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WO2002030480A1 - Materiau composite biocompatible pour applications medicales - Google Patents

Materiau composite biocompatible pour applications medicales Download PDF

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Publication number
WO2002030480A1
WO2002030480A1 PCT/DE2001/003910 DE0103910W WO0230480A1 WO 2002030480 A1 WO2002030480 A1 WO 2002030480A1 DE 0103910 W DE0103910 W DE 0103910W WO 0230480 A1 WO0230480 A1 WO 0230480A1
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WO
WIPO (PCT)
Prior art keywords
composite material
material according
biocompatible composite
biocompatible
cells
Prior art date
Application number
PCT/DE2001/003910
Other languages
German (de)
English (en)
Inventor
Peter-Jürgen Müller
Stephanie MÖLLER
Jörg OZEGOWSKI
Gundela Peschel
Hans-Georg Kastner
Matthias Hilliger
Original Assignee
Hans-Knöll-Institut für Naturstoff-Forschung e.V.
Friedrich-Schiller-Universität Jena
Biocell Teterow Gmbh & Co. Kg
Innovent Technologieentwicklung
HILLIGER, Monika, Maria
HILLIGER, Stephan, Matthias, Friedrich
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Hans-Knöll-Institut für Naturstoff-Forschung e.V., Friedrich-Schiller-Universität Jena, Biocell Teterow Gmbh & Co. Kg, Innovent Technologieentwicklung, HILLIGER, Monika, Maria, HILLIGER, Stephan, Matthias, Friedrich filed Critical Hans-Knöll-Institut für Naturstoff-Forschung e.V.
Priority to AU2002218134A priority Critical patent/AU2002218134A1/en
Publication of WO2002030480A1 publication Critical patent/WO2002030480A1/fr

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Classifications

    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • 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
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • 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
    • 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
    • A61L15/425—Porous materials, e.g. foams or sponges
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/129—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing macromolecular fillers

Definitions

  • the biocompatible composite materials consist of biopolymers of non-animal origin and can be used for very different medical applications. In a version for covering wounds, they are particularly suitable for large-area wounds. Other applications are the separation of organs by fabrics, e.g. after abdominal or heart surgery to prevent adhesions.
  • the biocompatible composite material can also be used to seal textile vascular prostheses.
  • the material can serve as a carrier material for animal and human cells, which are grown on the biocompatible composite material or the pores and then subsequently transferred to organs or to the wound surfaces.
  • animal and human cells which are grown on the biocompatible composite material or the pores and then subsequently transferred to organs or to the wound surfaces.
  • ephit cells, endothelial cells, Langerhans islet cells, liver cells, skin cells, dividing cells of the hair root or keratinocytes can be grown on or in the material.
  • a preferred area of application are chronic wounds that are difficult to heal and extensive burns.
  • tissue regeneration and ingrowth of implants in humans and animals is significantly improved.
  • the composite material is absorbed without residue during the healing process.
  • Biocompatible synthetic, semi-synthetic polymers and biopolymers are already used as biocompatible resorbable materials. There is a relatively large number of property rights for this.
  • a number of implant materials and wound covers are based on polymers, homopolymers and copolymers made from resorbable polyglycolide / polylactide (US 3636956, US 3463658, US 3982543, RU 2125859).
  • Polyalkanoate esters such as poly-ß-hydroxybutyrate are used in the form of cast films as well as in the form of compact implant material.
  • US 5641505 provides porous flexible membranes or tubes with wall thicknesses of approximately 10 ⁇ m to 1 mm and pore sizes between 0.1 ⁇ m and 30 ⁇ m made of polyhydroxybutyrate, a copolymer of poly- ⁇ -hydroxybutyrate and poly- ⁇ -hydroxyvalerianate or a combination of poly -ß-hydroxybutyrate with copolymers between the two polymers under protection.
  • the material is bioresorbable and contains pores with a pore diameter through which water and salts can be exchanged, but animal cells cannot pass through. The material is suggested for use in healing soft tissues.
  • hyaluronic acid esters or also chemically cross-linked hyaluronic acid or self-cross-linked hyaluronic acid are used 0.922.060, US 5,939,323, US 4,957,744 or INI 170,801) for medical and cosmetic applications.
  • a hyaluronic acid ester for example with the brand name HYAFF (Fidia, Italy), is available for wound care (hyalgin, laserskin).
  • HYAFF relatively hydrophobic ben foils are mechanically stable and can be provided with arrays of pores that are produced by laser. The pores are said to cause oxygen admission and drainage of wound fluid: Above all, however, they have the function that through them the skin cells can grow through to the wound surface.
  • EP 9707.833, EP 0.850.074, AU 6.930.096, WO 9.808.876 and EP 0.922.060 use membranes made of hyaluronic acid esters or crosslinked hyaluronic acid derivatives to prevent postoperative adhesions.
  • US 5,849,368 describes a process for rendering non-polar or slightly polar, hydrophobic surfaces of plastic material or rubber hydrophilic by means of plasma and subsequent coating with hydrophilic materials.
