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WO2019193053A1 - Fibres électrofilées de polymères biocompatibles appropriées pour des échafaudages tissulaires - Google Patents

Fibres électrofilées de polymères biocompatibles appropriées pour des échafaudages tissulaires Download PDF

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Publication number
WO2019193053A1
WO2019193053A1 PCT/EP2019/058406 EP2019058406W WO2019193053A1 WO 2019193053 A1 WO2019193053 A1 WO 2019193053A1 EP 2019058406 W EP2019058406 W EP 2019058406W WO 2019193053 A1 WO2019193053 A1 WO 2019193053A1
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Prior art keywords
propanol
mixture
copolymer
process according
fibers
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PCT/EP2019/058406
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English (en)
Inventor
José Ramón SARASUA OIZ
Jorge FERNÁNDEZ HERNÁNDEZ
Original Assignee
Universidad Del Pais Vasco/ Euskal Herriko Unibertsitatea (Upv/Ehu)
Polimerbio, S.L.
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Publication of WO2019193053A1 publication Critical patent/WO2019193053A1/fr

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Classifications

    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
    • D01D5/0038—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion the fibre formed by solvent evaporation, i.e. dry electro-spinning
    • 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
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D1/00—Treatment of filament-forming or like material
    • D01D1/02—Preparation of spinning solutions
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
    • D01F6/58—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products
    • D01F6/62—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from polyesters
    • D01F6/625—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from polyesters derived from hydroxy-carboxylic acids, e.g. lactones

Definitions

  • the present invention concerns a process for preparing electrospun fibers, the fibers resulting from the process, as well as non-woven composites prepared from the fibers.
  • electrospinning also known as electrostatic spinning
  • liquids and/or solutions capable of forming fibers are well known and has been described in a number of patents as well as in the general literature.
  • the process of electrospinning generally involves the creation of an electrical field at the surface of a liquid .
  • the resulting electrical forces create a jet of liquid which carries electrical charge.
  • the liquid jets may be attracted to other electrically charged objects at a suitable electrical potential.
  • the hardening and drying of the elongated jet of liquid may be caused by cooling of the liquid, i.e. where the liquid is normally a solid at room temperature; evaporation of a solvent, e. g. by dehydration, (physically induced hardening); or by a curing mechanism (chemically induced hardening).
  • the produced fibers are collected on a suitably located, oppositely charged receiver and subsequently removed from it as needed, or directly applied to an oppositely charged generalized target area.
  • Fibers produced by this process have been used in a wide variety of applications, and are known, from U. S. Patent Nos. 4,043,331 and 4,878,908, to be particularly useful in forming non-woven mats suitable for use in wound dressings.
  • One of the major advantages of using electrospun fibers in wound dressings is that very thin fibers can be produced having diameters, usually on the order of about 50 nanometers to about 25 microns, and more preferably, on the order of about 50 nanometers to about 5 microns. These fibers can be collected and formed into non-woven mats of any desired shape and thickness. It will be appreciated that, because of the very small diameter of the fibers, a mat with very small interstices and high surface area per unit mass, two characteristics that are important in determining the porosity of the mat, can be produced.
  • Wound dressings formed using non-woven mats of these polymeric fibers may provide particular benefits depending upon the type of polymer or polymers used. Biocompatible polymers are particularly desirable since they do not cause a negative reaction from the body upon application of the wound dressing .
  • the ability to electrospin the fibers also allows for variability in the composition of the fibers, their density of deposition and their inherent strength.
  • the composition of the fibers being electrospun it will be appreciated that fibers having different physical or chemical properties may be obtained. This can be accomplished either by spinning a liquid containing a plurality of components, each of which may contribute a desired characteristic to the finished product, or by simultaneously spinning, from multiple liquid sources, fibers of different compositions that are then simultaneously deposited to form a mat.
  • the resulting mat of course, would consist of intimately intermingled fibers of different material.
  • the wound dressing may be interacting with the extracellular matrix (ECM) of the soft tissue.
