EP3544644A1 - Matériau pour implant osseux et procédé de fabrication d'un tel matériau - Google Patents

Matériau pour implant osseux et procédé de fabrication d'un tel matériau

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Publication number
EP3544644A1
EP3544644A1 EP17811852.7A EP17811852A EP3544644A1 EP 3544644 A1 EP3544644 A1 EP 3544644A1 EP 17811852 A EP17811852 A EP 17811852A EP 3544644 A1 EP3544644 A1 EP 3544644A1
Authority
EP
European Patent Office
Prior art keywords
linker
polysaccharide
peek
bone
acid
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP17811852.7A
Other languages
German (de)
English (en)
Inventor
Michael GIESSL
Helmut COELFEN
Dietmar Schaffarczyk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Stimos GmbH
Original Assignee
Stimos GmbH
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.)
Filing date
Publication date
Priority claimed from DE102016122837.0A external-priority patent/DE102016122837A1/de
Application filed by Stimos GmbH filed Critical Stimos GmbH
Publication of EP3544644A1 publication Critical patent/EP3544644A1/fr
Withdrawn legal-status Critical Current

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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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/32—Phosphorus-containing materials, e.g. apatite
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/04—Coatings containing a composite material such as inorganic/organic, i.e. material comprising different phases
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to a material for a bone chenimplantat comprising a support structure having an upper ⁇ surface that comprises at least one biocompatible material, egg ⁇ ne covalently bound to this surface matrix, and intercalated in the matrix of calcium phosphate.
  • the present invention further relates to a method for producing the material according to the invention, a bone implant to the material of the invention is applied, as well as its Ver ⁇ use as bone implant material.
  • the organic components in the bone are made up of 95% collagen, and from 5% proteoglycans and other haftvermit ⁇ telnden glycoproteins.
  • the mineral portion of bone is composed almost entirely of calcium phosphate in the modifi cation of ⁇ Hydroxylapat it.
  • the hard material properties of hydroxyapatite combine with the elastic properties of the organic components to make the bone a very versatile composite material.
  • cytokines and growth factors released spree- re to recruit white blood cells to Wun ⁇ de.
  • monocytes mononuclear cells such as monocytes recruited.
  • Mononuclear cells differentiate into macrophages and attach themselves to the surface of the implant.
  • macro phages are responsible for the wound by bacteria, cell debris and other impurities ⁇ via phagocytosis rei ⁇ Nigen.
  • the implant material is also perceived by the body as a foreign body. However, since the implant is substantially larger than the macrophages, they can be the material do not phagocytize.
  • the macrophages fuse and form multinucleated giant cells in order to enclose the foreign body.
  • the macrophages also provide for the recruitment of other cells, such as fibroblasts, which deposit fibrous tissue on the surface of the implant.
  • DIE ser consists of bone precursor cells and fibroblasts, wel ⁇ che in a disordered matrix of non-collagenous proteins and collagen are. This matrix is gradually formed by said cells as a first response and is constructive ⁇ turally similar to the woven bone.
  • the soft callus is finally gradually rebuilt by osteoblasts into ordered lamellar bone structure. Osteoblasts secrete type I collagen, calcium phosphate and calcium carbonate with an arbitrary, random orientation.
  • the remodeling phase overlaps with the formation of the hard callus. This is achieved by resorption of disordered bone structures by osteoclasts and subsequent formation of ordered bone structures by osteoblasts.
  • Po ⁇ tentielle bone materials should rosionsbe pretechnik a reliable strength, high resistance, high abrasion resistance, corrosion, therefore, and have a similar bone Stiff ⁇ ness. The latter plays a major role in the context of so-called "stress shielding".
  • the bone ⁇ chen is a dynamic system which off depending on the mechanical stress or is established. Now, a Knochenim- plantatmaterial used, which has a higher compared to bone ⁇ substance stiffness, this takes a large part of the mechanical load, thus the surrounding bone is gradually reduced.
  • a potential implant material should either be as bioinert or bioactive as possible.