  • the coating of medical products or implants with hyaluronic acid is given in WO 9.624.392.
  • EP 0.470.007 describes a wound covering made of a hydrophobic porous membrane which has been coated hydrophilically with a nonionic surface-active substance.
  • US 5,916,585 is concerned with hydrophobic biodegradable polymer material on the surface of which a hydrophilic polymer has been immobilized or chemically crosslinked.
  • WO 0.037.124 and US 5,644,049 use a biodegradative network of hyaluronic acid ester in the form of a film, a membrane, a sponge, a hydrogel, a guide channel, a thread, a gauze or a non-woven, crosslinked hyaluronic acid as a carrier of mammalian cells , with microspheres, sponge fragments, fibers and granules from hyaluronic acid derivatives being contained as the biologically active component.
  • the material can be used in biomedical and sanitary applications including in dermatology, urology, orthopedics, otology, microsurgery, plastic surgery and in the cardiovascular area.
  • US 5J66.631 describes implant materials which contain bioabsorbable microspheres with a diameter between 10 ⁇ m and 1,500 ⁇ m in a freeze-dried hydrophilic and biocompatible collagen matrix, which consist of polylactide / polyglycolic acid copolymers, collagen, cross-linked collagen, hyaluronic acid and cross-linked hyaluronic acid, alginate and cellulose derivative ten, collagen, polystyrene, dextran, polyacrylamide, cellulose, calcium alginate, latex, polysulfone or glass.
  • a freeze-dried hydrophilic and biocompatible collagen matrix consist of polylactide / polyglycolic acid copolymers, collagen, cross-linked collagen, hyaluronic acid and cross-linked hyaluronic acid, alginate and cellulose derivative ten, collagen, polystyrene, dextran, polyacrylamide, cellulose, calcium alginate, latex, polysulfone or glass.
  • WO 9,961,080 and AU 4,368,099 describe materials which use hyaluronic acid derivatives with three-dimensional structures, including cavities, communicating pores; Contain needles or fibers of the same material and serve for temporary tissue replacement.
  • Polymeric microspheres with a diameter between 10 nm and 2 mm consist of a water-insoluble polylactide or of polyhydroxybutyrate. Their manufacture for biomedical applications is described in US 5,922,357.
  • the microspheres are coated with a water-soluble polymer such as dextran, chitosan, pectin, hyaluronic acid cellulose, starch, pullulan, inulin, heparin and heparin-like synthetic polymers.
  • Hyaluronic acid in native form is therefore a frequently used constituent of materials.
  • a formulation in the form of liquid, cream, gel, hydrogel, hydrocolloid or as a cover for the treatment of wounds contains hyaluronic acid and plasma fibronectin as constituents of the amniotic liquid (US 5,604,200) which creates a humid environment like that found in a fetus in the uterus and is used to treat burns and open wounds. Because of its human-identical composition (WO 0.016.818 and US 4,813,942), hyaluronic acid is of particular importance for wound coverings.
  • US 5,955,578 describes a framework material derivatized with hyaluronic acid for various medical purposes, such as tissue regeneration, tissue reconstruction and wound healing, and a method of production.
  • the materials can contain biologically active molecules such as growth factors.
  • hyaluronic acid fractions with molecular weights of 50,000 D to 100,000 D stimulate wound healing particularly well.
  • US 5,644,049 describes materials which consist of an interpenetrating polymeric network, where one component can be an acidic polysaccharide such as hyaluronic acid or a derivative thereof and the second component is a synthetic polymer.
  • Uronides of hyaluronic acid are produced by the action of the enzyme hyaluronate lyase on hyaluronic acid or its salts (WO 0.044.342)
  • sulfated glycosaminoglycans are proposed as ingredients of the wound covers and implants. Other property rights use poorly soluble polyelectrolytes.
  • wound healing is accelerated by heparin or heparin sulfate in the presence of chitosan.
  • carboxymethylchitosan for wound healing is proposed in US 5,679,658.
  • US 5,929,050 describes compositions which contain chondroitin sulfate and glycosaminoglycans.
  • US 4,570,629 provides hydrophilic bipolymeric copolyelectrolytic material based on linear water-soluble anions such as keratin and and a water-soluble linear cationic biopolymer of collagen and glucosaminoglycan under protection.
  • WO 0.016.817 describes a dermal scaffold made of chitosan / collagen for wound healing
  • EP 0.477.979 mentions chitin / chitosan as a wound healing filling material for wounds.
  • WO 9.822.H4 uses to accelerate tissue repair e.g. Chitosan, chitin and glucosamine, hyaluronic acid and sucrose octasulfate.
  • US 5,520,916 and US 5,824,335 use threads embedded in a matrix.
  • the threads can consist of esters of hyaluronic acid.
  • a certain pore size should allow the growth of grown cells to the wound base, on the other hand, in the case of materials that are intended to prevent tissue growth, the access of cells should be blocked by appropriately small pores.