  • ECM extracellular matrix
  • Native ECM consists of different shapes and sizes fibers such as collagen (1-20 pm, depending on the type of tissue), elastin (0.1-0.2 pm), fibronectin (10 nm-1 pm), and laminin (5-10 nm), which have both structural and adhesive functions.
  • electrospun scaffolds for tissue engineering microfibrous and nanofibrous.
  • Microfibrous scaffolds provide topography and orientation, promote 3D-space for cell growth and cell penetration.
  • Nanofibrous structures promote high surface area that improves cell adhesion, proliferation and differentiation, although have only 2D-space for cell growth and low porosity, which is one of the main characteristics of the synthetic scaffolds, providing nutrients and metabolites diffusion and cellular infiltration.
  • Tissue engineering can be defined as an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain or improve tissue function.
  • tissue engineering There are three strategies in tissue engineering : the use of isolated cells or cell substitutes, the delivery of tissue-inducing substances such as growth and differentiation factors to targeted locations, and the cell culture in three dimensional scaffolds.
  • tissue-inducing substances such as growth and differentiation factors to targeted locations
  • the cell culture in three dimensional scaffolds There are many criteria that must be fulfilled to create an ideal scaffold.
  • the matrix should have a structure that acts as a template for tissue growth in three dimensions and stimulates new growth in the shape dictated by the scaffold.
  • the matrix To allow a tissue to grow in 3-D, the matrix must be a network of interconnected pores that let cells migrate through the scaffold and promote tissue growth throughout the template.
  • the pore network must allow the culture media to reach all cells, providing them with essential nutrients. Once the tissue engineered construct has been implanted, the pores must be connected sufficiently such that blood can penetrate to provide those nutrients.
  • An ideal scaffold would stimulate blood vessels to grow inside the pore network (angiogenesis) and not only act as a template for tissue growth, but it should also activate the cells of the tissue for self-regeneration. It has to be considered that cells seeded on the scaffolds receive and process a multiple combination of physicochemical and biological cues that will define their attachment, proliferation and differentiation and, in consequence, the cell cycle.
  • the scaffolds should act as a delivery system for the controlled release of cell- and gene-stimulating agents.
  • Common synthetic polymers lack in signals on their surface that promote the appropriate biological functions of the seeded cells. Growth factors can be incorporated into biodegradable polymer to immobilise proteins of specific binding sites. Alternatively, the incorporation of inorganic bioactive particles such as hydroxyapatite or bioactive glasses has been found to stimulate the cell proliferation.
  • the scaffold should be biodegradable or bioresorbable leaving eventually no trace of its presence.
  • the material by-products should be ones that can be excreted or metabolised by the body.
  • the degradation and resorption rates must be controllable so that it can be tailored to match the cell/tissue growth in vitro and/or once it has been implanted, transfer gradually the mechanical loads from the scaffold to the regenerated host tissue.
  • the mechanical properties of the tissue engineered construct should also match that of the host tissue and the structure and strength must be maintained until enough tissue has been regenerated.
  • Tissue repair after injury is a complex, metabolically demanding process that depends on the tissue ' s regenerative capacity and the quality of the inflammatory response.
  • the first stage of the immune system response is inflammation, in three distinct phases, which helps to restore normal tissue architecture.
  • necrotic debris, the clotting reaction, and any invading microbes collectively mobilize the recruitment of key inflammatory cells, and so the release of inflammatory substances, including cytokines, free radicals, hormones and other small molecules are triggered.
  • cytokines including cytokines, free radicals, hormones and other small molecules
  • Neutrophils, monocytes, and other innate immune cells are recruited to the wound site to clear cell debris and remove infectious organisms.
  • the pro-inflammatory response begins to subside, with key inflammatory cells such as macrophages switching to a reparative phenotype.
  • tissue homeostasis is restored when the inflammatory cells either exit the site of injury or are eliminated through apoptosis.
  • ROS Reactive Oxygen Species
  • oxidative stress affects cellular structures (including lipids, membranes, proteins and DNA) leading to inflammation, cellular apoptosis and senescence
  • cells make use of a wide-range of molecules and enzymes to prevent the accumulation of ROS.