  • the implant is therefore biocompatible and builds at best a positive connection with the bone substance (Contact osteogenesis).
  • Contact osteogenesis the bone substance
  • Implants made of Ti ⁇ tan, aluminum, cobalt, chromium and polyetheretherketone (PEEK) are among this type of material.
  • bioactive material promotes rapid implantation of the implant into the surrounding tissue, thus ensuring rapid and long-lasting fixation of the implant in the body.
  • This effect is referred to as so-called "osseointegrate ion". Therefore, bioactive materials often show osteoconductive and osteoinductive properties and are usually highly hydrophilic. Often such material ⁇ lien be absorbed by the body. Hydroxylapatite, tricalcium phosphate and some bioglasses are among the bioactive materials. Bi ⁇ oaktive materials can cause in the body, in the worst case, an immune response.
  • both the low adhesion of the calcium phosphates to the implant is disadvantageous, and also their cohesive cohesion within the individual calcium phosphate layers.
  • these methods should be generated in order to favor the healing of the bone material in the bone mög ⁇ lichst like structure on the surface.
  • the bone itself is a highly hierarchical composite material consisting of a matrix and a mineral phase.
  • gelatin is usually produced by physical and chemical degradation or thermal denaturation of native collagen .
  • gelatin is water-soluble at a physiological pH and melts at a sol-gel transition temperature of 25 to 30 ° C. After cooling arise transparent gels.
  • the prior art is just ⁇ if the non-covalent deposition of gelatin on top ⁇ surfaces of arterial implant materials reported.
  • gelatin was covalently coupled to PEEK and mineralized with calcium phosphate Product Calciump-, so as to form a bone-like layer to very good proliferation of osteoblasts guide ⁇ te.
  • the problem with gelatin-based coatings is that gelatine is an animal product that requires Class III certification.
  • an object of the present OF INVENTION ⁇ dung relates to a material for a bone implant comprising:
  • the matrix has at least one polysaccharide.
  • material for bone implants and “Knochenim ⁇ plantatmaterial” are used interchangeably herein.
  • the OF INVENTION ⁇ dung-date material for bone implants has bioactive egg on properties.
  • bioactive be ⁇ features to enable rapid growth into the surrounding tissue and to ensure fast and langanhal ⁇ tend fixation of the implant in the body the property of the inventive material for bone implants. This property results from the technical features defined in sub-items (a) to (c) above in combination with the characterizing part.
  • polysaccharides are not discussed in connection with the biomim ⁇ mineralization of calcium phosphate - if more than ⁇ only as glycoproteins. But polysaccharides play a role in the biomineralization of calcium carbonate (egg shells - keratan sulfate, coccolith exoskeletons etc.), but even there they are very little studied compared to Protei ⁇ nen because polysaccharides are notoriously difficult to characterize. The inventive approach can therefore be regarded as a departure from most ⁇ th approaches. It is therefore an obvious idea not to think of polysaccharides in building a bone-like bioin ⁇ spir Being coating for an implant.
  • a material layer is to be understood to mean a support structure Minim ⁇ least, which is composed of the biocompatible material and which rix with the Mat- be connected or can be covalently linked.
  • Support structure may, for example, an outermost layer of a completely made of the biocompatible material, wherein ⁇ play shaping, its basic structure of the implant. Or it can be applied to a basic structure made of another material, such as the biocompatible material.
  • biokompati ⁇ bel be understood as the property of a material or substance to be used in vivo and in this case a few to have or to kei ⁇ ne negative impact on the patient or the healing process to be used without sequelae ,
  • a matrix is to be understood here as meaning a structure which has as its main constituent a polysaccharide in which calcium phosphate is incorporated.
  • the polysaccharide can be any polysaccharide which can be used by the person skilled in the art. If the polysaccharide is an animal polysaccharide, a substance can be used whose properties are well known and tested.
  • the Polysac ⁇ CharID is a vegetable polysaccharide, thereby providing a vegetable material may be used, of medically safe is.
