strings, cords, woven meshes, or tertiary structures described herein are mechanically stable down to a reduced pressure of about 75 mmHg. In yet another embodiment, the threads, strings, cords, woven meshes, or tertiary structures described herein are mechanically stable down to a reduced pressure of about 150 mmHg. In yet another embodiment, the bandage comprises at least one layer of woven mesh. In yet another embodiment, the bandage comprises from 2 to about 10 layers of woven mesh. In yet another embodiment, the pad is a foam. In yet another embodiment, the pad is a polyurethane open cell foam.

0063In some embodiments, the tube connects the pad to the negative pressure source. In yet another embodiment, a removable canister is inserted between the pad and the negative pressure source to allow fluid communication with the pad and the negative pressure source.

0064In some embodiments, the threads, strings, cords, woven meshes, or tertiary structures described herein are not hydrated. Thus, in these embodiments, the bandage can absorb the wound exudate when placed in contact with the wound. In other embodiments, the threads, strings, cords, woven meshes, or three-dimensional structures described herein are hydrated. Thus, in these embodiments, the bandage can keep the wound moist when placed in contact with the wound.

0065In some embodiments, a fluid-mounted input port is connected to the pad. Thus, in these embodiments, the fluid can be administered into the wound. In some embodiments, the fluid is saline. In other embodiments, the fluid contains a diagnostic or therapeutic agent.

0066In some embodiments, the threads, strings, cords, woven meshes, or three-dimensional structures described herein are used as anti-adhesion materials. In some embodiments, the woven meshes described herein are used in anti-adhesion materials.

0067In some embodiments, a method of treating wrinkles in a subject is provided. For example, as shown in FIG. 3A, the wrinkles may be in the periorbital region. For example, as shown in Figures 1, 2A, and 2B, the thread may be attached to the needle. For example, as shown in FIG. 3B, the end of the needle can be inserted through the skin surface of the subject into the dermis adjacent to or within the wrinkles. In some embodiments, the thread is inserted into the subcutaneous space instead of the dermis. The needle can then traverse the subject's dermis beneath the wrinkles, for example as shown in FIG. 3C. The needle can then exit the subject's skin on the opposite edge of the wrinkle, for example as shown in Figure 3D. The needle can then be pulled end-to-end until the needle is removed from the object so that the thread is pulled into the position previously occupied by the needle below the wrinkle, for example as shown in FIG. 3E. Finally, as shown in FIG. 3F, for example, the excess thread is cut from the needle on the surface of the subject's skin and the thread remains implanted.

0068Although not bound by theory, the above method can successfully treat wrinkles as shown in Figures 5A, 5B and 5C. Typical wrinkles are shown in Figure 5A. FIG. 5B shows a thread transplanted under a wrinkle that has not yet been hydrated. As shown in Figure 5C, the threads transplanted under the wrinkles are completely hydrated and at the same time the surface appearance of the wrinkles is flattened.

0069In some embodiments, the method can be used to rejuvenate the skin of a subject in need of the method. In many of these embodiments, the yarn contains a significant amount of non-crosslinked hyaluronic acid. In some of these embodiments, the yarn comprises an antioxidant, vitamin E, or retinol, or a combination thereof.

0070In some embodiments, methods of treating hair loss in a subject are provided. Subjects, such as men with typical androgenetic alopecia, are shown in Figure 4A, and areas where hair growth (and imaginary hairline) is desirable are shown in Figure 4B. Threads can be attached to the needle, for example, as shown in Figures 1, 2A, 2B and 4C. For example, as shown in Figure 4C, the end of the needle can be inserted into one of the hairline. The needle can then cross the area beneath the subject's hairline and exit the subject's skin, for example as shown in FIG. 4D. Then, as shown in FIG. 4E, for example, the needle can be pulled end-to-end until the needle is removed from the object so that the thread is pulled to the position previously occupied by the needle. Finally, as shown in FIG. 4D, for example, the excess thread is cut from the needle on the surface of the subject's skin and the thread remains implanted.

0071In some embodiments, methods for treating tumors are provided in subjects who require treatment of the tumors. For example, as shown in Figures 1, 2A and 2B, the thread can be attached to the needle. The end of the needle can be inserted into the tumor of interest. The needle can then cross the tumor and then exit the tumor. The needle can then be pulled terminally until the needle is removed from the tumor of interest so that the thread is pulled into the position previously occupied by the needle. Finally, the excess thread is cut from the needle and the thread remains implanted in the tumor of interest. In some of the above embodiments, the thread comprises an anti-cancer agent. In some embodiments, the threads are crosslinked and contain a Bcl-2 inhibitor.