  • the oxidative stress can also be effectively neutralized by enhancing cellular defenses with the delivery of natural and synthetic antioxidants.
  • These compounds can be loaded into biomaterials for prolonged and targeted delivery; thereby increasing their bioavailability.
  • the design of tissue engineered scaffolds with antioxidants incorporated in them aims to ensure a continuous release at the implant site so as to aid the healing process and at the same time attenuate the inflammation reactions related to bio-absorbable polymers (implantation and local accumulation of degradation products that also may generate ROS).
  • Electrospun gelatin nanofibers as drug carrier effect of crosslinking on sustained release. Materials Today: Proceedings 2016, 3, 3484-3491) and quercetin in poly(lactide-co-glycolide)-PCL nanofibers (Vashisth, P.; Singh, R.P.; Pruthi, V. A controlled release system for quercetin from biodegradable poly(lactide-co-glycolide)-polycaprolactone nanofibers and its in vitro antitumor activity. Journal of Bioactive and Compatible Polymers 2016, 31, 260-272).
  • the present invention concerns a process for preparing an electrospun fiber, said process comprising the steps of: a) dissolving a biocompatible polymer or a mixture of biocompatible polymers in an organic solvent, said organic solvent comprising a solvent selected from the group consisting of protogenic organic solvents, protophilic organic solvents, and any mixture thereof, wherein said organic solvent has a pK a of at least 10,
  • step b electrospinning the solution obtained in step a).
  • the present invention concerns an electrospun fiber obtainable by the process according to the present invention.
  • the electrospun fibers obtained by the process of the present invention display a three-dimensional structure distinct from the electrospun fibers prepared according to the prior art.
  • the present invention concerns a non-woven composite, such as a wound dressing or tissue scaffold, comprising electrospun fibers according to the present invention.
  • Figure 1 shows a good example of different fiber morphologies produced with poly(e- caprolactone) using different solvents: (a) nanofibers of ⁇ 200 nm in diameter using formic acid (FA), (b) microfibers of ⁇ 2 pm with trifluoroethanol (TFE) as solvent and (c and O a 200 nm/lpm fiber mix fabricated with TFE-methanol.
  • Field Emission Scanning Electron Microscopy (FE-SEM) images have a magnification of lOOOx with the exception of image (c ' ) that was obtained at 5000x.
  • Figure 2 shows the FE-SEM images of non-woven mats prepared from poly(e- caprolactone) fibers loaded with 5% of antioxidant (quercetin), wherein said fibers have been prepared by dissolving in (a) tetrahydrofuran (THF), (b) trifluoroethanol (TFE), (c) TFE-methanol (MET), and (d) TFE-formic acid (FA).
  • THF and TFE-formic acid mats with a fiber distribution of the same diameter were obtained : microfibers of ⁇ 2 pm in diameter using THF or nanofibers ⁇ 200 nm diameter fabricated with TFE- formic acid.
  • TFE-methanol was used as solvent mix nano- microstructured scaffolds with fibers of ⁇ 200 nm and ⁇ 1 pm were produced.
  • TFE was also successfully employed to fabricate mats that exhibited three types of fiber morphologies leading to higher pore sizes: nanofibers of around 200 nm of diameter, microfibers of ⁇ 1 pm diameter and some fibers of large dimensions (4 pm of diameter) which had dilatations of almost 10 pm.
  • Figure 3 shows a macroscopic view of poly(e-caprolactone) electrospun scaffolds loaded with several antioxidants. These mats were fabricated using TFE-methanol as solvent mix (THF in the case of allicin) : (Al) Acetyl cysteine, (A2) Allicin, (A3) Crocin, (Bl) Curcumin, (B2) Curcumin-piperine, (B3) Piperine, (Cl) Polydatin, (C2) Quercetin, (C3) Rutin.