  • Synthetic - - Spare ⁇ materials for polysaccharides are understood as beispielswei- se polymers of polyacrylic acid or vinyl and acrylic monomers (possible species see below) under polysaccharides are here also.
  • all of the features mentioned on the polysaccharide - chemical, material or a method, a use or a bone implant - suitably - in any combination also apply to the synthetic substitute (s).
  • the matrix comprises at least one ⁇ polymers of polyacrylic acid and / or a polymer of vinyl and acrylic monomers instead of the polysaccharide.
  • the polysaccharide may be, for example, alginic acid, alginate, hyaluronic acid, hyaluronate, pectin, carrageenan, agarose, Anky ⁇ loose and chitosan. Any other glycosaminoglycan, such as heparin / heparan sulfate, chondroit insulfate / dermatan sulfate or keratan sulfate, would also be possible. Also conceivable are hemicelluloses, such as xylans or mannans after a carboxyfunctionalization, or also xanthan, gellan, fucogalactan or welan gum.
  • the polysaccharide is from ⁇ selected from a group consisting of alginic acid, alginate, hyaluronic acid, hyaluronate, pectin, carrageenan, agarose, Anky ⁇ loose and chitosan. This can be many different substances are used, which can be selected individually, due to their special properties ⁇ .
  • Hyaluronic Acid is a linear polysaccharide composed of disaccharide repeating units. These are composed of D-glucuronic acid and N-acetyl-glucosamine, which are linked via ⁇ -1,4 and ⁇ -1,3 glycosidic bonds (see below).
  • the carboxyl groups of Hy ⁇ aluronsaure are largely present as the sodium salt, it is thus negatively charged and immobilized a variety of Wassermo ⁇ molecules, even at very low concentrations, an aqueous solution is therefore very viscous.
  • Hya is used in many ways in the medical and healthcare industry. Because hyaluronic acid is considered ⁇ widely biocompatible and safe, there are very many applications. This also makes them very inte ⁇ esting as the starting material for the surface coating of bone implants.
  • hyaluronic acid was extracted mainly from chicken combs that are produced as waste in food production. Meanwhile, however, the production is carried out by culturing genetically engineered biotechnologically streptococcus bacteria, thereby reducing the risk for the contamina tion ⁇ deleted with animal pathogens.
  • Alginic acid is a copolymer of the two uronic acids D-mannuronic acid (M) and L-guluronic acid (G). Alginic acid from plants or algae are obtained wes ⁇ half their composition and sequence distribution twitches ⁇ purity strongly depends on the origin of the plant / algae and their species. The G and M are each linked via beta-1,4 glycosi ⁇ sized bonds. The good gelling properties of alginic acid are due to the G blocks, which com- plex the calcium ions. Xieren. Since alginic acid comes from natural sources, it must be ensured that potential contaminants such as heavy metals, endotoxins, proteins, etc. have been removed, otherwise immune reactions can occur. Provided that it has been sufficiently purified, alginic acid, like hyaluronic acid, does not cause an immune or inflammatory reaction in the body, so it has good biocompatibility.
  • alginic acid is not degradable in the human body as there is no alginase. Because of the good biocompatibility alginic acid is used in numerous bi ⁇ o committeeischen applications, for example in wound ⁇ pads and comes when RGD peptide-modified to be used in Be ⁇ costume as bone implant material. If alginic acid is used in combination with hydroxyapatite, the formation of bone tissue can be additionally stimulated.
  • the matrix has a more three-dimensional structure that is similar to the target bone structure, making the Mineralisie ⁇ tion can be facilitated.
  • Chitosan a linear polysaccharide-based biopolymer.
  • Chitosan may also utilize the material's hemostatic efficacy and antimicrobial properties.
  • Chitosan are the following material properties also supplied ⁇ addressed non-allergenic, non-toxic, wound-healing, antibak ⁇ -bacterial, hemostatic, bacteriostatic, fungicidal action (biodegradable) and anti-microbial.