  • a polyester mesh (US 5,972,332) is used to transfer keratinocyte cell turf directly to the wound surface. Smaller pores are said to prevent microorganisms from growing through. It can thus be stated that there are serious disadvantages with materials according to the prior art. It is disadvantageous, for example, that the physiologically very advantageous hyaluronic acid and its salts are soluble in water and do not form a mechanically stable material under moist conditions. Ingestion of body fluids or wound exudate produces a fluid that becomes less and less viscous with increasing dilution. In order to avoid this disadvantage, the hyaluronic acid has been chemically crosslinked or has been
  • Derivatives such as the hyaluronic acid ester used.
  • the derivatives are sparingly or not soluble in water; however, their functional groups, which produce the advantageous physiological properties, are blocked.
  • the semi-synthetic hyaluronic acid ester disintegrates under physiological conditions not only into the physiologically very favorable hyaluronic acid but also into cell-toxic alcohols such as butanol. The latter leads to local inflammatory reactions with rapid absorption.
  • a general disadvantage of the chemically crosslinked hyaluronic acids in addition to their reduced healing effect is that toxic crosslinking agents are used for their production.
  • Films made of polylactide or polyhydroxyalkanoates are proposed for wound care and for closing organ or tissue defects.
  • Polylactide is a mechanically stable, synthetically produced polymer that breaks down into lactic acid in the organism. They are somewhat less hydrophobic than the hyaluronic acid esters.
  • lactic acid leads to local accumulations of lactic acid during absorption in the body, which usually lead to tissue irritation.
  • the polyhydroxyalkanoates are better tolerated by the body, but have a hydrophobic surface.
  • the aim of the invention is to develop a material which does not have the disadvantages of the known technical solutions, is particularly biocompatible and is available.
  • the production of larger areas is to be carried out in a simple manner. This is not the case with the materials mentioned in the patent literature.
  • the material is said to contain pores with pore sizes adapted to the applications, it should be of biological origin but not be from mammals and contain no protein. It should be versatile, e.g. for covering or sealing or closing organ and tissue defects, as a carrier in cell cultivation, for covering large wound surfaces, for sealing vessel walls and implants and as a resorbable implant for separating organs. It is said to have a promoting effect on the healing of organ and tissue defects and not to have the disadvantages of previous materials. In particular, they should combine good flexibility with high hydrophilicity and swellability of the surface.
  • the cultivation of adhesive human or animal cells is to take place on the material or in the pores as a carrier, and the overgrown carriers are to be used to treat tissue defects, in particular chronic, difficult to treat wounds or burns.
  • Culturing animal cells e.g. Keratinocytes on the carrier material should preferably be made on flat surfaces.
  • the backing materials must be so flexible that they conform to the irregular surfaces of the wound surface.
  • the mechanical properties should make it easy for the attending physician to handle.
  • the material should also be easy to produce in a form adapted to the organs or implants.
  • the cells located on the carrier material should be able to grow through macropores or openings larger than 10 ⁇ m to the wound surface.
  • the wound coverings or carrier materials are said to have broken down after a while and living tissue has taken its place.
  • a material must be found which is completely biocompatible, can remain in the body without irritation and which is broken down or resorbed within a certain period of time without harmful side effects or the occurrence of toxic products.
  • the surface should have low swellable properties and the inside should be connected to the outside by pores.
  • the material should be easy to manufacture and commercially usable without much effort.
  • the invention is based on the scientifically technical task of producing a new, suitable, biocompatible and resorbable material which is suitable for a variety of medical purposes Applications can be used and meets commercial requirements.
  • the object on which the invention is based is achieved in that two types of biocompatible, known per se, very different in their properties and alone not suitable for the intended applications, are combined in the form of a composite material.
  • the new composite material consists of polyalkanoate esters as a matrix, in which microparticles are embedded, which consist of one or more polysaccharide polyelectrolytes and / or their salts and / or their derivatives with a spherical, fibrous or irregular shape with a diameter between 0.1 ⁇ m up to 500 ⁇ m and which may contain auxiliary substances, active substances or medicinal products.
  • the new material is a composite material consisting of a hydrophobic matrix with hydrophilic particles as a filler.
  • the polyalkanoate is dissolved in a water-immiscible solvent, preferably chloroform, and the polyelectrolytic particles are suspended in the solution. The solvent is then removed.
  • a water-immiscible solvent preferably chloroform
  • it is provided with pores and / or slot-shaped openings.
  • the pores are created in two ways.
  • the suspension is mixed with easily water-soluble, non-polyelectrolytic pore-forming particles.
  • the particles consist of the components of cell culture media such as glucose or amino acids, which are later removed by leaching.
  • the pores have diameters in the range from 1 ⁇ m to 100 ⁇ m (micropores). Larger pores (macropores) in particular can also be created by suspending an aqueous solution or an aqueous solution of a polyelectrolyte with ethanol in the form of small drops in the solution. After drying, instead of the droplets, predominantly pores with diameters from 10 ⁇ m to 1000 ⁇ m are formed.
  • Poly- ⁇ -hydroxybutyrate of biological origin is preferably used as the matrix-forming polyalkanoate ester.