  • TFE-methanol solvent mix
  • Figure 4 shows the chemical formulas of several antioxidants and their thermal curves obtained using Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). N-acetyl-L-cysteine, allicin, crocin, curcumin, piperine, polydatin, quercetin and rutin are all of them a representative sample of non-enzymatic antioxidants.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • protogenic solvent and “protophilic solvent” are used in the present context in accordance with IUPAC recommendations ( Glossary of terms used in physical organic chemistry (IUPAC Recommendations 1994)). As such, they refer to solvents capable of forming hydrogen bonds.
  • biocompatible polymers
  • biocompatible polymer refers to any polymer which when in contact with the cells, tissues or body fluid of an organism does not induce adverse effects such as immunological reactions and/or rejections and the like.
  • biodegradable polymer refers to any polymer which can be degraded in the physiological environment such as by proteases.
  • biodegradable polymers may be of natural origin or of synthetic origin.
  • the biodegradable polymers of synthetic origin are typically polyesters.
  • biocompatible and biodegradable polyester polymers examples include polycaprolactone, polylactide, polyethylene brassylate, poly(co-pentadecalactone), copolymer of lactide and caprolactone, copolymer of lactide and valerolactone, copolymer of lactide and ethylene brassylate, copolymer of w-pentadecalactone and e- decalactone, copolymer of w-pentadecalactone and d-hexalactone, and copolymer of ethylene brassylate and d-hexalactone.
  • antioxidants and biocompatible polymers being “completely miscible” in the context of the present invention, it means that the electrospun mixture of the antioxidant and polymer is present as a single amorphous phase, as demonstrated by the single glass transition temperature of the antioxidant loaded electrospun fiber.
  • antioxidants are molecule that inhibits the oxidation of other molecules. Based on their activity, antioxidants can be categorized as enzymatic and non-enzymatic. The former act by breaking down and removing free radicals after converting oxidative products to hydrogen peroxide (H 2 0 2 ) and then to water in a multi-step process. Examples of enzymatic antioxidants are catalase (CAT), glutathione peroxidase (GSHPx), superoxide dismutase (SOD) and peroxiredoxin I-IV. On the contrary, non- enzymatic antioxidants work by interrupting free radical chain reactions.
  • CAT catalase
  • GSHPx glutathione peroxidase
  • SOD superoxide dismutase
  • I-IV peroxiredoxin I-IV
  • the main antioxidants in this category are vitamins (vitamin E, vitamin C and vitamin A), bioflavonoids (a group of natural benzo-y-pyran derivatives widely distributed in fruits and vegetables including flavonols, flavones, flavonones, anthocyanidin and isoflavones), carotenoids (lycopene and b-carotene are the most prominent among the other 600 different compounds), hydroxycinnamates (ferulic acid, caffeic acid, sinapic acid and p-coumaric acid), other natural antioxidants (theaflavin, theaflavin-3-gallate, allicin, piperine and curcumin), other polyphenols (tannic acid, polydatin, resveratrol), physiological antioxidants (uric acid in plasma and glutathione (GSH)) or synthetic antioxidants such as cinnamic acid derivatives, melatonin or selegiline.
  • bioflavonoids a group of natural benzo-y-pyran derivative
  • the oxidant is selected from the group consisting of N-acetyl-L-cysteine, allicin, crocin, curcumin, piperine, polydatin, quercetin, rutin, and mixtures thereof.
  • Figure 4 shows the structure of the non-enzymatic antioxidants acetyl cysteine, allicin, crocin, curcumin, piperine, polydatin, quercetin, and rutin, as well as their DSC and TGA curves.
  • the present invention concerns a process for preparing an electrospun fiber, said process comprising the steps of: a) dissolving a biocompatible polymer or a mixture of biocompatible polymers in an organic solvent, said organic solvent comprising a solvent selected from the group consisting of protogenic organic solvents, protophilic organic solvents, and any mixture thereof, wherein said organic solvent has a pK a of at least 10,
  • step b electrospinning the solution obtained in step a).
  • the organic solvent employed during the electrospinning process influences the three-dimensional structure of the resulting fibers.
  • the organic solvent employed during the electrospinning process can control the diameter of the fibers resulting from the process.