  • the invention is also directed to chitosan as al ⁇ lenberg substance without a combination with the above compounds or compounds ⁇ .
  • the invention is also directed to an inventive use of chitosan as a material - medically and / or non-implantable and / or with and without body contact.
  • the He ⁇ invention further directed to a novel use of the chitosan as a component of a personal care product, into ⁇ particular a tooth brush (toothbrush head), a comb, a hair brush, a nail brush, a nail file, etc.
  • the invention is also directed to an oF iNVENTION ⁇ -making proper use of chitosan as a component of a health product, particularly a sleeping mask, a beauty plaster etc.
  • the invention is further directed to a novel use of the chitosan as a component of a medical device, in particular for wound ⁇ supply (binding, plasters, swabs , Cooling compress etc.).
  • the structure of the coating can be adjusted specifically, since, for example, linear can be combined with branched polysaccharides.
  • branched amylopectin from vegetable starch can be combined with the linear amylose. Chemically, both molecules are identical but not structural.
  • a promising pair for chemically different Po ⁇ lysaccharide the neutral amylose example would be to couple with the negatively charged alginate, which 2+ ions can be cross-linked through addition of Ca additionally. About this crosslinking washing and applying the next alginate (Layer by Layer Assembly, LBL) can then subsequently also further layers of alginate are connected via simple Imoniagnie ⁇ tion of the layer with Ca 2+. An extreme combination would be the negative alginic acid with the positive chitosan. These ionically stabilized "layer by layer assemblies" can be covalently linked by suitable crosslinking chemistry (by means of EDC or the like). In between, all combinations of polysaccharides are continuously available via a common chemical bond via ester bonds.
  • the polysaccharide is a chemically modified polysaccharide.
  • che ⁇ mixed mean modified to artificial, laboratory chemical modification of a sugar of the polysaccharide were made, for example at a free group, for example hydroxyl, aldehyde or acid group on the polysaccharide.
  • a ⁇ set range can be extended.
  • inactive groups can be "converted" into active groups or it can be targeted An undesirable property can be eliminated.
  • HMDA and ADH are both diamide linkers.
  • the material according to the invention for bone chenimplantate to solid materials or bodies are applied, which are used as bone implant USAGE ⁇ dung. These bodies may have any desired or required three-dimensional shape.
  • the whole surface of the invention comprises ma- terials for bone implants in the preceding subsection
  • Suitable Ma ⁇ terialien to which the inventive material can be introduced ⁇ can in this case from terialien known in the prior art ceramic materials, metals, polymers, Kompositma- or combinations thereof. This would, for example, as metals: titanium / stainless steel, as miken Kera ⁇ : Zircon (dioxide) as a polymer: polyetherketone (PEK) and total PEK family, but especially: polyether ether ketone (PEEK), polyether ketone ketone (PEKK) , Polyether ketone ether ketone ketone (PEKEKK); Carbon Fiber Reinforced PEEK (CFR
  • PEEK polyethylene ⁇
  • UHMWPE Ultra-High-Molecular-Weight polyethylene
  • PMMA polymethyl methacrylate
  • PET polyethylene terephthalate
  • PA polyamides
  • PLA polylactides
  • PPSU polyphenylene sulfone
  • PEEK polyetheretherketone
  • thermoplastic high-performance plastic is a very widespread thermoplastic high-performance plastic.
  • the semi-crystalline plastic is we ⁇ gen its high solvent resistance, the high
  • PEEK has been available in implantable quality on the market. Since then, the market share of PEEK has greatly increased as the ⁇ plantatsmaterial.
  • PEEK is widely used in medical technology as a bone substitute material and implant, for example as a fusion cage for spinal fusion in intervertebral disc injuries. Since PEEK is permeable to X-ray radiation and does not interact with magnetic fields, the patient can easily be observed with an imaging procedure after an operation in order to follow the healing process in the affected area.