  • Auxiliaries, active substances or medicaments present in the material according to the invention additionally influence the physiological properties of the material.
  • the polyelectrolytic microparticles in the matrix should be as small as possible. Their diameter is less than 100 ⁇ m, preferably less than 1 ⁇ m.
  • the polyelectrolytic microparticles create a swellable, soft and biocompatible consistency of the material when water enters.
  • the polyelectrolytic properties of the microparticles according to the invention give rise to a particularly high osmotic swelling pressure in the area of the microparticles when water enters, which is responsible for the tissue-like mechanical properties of the surfaces of the composite material and of the sheetlike structures produced from it.
  • the source pressure is over the
  • the microparticles consist of the very easily and completely water-soluble polyanionic hyaluronic acid or, in another embodiment, of pectic acid, xanthan and or their salts and / or their derivatives.
  • Derivatives are the uronides of hyaluronic acid or pectic acid or the sulfated polysaccharides or their salts.
  • the uronides are obtained in a manner known per se by the partial degradation of the hyaluronic acid via a ⁇ -elimination with the enzyme hyaluronate lyase or the pectic acid with the enzyme pectate lyase.
  • An advantage of them is that, owing to the double bonds, they have very intensive radical-trapping and angiogenic properties with limited swellability. They promote cell growth and the healing process in a similar way to natural hyaluronic acid. They will be lighter than the high molecular hyaluronic acid from the matrix surface through water with the formation of pores with pore sizes from 1 ⁇ m to 1000 ⁇ m.
  • Sulphated polyelectrolytic polymers preferably sulphated hyaluronic acid with degrees of sulphation between 0.1 to 3.9, preferably 1 to 3, reduce the adhesive behavior of blood and animal cells on the material surface due to their presence. Their presence as a minor component can therefore regulate the adhesion of the cells. Their presence according to the invention in foils which are used for separating organs after operations with the aim of avoiding adhesions or for sealing textile vascular implants is particularly advantageous.
  • the microparticles are produced from polyelectrolytes, selected from the alkaline earth metal salts of alginic acid which are less soluble in water but swellable in water, the polycationic chitosan which is only soluble under slightly acidic pH conditions, or the sparingly soluble polyelectrolyte complexes of chitosan with the polyanionic biopolymers with hyaluronic acid.
  • polyelectrolytes selected from the alkaline earth metal salts of alginic acid which are less soluble in water but swellable in water, the polycationic chitosan which is only soluble under slightly acidic pH conditions, or the sparingly soluble polyelectrolyte complexes of chitosan with the polyanionic biopolymers with hyaluronic acid.
  • the water-soluble polyanionic component is bound to the biocompatible composite material in a form which is difficult to dissolve in water. Coating with a chitosan-containing solution reduces
  • the pore-forming, water-soluble particles are released from the matrix when liquid enters and leave pores up to a size of 1 mm.
  • the particles consist of crystals or aggregates of substances that are present in the culture media of cell culture, such as glucose, sucrose, L-amino acids, sodium bicarbonate, sodium or potassium phosphates, magnesium sulfate, potassium chloride or common salt.
  • the diameter of the pore-forming particles determines the pore diameter. Pores can be present in the material as open, closed or continuous cavities. Although it was known that pores can be produced by leaching sodium chloride crystals with water in cast films.
  • a new aspect of the invention is that leaching takes place only during the use of the cast films in an aqueous environment, such as is present in the human body or in a cell culture.
  • Another new feature is that particles from other nutrient media are used to form pores through leaching. This avoids the problem that an independent leaching step would lead to undesired losses of the polyelectrolytic polymers.
  • the composition of the culture medium must take into account the additional constituents added by leaching.
  • a water-soluble plasticizer preferably an ester of citric acid, can also be added as an auxiliary during the production of the material. The plasticizer prevents embrittlement of the material and increases flexibility. It is advantageous that the water-soluble plasticizers of the citric acid ester type can be easily removed by washing.
  • the biocompatible composite material is varied in an application-specific manner by the presence of further constituents, such as auxiliaries, active ingredients or pharmaceuticals, or by special designs of the manufacturing process.
  • auxiliaries such as auxiliaries, active ingredients or pharmaceuticals
  • antibiotics or anti-inflammatory or anticoagulant agents can be added.
  • the hyaluronic acid uronides and the sulfated polysaccharides, for example of the sulfated hyaluronic acid type have such active ingredient properties.
  • the biocompatible composite material would have such surprisingly good physiological properties and biocompatibility. It has been found to be very advantageous that the microdisperse polyelectrolytic particles produce a biocompatible hydrophilic outer and inner surface of the materials.
  • the use of hyaluronic acid, its salts, its polyelectrolyte complex with chitosan and its uronides as polyelectrolytic particles according to the invention is particularly advantageous. In native form, these compounds have outstanding wound healing, angiogenic and radical-trapping properties.
  • biocompatible composite material activates the macrophages, which release growth factors which promote cell growth.