  • the organic solvent comprises a solvent selected from the group consisting of protogenic organic solvents, protophilic organic solvents, and any mixture thereof, wherein the organic solvent has a pK a of at least 10.
  • the organic solvent comprises at least 50% (v/v) of a solvent selected from the group consisting of protogenic organic solvents, protophilic organic solvents, and any mixture thereof, such as at least 60%, e.g. at least 70%, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%.
  • the organic solvent is selected from the group consisting of protogenic organic solvents, protophilic organic solvents, and any mixture thereof, wherein the organic solvent has a pK a of at least 10.
  • the organic solvent comprises a solvent selected from the group consisting of trifluoroethanol, l,l,l-trifluoro-2-propanol, 3,3,3-trifluoro-l-propanol, 2- trifluoromethyl-2-propanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, nitromethane, and mixtures thereof.
  • a solvent selected from the group consisting of trifluoroethanol, l,l,l-trifluoro-2-propanol, 3,3,3-trifluoro-l-propanol, 2- trifluoromethyl-2-propanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, nitromethane
  • the organic solvent is selected from trifluoroethanol, l,l,l-trifluoro-2- propanol, 3,3,3-trifluoro-l-propanol, 2-trifluoromethyl-2-propanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, nitromethane, and mixtures thereof.
  • the organic solvent comprises a mixture of two or more solvents selected from the group consisting of protogenic organic solvents and protophilic organic solvents having a pK a of at least 10.
  • the solvent is a mixture of two or more solvents selected from the group consisting of protogenic organic solvents and protophilic organic solvents having a pK a of at least 10.
  • the organic solvent comprises a mixture of two or more solvents selected from the group consisting of trifluoroethanol, l,l,l-trifluoro-2- propanol, 3,3,3-trifluoro-l-propanol, 2-trifluoromethyl-2-propanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, and nitromethane.
  • solvents selected from the group consisting of trifluoroethanol, l,l,l-trifluoro-2- propanol, 3,3,3-trifluoro-l-propanol, 2-trifluoromethyl-2-propanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, and nitrome
  • the organic solvent is a mixture of two or more solvents selected from the group consisting of trifluoroethanol, l,l,l-trifluoro-2- propanol, 3,3,3-trifluoro-l-propanol, 2-trifluoromethyl-2-propanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, and nitromethane.
  • the organic solvent comprises a mixture of two or more solvents selected from the group consisting of protogenic organic solvents and protophilic organic solvents having a pK a of at least 10, wherein the biocompatible polymer is soluble in one of the two solvents and insoluble or only sparingly soluble in the other of the two solvents ("the antisolvent").
  • the amounts of solvent and antisolvent are such that the biocompatible polymer is soluble in the combined organic solvent used in the process of the invention.
  • the organic solvent comprises a mixture of two or more solvents selected from the group consisting of protogenic organic solvents and protophilic organic solvents having a pK a of at least 10, wherein the biocompatible polymer is soluble in one of the two solvents and insoluble or only sparingly soluble in the other of the two solvents.
  • the organic solvent is selected from trifluoroethanol, methanol, and mixtures thereof.
  • the solvent is a mixture of trifluoroethanol and methanol.
  • the volume ratio of trifluoroethanol and methanol is in the range of 5 : 1 to 20 : 1, such as in the range 10 : 1 to 17 : 1, more preferably in the range 12 : 1 to 16 : 1, such as 14: 1.
  • biocompatible polymers suitable for electrospinning are known in the art. They include polycaprolactone, polylactide, polyethylene brassylate, poly(co- pentadecalactone), copolymer of lactide and caprolactone, copolymer of lactide and valerolactone, copolymer of lactide and ethylene brassylate, copolymer of w- pentadecalactone and e-decalactone, copolymer of w-pentadecalactone and d- hexalactone, and copolymer of ethylene brassylate and d-hexalactone.
  • Biocompatible polymers used in electrospinning are typically also biodegradable.
  • the biocompatible polymer is a biodegradable polymer.
  • Biodegradable polymers may be of natural origin or of synthetic origin.
  • the biodegradable polymers of synthetic origin are typically polyesters.