  • the good mechanical properties ⁇ properties of PEEK which are very similar to those of cortical bone (cortical bone), qualify PEEK as a well-suited
  • PEEK is one of the materials that almost completely bioinert behave, so do not enter into any specific interaction with the body. PEEK is neither repelled nor well absorbed by the body integrated into the bone, it is therefore ideally to a good contact of the bone with the implant. Partial tissue encapsulation occurs, which reduces mechanical stability and may result in loss of the implant.
  • some methods have been developed to achieve bioactivity of the material, such as coating with calcium phosphate and also adding hydroxylapatite particles to the polymer. Other methods of surface modification of PEEK are possible and are for example as described in the following sections.
  • the polymer substrate may be coated with a functional poly ⁇ mer.
  • a functional poly ⁇ mer Here is introduced compared to the modes ⁇ fication small molecule, a multiple of funktionel ⁇ len groups in dependence of the molecu ⁇ large Klobuk of the introduced polymer.
  • the graft-ing from method when initiated from the surface of the sub ⁇ strats from a polymer chain and increasingly growing.
  • the substrate must be able to act as an initiator for example, be a radical-radical polymerisation ⁇ tion, and must be able to make it through a activator reagent to it.
  • the graft-ing from strategy to reach a higher functionalization because the Polymerket ⁇ th grow gradually and be introduced not listed as a finished polymer.
  • the reverse approach, the grafting-to is based on a finished polymer, which is grafted with a suitable Me ⁇ mechanism to the surface.
  • a disadvantage of this method is that when grafting finished polymers, neighboring potential binding sites are strongly blocked by the macromolecules, this does not happen in the grafting from approach. In contrast, control over the polymer length and molecular weight distribution of the applied polymers can only be achieved with the grafting-to approach.
  • coated substrates also decreased significantly, which increased the hydrophilicity of the surface and thus the acceptance of bone-forming cells (see J. Chem.
  • a surface-induced polymerization can be considered.
  • Oberflä ⁇ chenmodtechnik by means of small molecules can be in egg ⁇ ner variety of organic polymers to introduce linker, thereby further modifications may be carried out at the surface.
  • a UV-indexed polymerization (UV: Ultraviol ⁇ lett) into consideration.
  • radical initiator Rather than apply a radical initiator or other initiators to the surface, it is according to the substrate possible radicals directly on the surface to erzeu ⁇ gene.
  • This can be for example by auxiliary reagents, such as benzophenone (BP), benzoyl benzoic acid, or other photoinitiators reach the Upon UV excitation abstract hydrogen atoms of suitable polymers and thereby generate radicals on the polymer ⁇ surface, which can initiate a chain start.
  • BP benzophenone
  • benzoyl benzoic acid or other photoinitiators reach the Upon UV excitation abstract hydrogen atoms of suitable polymers and thereby generate radicals on the polymer ⁇ surface, which can initiate a chain start.
  • Polymers, such as PET form hydroxyl and peroxide groups on the surface after argon plasma treatment in air. These under excitation with UV light also serve as a radical starter. With polyethylene, this was also done under similar conditions.
  • the photoinitiator BP is known to undergo a photopinacoleactive reaction upon exposure to UV. This results in the formation of a semibenzopinacol radical which can serve as an initiator in polymerizations.
  • photoindu ⁇ ed division radicals can also arise start the polymerization from the excited molecule.
  • the polymer polyetheretherketone (PEEK) having in the polymer backbone BP ⁇ A units, which behave similarly (see also M. Kyomoto; K. Ishihara, Applied Materials & Acs interfaces 2009, 1, 537- 542). In 2009, Kyomoto demonstrated that the surface of untreated PEEK under UV action is capable of initiating free-radical polymerizations of various acrylic acid derivatives.
  • the covalently bonded matrix typically has one
  • the covalently bonded matrix can have a layer thickness of 1 nm to 10 micrometers ([im), preferably from 10 nm to 1 [im, more preferably from 20 nm to 500 nm, more preferably from 30 nm to 300 nm, more be ⁇ vorzugt from 50 nm to 200 nm, and most preferably at from 100 to 150 nm.