0072In an exemplary embodiment, the methods of the invention can be used to treat pancreatic tumors. FIG. 6A shows the human pancreas with the tumor, while FIG. 6B shows the needle to which the thread is attached. The pancreas can be reached by surgery or by a minimally invasive method, for example by laparoscopy. The end of the needle can be inserted into a pancreatic tumor. The needle can then cross the pancreatic tumor as shown in Figure 6C and then exit the tumor. The needle can then be pulled distally until the needle is removed from the pancreatic tumor so that the thread is pulled into the position previously occupied by the needle. Finally, the excess thread is cut from the needle and the thread remains implanted in the pancreatic tumor. This process can be repeated many times to obtain a pancreatic tumor with many threads transplanted, as shown in Figure 6D. In some embodiments, the thread comprises an anti-cancer agent.

0073In some embodiments, methods for treating dilated tortuous veins are provided in subjects who require treatment of dilated tortuous veins. Threads can be attached to the needle, for example, as shown in Figures 1, 2A, and 2B. The end of the needle can be inserted into the dilated tortuous vein of interest. The needle can then cross the dilated tortuous vein and then exit the vein. The needle can then be pulled terminally until the needle is removed from the dilated tortuous vein of interest so that the thread is pulled into the position previously occupied by the needle. Finally, the excess thread is cut from the needle and the thread remains implanted in the dilated tortuous vein of interest. In some embodiments, the needle is flexible. In another embodiment, the thread becomes coiled upon hydration, making it easier to occlude blood vessels.

0074In some embodiments, a method for reconstructing a papilla is provided in which a three-dimensional cylindrical implant consisting of crosslinked threads is implanted under the skin. The implant may contain a therapeutic agent, eg, a chondrocyte adhesive compound. FIG. 7A shows a graft composed of a plurality of concentric coil layers of yarn molded to form a papilla, whereas FIG. 7B shows a cross-sectional view of the graft of FIG. 7A. FIG. 7C shows how the implant of FIG. 7A can be used for papilla reconstruction.

0075In some embodiments, methods for regrowth of nerves or blood vessels are provided. As shown in FIG. 8, a needle can be used to place the thread on a particular line that can promote the regrowth of nerves or blood vessels.

<p num="0076"> The present invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many changes can be made to materials and methods without departing from the scope of the invention.</p><p num="0077">Example 1: Synthesis of crosslinked yarn Crosslinked yarns 0.004 "to 0.006" in diameter were made by forming gels with concentrations of 5% by weight hyaluronic acid and 0.4% by weight BDDE and the rest consisting of water. The gel was extruded into a thread by a nozzle with an inner diameter of 0.02 inches and a tapered tip, a syringe pressure of 20 psi, and a linear movement speed commensurate with the speed of gel ejection from the syringe. However, there are numerous combinations of extrusion parameters that can produce threads of the desired thickness. The yarn was dried, then the yarn was rinsed with hydrated water and then the yarn was stretched during drying. During multiple cycles of rinsing and drying, the total length of the yarn increased by about 25% to about 100%. The yarn produced as described above fails at a tension of approximately 0.25 kg to approximately 1.50 kg and expands in diameter by approximately 25% to approximately 100% when hydrated. It can survive as a thread for 1-9 months in vivo.</p><p num="0078">Example 2: Treatment of corpse wrinkles with hyaluronic acid threads One or two hyaluronic acid threads with a thickness of 0.004 inch to 0.008 inch were attached to a subcutaneous needle (22 to 25 Ga). Both non-crosslinked yarn and yarn crosslinked with BDDE were used. The needle was able to traverse the corpse head of a 50-year-old woman, such as the nasolabial folds, perioral, periorbital, frontalis muscle (forehead), and wrinkles between the eyebrows. The needle could be pulled through the skin so that the thread was at the position where the needle was first inserted.</p><p num="0079">Example 3: Placement of hyaluronic acid thread in a dog Acute dog studies and chronic dog studies were conducted. One or two hyaluronic acid threads with a thickness of 0.004 inch to 0.008 inch were attached to a subcutaneous needle (22 to 25 Ga). Both non-crosslinked yarn and yarn crosslinked with BDDE were used. In all cases, the needle was able to pull the attached thread through the dermis. Within minutes, most threads had a visible effect on the animal's skin surface in the form of linear ridges.</p><p num="0080">Example 4: Comparison of tensile strengths of various hyaluronic acid threads The tensile strength of the self-crosslinked hyaluronic acid yarn was compared with the yarn crosslinked using the method of Example 1. The method of self-crosslinking hyaluronic acid (see USPTO 6,387,413) was reproduced, and the threads of non-crosslinked hyaluronic acid were repeatedly frozen and thawed. All such samples had lower breaking tensions than yarns made using the same extrusion parameters as described above and crosslinked with BDDE.</p><p num="0081"> Finally, it should be noted that there are alternative ways of implementing the present invention. Accordingly, aspects of the invention can be considered exemplary and not limiting, and the invention is not limited to the details presented herein, but is the scope and equivalent of the appended claims. It can be changed in the thing. All references and publications cited herein are incorporated by reference in their entirety.</p>