  • the biocompatible polymer is a biodegradable polymer of synthetic origin.
  • the biocompatible polymer is a biodegradable polyester.
  • the biocompatible polymer is selected from the group consisting of polycaprolactone, polylactide, polyethylene brassylate, poly(co- pentadecalactone), copolymer of lactide and caprolactone, copolymer of lactide and valerolactone, copolymer of lactide and ethylene brassylate, copolymer of co- pentadecalactone and e-decalactone, copolymer of w-pentadecalactone and d- hexalactone, copolymer of ethylene brassylate and d-hexalactone, and any mixture thereof.
  • the biocompatible polymer is selected from the group consisting of polycaprolactone, polylactide, polyethylene brassylate, poly(co- pentadecalactone), copolymer of lactide and caprolactone, copolymer of w- pentadecalactone and e-decalactone, copolymer of ethylene brassylate and d- hexalactone, and any mixture thereof.
  • the biocompatible polymer is polycaprolactone.
  • the biocompatible polymer is selected from the group consisting of polyethylene brassylate, poly(co- pentadecalactone), copolymer of lactide and caprolactone, copolymer of lactide and valerolactone, copolymer of lactide and ethylene brassylate, copolymer of w- pentadecalactone and e-decalactone, copolymer of w-pentadecalactone and d- hexalactone, copolymer of ethylene brassylate and d-hexalactone, and any mixture thereof.
  • the electronspun fibers employed in wound dressings may advantageously incorporate an antioxidant in order to scavenge reactive oxygen species.
  • the electrospun fiber according to the invention comprises one or more antioxidant compounds, the one or more antioxidant compounds being dissolved together with the biocompatible polymer in step a) of the process according to the invention.
  • antioxidants can be incorporated into the fibers in an advantageous manner if the biocompatible polymer and the antioxidant are completely miscible.
  • the one or more antioxidant compounds and the biocompatible polymer or mixture of biocompatible polymers are selected so that they are completely miscible.
  • the antioxidant is selected from the group consisting of vitamins, bioflavonoids, carotenoids, hydroxycinnamates, other natural antioxidants, such as theaflavin, theaflavin-3-gallate, allicin, piperine and curcumin, other polyphenols, such as tannic acid, polydatin, and resveratrol, physiological antioxidants, such as uric acid in plasma and glutathione (GSH), synthetic antioxidants, such as cinnamic acid derivatives, melatonin and selegilineallicin, crocin, curcumin, piperine, polydatin, quercetin, and any mixture thereof.
  • vitamins bioflavonoids, carotenoids, hydroxycinnamates
  • other natural antioxidants such as theaflavin, theaflavin-3-gallate, allicin, piperine and curcumin
  • other polyphenols such as tannic acid, polydatin, and resveratrol
  • physiological antioxidants
  • the antioxidant is selected from the group consisting of allicin, crocin, curcumin, piperine, polydatin, quercetin, and any mixture thereof. In still another embodiment, the antioxidant is selected from the group consisting of allicin, curcumin, piperine, polydatin, quercetin, and any mixture thereof.
  • the electrospun fiber of the invention comprises one or more antioxidant compounds and/or one or more antibiotic compounds, the one or more antioxidant compounds and/or the one or more antibiotic compounds being dissolved together with the biocompatible polymer in step a) of the process of the invention.
  • the electrospun fiber of the invention comprises one or more antibiotic compounds, the one or more antibiotic compounds being dissolved together with the biocompatible polymer in step a) of the process of the invention.
  • the one or more antibiotic compounds are selected from the group consisting of tobramycin, norfloxacin, nitrofurantoin, levofloxacin, ciprofloxacin, cefdinir, and amoxicillin.
  • the present invention concerns an electrospun fiber obtainable by the process according to the present invention.
  • Electrospun fibers such as the fibers according to the present invention, are typically used to prepare non-woven composites, such as wound dressings or tissue scaffolds used in tissue engineering.
  • the present invention concerns a non-woven composite comprising electrospun fibers according to the present invention.