  • the preferably used hyaluronic acid enclosed as microdisperse particles remains, although water-soluble, partly in the matrix of the material when water enters. It swells and regulates further water access. The swelling makes the cast films very flexible. Irregularly shaped wound surfaces are largely covered by the adherent surface. The adherence of adherent cells is promoted for the same reason.
  • the environment around the pores formed by suspension of aqueous solutions of polyelectrolytes and their inner walls proved to be particularly suitable for the growth and growth of keratinocytes.
  • the suspension containing dissolved polyalkanoate esters, microparticles, pore-forming particles and other constituents is suspended in an organic solvent such as chloroform or methylene chloride.
  • the suspension is applied to a mold as a casting solution and the film is produced by evaporation of the organic solvent.
  • the shape is a flat surface e.g. a glass plate or a carrier material made of plastic, in another a textile knitted fabric, for example in the form of a vascular implant, or it has an irregularly shaped surface.
  • Flat structures or membranes according to the invention have a thickness of 1 ⁇ m to 500 ⁇ m, preferably 10 ⁇ m to 20 ⁇ m, depending on the application.
  • They can have continuous pores with opening widths that are approximately between 10 ⁇ m and 1000 ⁇ m or arrangements of slots with lengths between 0.5 mm and 10 mm. The latter are made by cutting with cutting tools.
  • Other macropores can be produced in a known manner by piercing with piercing tools or using laser beams. The macro pores make the material permeable to the cells cultivated on the film surface. The growth of the wound surface through divisible skin cells is made possible. In addition, the wound exudate can flow off when the cast films are used as a wound covering.
  • a micro- to macroporous structure is also produced according to the invention by producing a highly viscous suspension according to the invention with a content of at least 40 g / l polyhydroxyalkanoate and suspending an aqueous solution of the polyelectrolytes in this solution, which may be mixed with an amount of ethanol beforehand where the polyelectrolyte is just not yet failing.
  • aqueous solution of the polyelectrolytes in this solution which may be mixed with an amount of ethanol beforehand where the polyelectrolyte is just not yet failing.
  • evaporation for example of chloroform
  • continuous micropores as well as macropores are formed in the cast films, depending on the size of the suspended particles.
  • the syrup-like, highly viscous state of the suspension prevents the organic and the suspended aqueous phase from segregating during the pouring process.
  • a microporous to macroporous structure is preformed by the polyelectrolytic microarticles and / or by the pore-forming nutrient medium components.
  • the particles are washed out or dissolve after implantation in the tissue fluid or during cell cultivation in the medium of cell cultivation with the formation of cavities.
  • Other fabrics according to the invention are formed by dipping molds into the suspension of the polyelectrolytic microparticle and the polyalkanoate ester in an organic solvent and then evaporating the solvent and, if necessary, repeating the procedure.
  • the fabric can then be detached from the shape or it can remain on the form.
  • the material remains as a thin film on the surface or between the meshes of the textile vascular implant.
  • the culture of cells on and inside the material according to the invention takes place with cells of different origins such as, for example, epithelial cells, endothelial cells, Langerhans islet cells, liver cells, skin cells, actively dividing cells of the hair root and generation cells.
  • the material is overlaid with a cell cultivation medium known per se and, if necessary, moved slowly. After about 6 hours, the pore-forming particles are washed out and the culture is inoculated with adherent cells. After waxing, the materials are removed and implanted under aseptic conditions or placed on wound surfaces.
  • Fine cleaning of the 3-PHB 100 g of 3-poly-ß-hydroxybutyrate (3-PHB) with a molecular weight of 1J00 kD are mixed with 50 g of silica gel 1020 P (chemical plant Bad Köstritz) with 5 l of freshly distilled chloroform and left under for 1 hour Warm to temperatures in the range of 62 ° C using a reflux condenser.
  • the silica gel was previously heated to a temperature of 180 ° C. for 10 hours in order to remove pyrogens in a drying oven.
  • the suspension is filtered by filtration at temperatures of about 50 ° C - 60 ° C through a filter with a pore size of 10 ⁇ m - 25 ⁇ m (Seitz T 1500).
  • the filtrate is mixed with 100 ml of chloroform and again with 10 g of silica gel 1020 P (chemical plant Bad Köstritz) and stirred for 1 hour while heating to temperatures of about 60 ° C.
  • the suspension is then filtered through a filter with a pore size of 3 ⁇ m - 8 ⁇ m (Seitz T 500) at temperatures of 50 ° C - 60 ° C.
  • the 3-PHB is then precipitated by pouring it into 80% aqueous methanol.
  • the 3-PHB is washed with ethanol and then dried at 40 ° C. in a vacuum drying cabinet.
  • a purified 3-PHB is obtained which is used to produce the composite materials in accordance with the examples below.
  • Example 2 60 g of 3-PHB prepared according to Example 1 is dissolved in one liter of freshly distilled chloroform. 4 g of an aqueous solution containing 20 g / l of sodium salt of hyaluronic acid with a molar mass in the range from 1,300 to 1,700 kD and 3.2 ml of absolute ethanol are added to this solution and the solution is stirred vigorously until the droplets of the aqueous phase are homogeneously suspended are. The suspension is spread with a squeegee on a glass plate. The distance of the Squeegee edge to the glass surface (gap width) is 500 ⁇ m.
  • films After drying the coated glass plates under a hood to remove the chloroform and standing in the air under clean room conditions, the film is swollen with a little water for injection and then lifted off its base. After drying the film in air at 56 ° C and removing the water, films are formed which are approximately 20 ⁇ m thick and contain pores in the size range from 10 ⁇ m to 100 ⁇ m.
  • Casting a coarse-pore film A film is produced as in Example 2, but the addition of ethanol is omitted. Pores with pore sizes between 20 ⁇ m to 500 ⁇ m are formed.
  • the starting materials are produced as in Example 2.
  • the casting solution is applied to a band-shaped film made of polyterephthalate and a width of 20 cm, which moves uniformly at a speed of 2 m / min under the stationary doctor blade, with a gap width of 300 ⁇ m. This is followed by drying under clean room conditions at 56 ° C to 58 ° C.
  • Example 7 Use of hyaluronic acid uronide in porous films:
  • Example 3 the sodium salt of hyaluronic acid uronide with a molecular weight of 20 kD is used instead of the sodium salt of hyaluronic acid. After pouring and drying according to Example 2, a large-pore film is formed. In a parallel experiment, L-phenylalanine is added as described in Example 6. Many small pores are formed.
  • Example 4 cast at a doctor blade spacing of 250 microns.
  • the film thickness of the films obtained after drying is 8 ⁇ m.
  • 3-PHB film according to Example 4 is cast on a plastic tape made of polyterephthalate.
  • the result is 3-PHB composite material films with a layer thickness of approximately 15 ⁇ m, which adheres to the plastic tape.
  • the film lying on the plastic tape is activated by passing the tape through a corona discharge.
  • the film is then sprayed with an aqueous 1% sodium uronide solution.
  • the molar mass of the uronide is 15 kD.
  • the amount of this solution applied is 1 ml to 3 ml per 100 cm 2 .
  • a chloroform solution containing 45 g / l of 3-PHB and solid hyaluronic acid particles corresponding to Example 4 is mixed with 100 ⁇ l of citric acid triethyl ester.
  • a film is cast in accordance with Example 3. The result is a stretchable film with an average film thickness of 12 ⁇ m.
  • Example 5 In a film production in accordance with Example 5, an additional 200 mg of saline particles with a particle diameter of approximately 30 ⁇ m are suspended. After production of the films according to Example 5, films are formed which have no pores. After the films have been introduced into a submerged cell culture medium, pores with a diameter of approximately 25 ⁇ m are formed by removing the saline particles and the hyaluronate particles.
  • Foils containing hyaluronate and chitosan Foils containing hyaluronate and chitosan:
  • chitosan 0.01 g is suspended in 10 ml of distilled water and concentrated acetic acid is added dropwise with stirring until the chitosan has dissolved.
  • Solution are given 5 ml of a solution containing 2 g / l sodium hyaluronate.
  • the precipitated gel-shaped polyelectrolyte complex consisting of chitosan and hyaluronic acid, is filtered off and washed with water.
  • the gel is pressed through a sieve with a pore size of 50 ⁇ m and the resulting gel particles are then suspended in a 3 PHB / chloroform solution.
  • a film according to Example 4 is produced with the solution.
  • a chitosan solution is sprayed onto a film strip produced in accordance with Example 4 in a second pass.
  • 0.05 g of chitosan is suspended in 1 liter of distilled water and concentrated acetic acid is added dropwise until the chitosan has dissolved.
  • the solution is sprayed onto the film strip using a spray device.
  • the spray density is in the range of about 20 spray drops per mm 2 with an average drop volume of 0.01 ⁇ l.
  • the film is then dried at 58 ° C.
  • chitosan 0.01 g is suspended in 5 ml of distilled water and, while stirring, concentrated acetic acid is added dropwise until the chitosan has dissolved.
  • This solution is suspended in 1 l of a 3-PHB / chloroform solution according to Example 2 and it is Cast foils. After the films have dried, a solution of 0.05 g / l hyaluronic acid is sprayed onto the film in the form of a thin layer of approximately 2 ⁇ m to 5 ⁇ m. The sprayed foils are then dried at room temperature.
  • a completely clear 3-PHB / chloroform solution prepared according to Example 1 which contains 60 g / l of 3-PHB, 4 g of an aqueous solution containing 20 g / l of sodium salt of hyaluronic acid with a molecular weight in the range of Contains 1,300 to 1J00 kD and 1 g of an acetic acid solution of 5 g / l chitosan and 3.2 ml of absolute ethanol and the solution stirred vigorously until the droplets of the aqueous phase are homogeneously suspended.
  • the chitosan solution is prepared by combining chitosan and water with the addition of just as much concentrated acetic acid in which the chitosan is completely dissolved.
  • the suspension is spread with a squeegee on a glass plate.
  • the distance from the squeegee edge to the glass surface is 500 ⁇ m.