  • the non-woven composite is a wound dressing.
  • the non-woven composite is a tissue scaffold.
  • the non-woven composite, such as a wound dressing or a tissue scaffold may, in addition to or instead of antioxidants, comprise further components useful in the healing of wounds or in tissue engineering.
  • the non-woven composite according to the present invention such as a wound dressing or a tissue scaffold, further comprises one or more proteins promoting cellular recruitment to the composite.
  • said one or more proteins are selected from the group consisting of chemokines, interleukins, and growth factors. These proteins are involved in migration and homing of mesenchymal stem cells (MSCs) to injured tissues. MSCs not only provide a source of progenitors for cell replacement, but also activate or empower other local cells (such as tissue-resident progenitor or stem cells, endothelial cells, and fibroblasts) to facilitate tissue regeneration via paracrine stimulation.
  • MSCs mesenchymal stem cells
  • PCL Poly(e-caprolactone) Purasorb PC12, with an weight average molecular weight (M w ) of 128.7 Kg mol 1 and a dispersity (D) of 1.76, was provided by Corbion. Allicin (mixture of diallyl disulfide and diallyl trisulfide) and Rutin were supplied by Cymit Quimica, while the rest of antioxidants were purchased from Sigma Aldrich : Curcumin (#C1386), Crocin (#17304), N-Acetyl-L-cysteine (#A7250), Piperine (#P49007) and Polydatin (#15721).
  • the antioxidant was dissolved in tetrahydrofuran (THF), trifluoroethanol (TFE) or in solvent mixes of TFE with formic acid (FA) or methanol (MET) to prepare PCL- antioxidant scaffolds. Then, the appropriate amount of PCL (4.0 g in 15 mL of solvent) was added to obtain a 5 % w/w antioxidant/polymer. After the preparation of the polymer solution, the mixtures were subsequently vortexed to ensure proper mixing.
  • THF tetrahydrofuran
  • TFE trifluoroethanol
  • F formic acid
  • MET methanol
  • Electrospinning was performed at room temperature (21 ⁇ 2°C) with controlled humidity ( ⁇ 40%) in a Nanospinner Ne-200 (Inovenso) system.
  • the tunable high-voltage power supply was connected to the tip of the needle (0.5 mm in diameter, positive lead) and attached to the collector (negative lead) with an alligator clip.
  • the needle-to-collector distance was 20 cm and the polymer solutions were sprayed using a syringe pump at an adjusted flow rate.
  • the electrospinning process was first optimized for PCL Purasorb PC12 before incorporating antioxidants into the polymer matrix.
  • Polymer mats were spun directly onto a plate-shaped collector (aluminium) for 45 min to achieve rectangular samples (6 x 5 cm) with a thickness of 100-150 pm.
  • the electrospun mats prepared according to Example 1 were examined using Field Emission Scanning Electron Microscopy (FE-SEM).
  • the PCL-antioxidant scaffolds were sputter-coated with a thin layer of gold ( ⁇ 15 nm) in an Emitech K550X and observed in a Hitachi SEM (Hitachi S-4800N).
  • the voltage used was 10-15 kV and the working distance was 7.0-9.0 mm with a magnification of lOOx, lOOOx, 5000x and 20000x.
  • Image J software Schoteider, C. A.; Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis, Nature methods 2012, 9(7), 671-675, PMID 22930834
  • Table 1 summarizes the electrospinning conditions and morphological properties obtained for scaffolds of PCL dissolved in TFE :MET 14: 1 (v:v) and TFE: FA 11 :4 (v:v).
  • Table 2 summarizes the results obtained when electrospinning PCL with immiscible antioxidants.
  • Table 3 summarizes the results obtained when electrospinning PCL with miscible antioxidants.
  • the thermal properties of the antioxidants were studied on a DSC Q200 (TA Instruments). Samples of 5-9 mg were heated at 20 °C min 1 from -80 °C to the end of the melting peak. After this first scan, the samples were quenched in the DSC and a second scan was made from -80 °C at the same rate. For the miscibility studies, DSC analysis was conducted on ⁇ 150 pm films that were prepared by solvent casting with TFE (THF in the case of allicin) as solvent.