  • a textile vascular implant made of plastic (Dacron) with an inner diameter of 0.5 cm and a length of 5 cm is immersed in a solution which is produced in accordance with Example 2. After excess solution has dripped off, the vascular implant is rotated in a horizontal position at a speed of rotation of 30 to 120 rpm in order to avoid the formation of drops. After the seal has set, a drying process of several days takes place in a clean room at temperatures from 40 ° C to 50 ° C. The immersion process is repeated for vessels with an inner diameter greater than 0.5 cm.
  • the medium DMEM (IBCO BRL, Cat. No. 41966-029) with the addition of 10 ml / i penicillin / streptomycin solution (GIBCO BRL., Cat. No. 043-05-140H) and 10 % fetal calf serum.
  • the keratinocyte cell line HaCaT is defined in multishells (NUNC, cat. No. 143982) (10 x 10 5 cells) sown in 0.8 ml DMEM per well. In the recess is a circular piece of the film to be examined from the biocompatible composite material or no film is inserted (control).
  • the number of adherent cells is determined after incubation for 72 h at 37 ° C., 5% CO 2 and 95% relative atmospheric humidity, then removing the medium, washing with PBS / EDTA solution, trypsinization with 0.02 ml 0, 25% trypsin solution by electronic cytoanalysis.
  • the average growth of the samples with the cells is between 70% and 95% compared to the control.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Composite Materials (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un matériau composite biocompatible et résorbable ainsi que sa fabrication. Ce matériau composite est constitué d'une matrice de polyhydroxyalcanoates contenant des microparticules de biopolymères polyélectrolytiques et/ou une composition polysaccharides de complexes polyélectrolytiques, lesquelles microparticules sont capables de gonfler dans l'eau. Ce matériau composite peut être utilisé de préférence comme structure plane, mais aussi comme biomatériau plus compact. En tant que structure plane, ce matériau présente des micropores et macropores et/ou des fissures formées de manière spécifiques à l'application. Ce matériau composite peut par exemple être utilisé pour recouvrir des plaies de grande dimension, cultiver des cellules humaines et animales adhésives et appliquer ces cellules sur des plaies, combler des dysfonctionnements organiques, imperméabiliser des prothèses vasculaires textiles à implanter, comme barrière pour la séparation d'organes afin d'empêcher des malformations et comme matériau de transplantation.
PCT/DE2001/003910 2000-10-11 2001-10-11 Materiau composite biocompatible pour applications medicales WO2002030480A1 (fr)

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AU2002218134A AU2002218134A1 (en) 2000-10-11 2001-10-11 Biocompatible composite material for medical applications

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DE10050870A DE10050870A1 (de) 2000-10-11 2000-10-11 Biokompatibles Verbundmaterial für medizinische Anwendungen

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WO2003043611A1 (fr) * 2001-11-21 2003-05-30 Lts Lohmann Therapie-Systeme Ag Dispositif contenant des microfibres pour la liberation controlee de substances
EP1547625A1 (fr) * 2003-12-23 2005-06-29 The Procter & Gamble Company Matériaux superabsorbants ayant des particules à base de multicomposants
EP1702064A2 (fr) * 2003-12-01 2006-09-20 Tissue Engineering Consultants, Inc. Composition biometrique renforcee par un complexe polyelectrolytique d'acide hyaluronique et de chitosane
EP1859792A1 (fr) * 2006-05-24 2007-11-28 Advanced in Vitro Cell Technologies, S.L. Nanoparticules de chitosan et de hyaluronan pour l'administration de principes actifs
WO2007135164A1 (fr) * 2006-05-24 2007-11-29 Advanced In Vitro Cell Technologies, S.A. Nanoparticules de chitosane et de hyaluronane pour l'administration de molécules actives
US7910124B2 (en) 2004-02-06 2011-03-22 Georgia Tech Research Corporation Load bearing biocompatible device
US8002830B2 (en) 2004-02-06 2011-08-23 Georgia Tech Research Corporation Surface directed cellular attachment
US9155543B2 (en) 2011-05-26 2015-10-13 Cartiva, Inc. Tapered joint implant and related tools
US9907663B2 (en) 2015-03-31 2018-03-06 Cartiva, Inc. Hydrogel implants with porous materials and methods
US9981067B2 (en) 2013-09-30 2018-05-29 Bioactive Regenerative Therapeutics, Inc. Biomimetic hybrid gel compositions and methods of use
US10350072B2 (en) 2012-05-24 2019-07-16 Cartiva, Inc. Tooling for creating tapered opening in tissue and related methods
US10758374B2 (en) 2015-03-31 2020-09-01 Cartiva, Inc. Carpometacarpal (CMC) implants and methods

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DE10212553A1 (de) * 2002-03-16 2003-09-25 Knoell Hans Forschung Ev Verwendung einer Formulierung zur in situ Biodegradation von Wundabdeckungen
DE102004002990A1 (de) * 2004-01-21 2005-08-18 Robert Dr. Simmoteit Material und Verfahren zum Stoffaustausch und Stofftransfer
DE102004047115B9 (de) * 2004-09-27 2007-10-31 Universität Hamburg Verfahren zur Herstellung einer Wundauflage

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Cited By (31)

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Publication number Priority date Publication date Assignee Title
WO2003043611A1 (fr) * 2001-11-21 2003-05-30 Lts Lohmann Therapie-Systeme Ag Dispositif contenant des microfibres pour la liberation controlee de substances
EP1702064A2 (fr) * 2003-12-01 2006-09-20 Tissue Engineering Consultants, Inc. Composition biometrique renforcee par un complexe polyelectrolytique d'acide hyaluronique et de chitosane
US8137696B2 (en) 2003-12-01 2012-03-20 Tissue Engineering Consultants, Inc. Biomimetic composition reinforced by a polyelectrolytic complex of hyaluronic acid and chitosan
EP1702064A4 (fr) * 2003-12-01 2008-05-07 Tissue Engineering Consultants Composition biometrique renforcee par un complexe polyelectrolytique d'acide hyaluronique et de chitosane
US7524514B2 (en) 2003-12-01 2009-04-28 Tissue Engineering Consultants, Inc. Biomimetic composition reinforced by a polyelectrolytic complex of hyaluronic acid and chitosan
US7537832B2 (en) 2003-12-23 2009-05-26 The Procter & Gamble Company Superabsorbent material and absorbent articles containing said material
EP1547625A1 (fr) * 2003-12-23 2005-06-29 The Procter & Gamble Company Matériaux superabsorbants ayant des particules à base de multicomposants
WO2005063310A1 (fr) * 2003-12-23 2005-07-14 The Procter & Gamble Company Matiere superabsorbante comprenant des particules a composants multiples
US8895073B2 (en) 2004-02-06 2014-11-25 Georgia Tech Research Corporation Hydrogel implant with superficial pores
US7910124B2 (en) 2004-02-06 2011-03-22 Georgia Tech Research Corporation Load bearing biocompatible device
US8002830B2 (en) 2004-02-06 2011-08-23 Georgia Tech Research Corporation Surface directed cellular attachment
US8486436B2 (en) 2004-02-06 2013-07-16 Georgia Tech Research Corporation Articular joint implant
WO2007135164A1 (fr) * 2006-05-24 2007-11-29 Advanced In Vitro Cell Technologies, S.A. Nanoparticules de chitosane et de hyaluronane pour l'administration de molécules actives
EP1859792A1 (fr) * 2006-05-24 2007-11-28 Advanced in Vitro Cell Technologies, S.L. Nanoparticules de chitosan et de hyaluronan pour l'administration de principes actifs
JP2009537604A (ja) * 2006-05-24 2009-10-29 アドヴァンスド イン ヴィトロ セル テクノロジーズ ソシエダッド アノニマ 活性分子の投与のためのキトサンおよびヒアルロナンのナノ粒子
US10376368B2 (en) 2011-05-26 2019-08-13 Cartiva, Inc. Devices and methods for creating wedge-shaped recesses
US9155543B2 (en) 2011-05-26 2015-10-13 Cartiva, Inc. Tapered joint implant and related tools
US9526632B2 (en) 2011-05-26 2016-12-27 Cartiva, Inc. Methods of repairing a joint using a wedge-shaped implant
US11944545B2 (en) 2011-05-26 2024-04-02 Cartiva, Inc. Implant introducer
US11278411B2 (en) 2011-05-26 2022-03-22 Cartiva, Inc. Devices and methods for creating wedge-shaped recesses
US10350072B2 (en) 2012-05-24 2019-07-16 Cartiva, Inc. Tooling for creating tapered opening in tissue and related methods
US10744230B2 (en) 2013-09-30 2020-08-18 Bioactive Regenerative Therapeutics, Inc. Biomimetic hybrid gel compositions and methods of use
US9981067B2 (en) 2013-09-30 2018-05-29 Bioactive Regenerative Therapeutics, Inc. Biomimetic hybrid gel compositions and methods of use
US10758374B2 (en) 2015-03-31 2020-09-01 Cartiva, Inc. Carpometacarpal (CMC) implants and methods
US10973644B2 (en) 2015-03-31 2021-04-13 Cartiva, Inc. Hydrogel implants with porous materials and methods
US11717411B2 (en) 2015-03-31 2023-08-08 Cartiva, Inc. Hydrogel implants with porous materials and methods
US11839552B2 (en) 2015-03-31 2023-12-12 Cartiva, Inc. Carpometacarpal (CMC) implants and methods
US9907663B2 (en) 2015-03-31 2018-03-06 Cartiva, Inc. Hydrogel implants with porous materials and methods
US10952858B2 (en) 2015-04-14 2021-03-23 Cartiva, Inc. Tooling for creating tapered opening in tissue and related methods
US11020231B2 (en) 2015-04-14 2021-06-01 Cartiva, Inc. Tooling for creating tapered opening in tissue and related methods
US11701231B2 (en) 2015-04-14 2023-07-18 Cartiva, Inc. Tooling for creating tapered opening in tissue and related methods

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