  • TFE TFE in the case of allicin
  • thermogravimetric analysis TGA
  • TGA thermogravimetric analysis
  • PCL poly( e-caprolactone)
  • Figure 4 shows the structure of N-acetyl-L-cysteine, allicin, crocin, curcumin, piperine, polydatin, quercetin and rutin, which are all of them a representative sample of non- enzymatic antioxidants.
  • Figure 4 shows their thermal curves obtained using DSC and TGA.
  • the antioxidants could mix homogeneously or not with the polymer.
  • the antioxidants could mix homogeneously or not with the polymer.
  • piperine and polydatin they form miscible composites with the polyester.
  • T g was observed in all three cases, demonstrating the presence of a single amorphous phase.
  • the T g of PCL at -64 °C for the pure compound
  • the melting temperature of the antioxidants shifted to lower temperatures at contents of 50 % or 25 %, with lower melting enthalpies associated to both PCL and the drug. This also occurs for quercetin although a second scan was not possible due to the flavonoid partially degrading in the first heat treatment. However, both quercetin and allicin also appear to be miscible with PCL.
  • the bio-composite films were homogeneous and took a colour typical of biological molecules.
  • acetyl cysteine, crocin and rutin were not miscible with PCL although crocin can be classified as partially miscible because its melting peak fell and moved towards lower temperatures when PCL was added.
  • the films were not homogeneous and even though they had a reddish-orange color, some pigment aggregates were observed .
  • DSC scans of 50-50 blends of acetyl cysteine and rutin with PCL result in the antioxidant melting peaks appearing at the same temperature as those of the pure molecules.
  • acetyl cysteine containing sample a double T g behaviour (at ⁇ -60 and 0 °C) was observed, a clear indication of the presence of two phases.

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Abstract

La présente invention concerne un procédé de préparation de fibres électrofilées à partir de polymères biocompatibles dissous dans un solvant organique comprenant des solvants organiques protogéniques et/ou des solvants organiques protophiles, les fibres obtenues au cours dudit procédé, ainsi que des composites non tissés préparés à partir des fibres.
PCT/EP2019/058406 2018-04-04 2019-04-03 Fibres électrofilées de polymères biocompatibles appropriées pour des échafaudages tissulaires WO2019193053A1 (fr)

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CN114522268A (zh) * 2021-12-16 2022-05-24 浙江瑞谷生物科技有限公司 一种皮肤修复材料及其制备方法和应用
CN116113449A (zh) * 2020-08-05 2023-05-12 奇拉布有限公司 包含聚己酸内酯多孔膜的高级敷料
CN116726243A (zh) * 2022-03-02 2023-09-12 上海交通大学医学院附属第九人民医院 一种槲皮素/聚己内酯纤维电纺膜及其制备方法、应用
CN119221154A (zh) * 2024-12-05 2024-12-31 射阳县林夕纺织有限公司 一种抗菌防螨多功能纤维及其制备方法及在床垫中的应用

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111035792A (zh) * 2019-12-13 2020-04-21 青岛农业大学 一种岩白菜素电纺膜愈伤医用敷料及其制备方法和应用
CN116113449A (zh) * 2020-08-05 2023-05-12 奇拉布有限公司 包含聚己酸内酯多孔膜的高级敷料
CN114522268A (zh) * 2021-12-16 2022-05-24 浙江瑞谷生物科技有限公司 一种皮肤修复材料及其制备方法和应用
CN114522268B (zh) * 2021-12-16 2023-02-10 浙江瑞谷生物科技有限公司 一种皮肤修复材料及其制备方法和应用
CN116726243A (zh) * 2022-03-02 2023-09-12 上海交通大学医学院附属第九人民医院 一种槲皮素/聚己内酯纤维电纺膜及其制备方法、应用
CN119221154A (zh) * 2024-12-05 2024-12-31 射阳县林夕纺织有限公司 一种抗菌防螨多功能纤维及其制备方法及在床垫中的应用

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