  • the covalently bound Matrix prefers the entire surface of the bone implant material of the present invention.
  • a hydroquinone derivative was coupled to the surface and a normal free-radical polymerization was carried out with a thermal radical initiator.
  • the immobilized hydroquinone quenched the growing polymer chain by homolytic cleavage of the OH bond, leading to chain termination.
  • the durable Aryloxylradikal is not too narrow-radical polymerization with the monomers present in the location, but can trap with a growing polymer radical ReKoM ⁇ bine and thus the polymer on the surface.
  • the inventive material includes for bone implants in said matrix intercalated calcium phosphate, calcium orthophosphate preferably in all mineral forms, more preferably selected from the group best ⁇ based amorphous calcium orthophosphate phosphate (ACP), Dicalciumpho- phosphate dihydrate (DCPD; brushite), octacalcium phosphate and hydro- xylapatit, even with partial fluoride, chloride or carbonate substitute nat ion, wherein ACP, it Hydroxylapat and Octacalciumpho ⁇ sphat are particularly preferred.
  • ACP ⁇ based amorphous calcium orthophosphate phosphate
  • DCPD Dicalciumpho- phosphate dihydrate
  • octacalcium phosphate and hydro- xylapatit even with partial fluoride, chloride or carbonate substitute nat ion, wherein ACP, it Hydroxylapat and Octacalciumpho ⁇ sphat are particularly preferred.
  • the polysaccharide is bound via a linker to the biocompatible material, where ⁇ selected at the linker from a group consisting of: a diamine linker or diamine linker in combination with a succinic acid linker, a (UV-grafted) polyacrylic re-linker or a photokoppelbaren Left, in particular ei ⁇ nem Azidoanilin linker.
  • ⁇ selected at the linker from a group consisting of: a diamine linker or diamine linker in combination with a succinic acid linker, a (UV-grafted) polyacrylic re-linker or a photokoppelbaren Left, in particular ei ⁇ nem Azidoanilin linker.
  • Corresponding linkers are known in the art. Here, photorelective or light-induced / light-inducible coupling should be understood as being photocoupled.
  • such light-inducible linkers can, in conjunction with a variety of substances or monomers, such as vinyl or acrylic monomers or polymers (polysaccharides) can be applied or a variety of substances can radically with UV Be polymerized light.
  • Examples include: methacrylic acid, phosphoric acid 2-hydroxyethyl methacrylate ester (as a mixture of monoester and diester, thereof monoester as normal monomer or diester as crosslinker), 2-hydroxyethyl methacrylate (as normal monomer or Co - monomer), ethylene glycol dimethacrylate (as cross-linker, mixture with other monomers), bis [2- (methacryloyloxy) ethyl] phosphate (as cross-linker, mixture with other monomers) and 2- (dimethylamino) ethyl methacrylate.
  • Coupling, for example, with azidoanilines can be applied to all polysaccharides which have carboxyl groups and which are directly functional analogous to hyaluronic acid, such as, for example, alginic acid, pectin, or carboxymethylcellulose.
  • hyaluronic acid such as, for example, alginic acid, pectin, or carboxymethylcellulose.
  • the hydroxyl group present in most polysaccharides in the 6-position can be functionalized analogously to the formation of carboxymethylcellulose to form a carboxyfunction (for example chitosan) and is therefore available for coupling with azidoanilines.
  • Methods for the covalent attachment of polysaccharides to, for example, PEEK are described below.
  • the invention comprises Ma ⁇ TERIAL for bone implants oxidic ceramic materials, titanium, polymeric materials, or composites, or consists of, wherein the polysaccharide is covalently bound matrix is bound with titanium or oxidic ceramic materials through a silane linker.
  • silane linker and entspre ⁇ standard practices for binding of polysaccharides are known in the art.
  • the present invention relates to a material for bone implants to collectively ⁇ :
  • the biocompatible material is PEEK
  • the polysaccharide is alginic acid
  • the calcium phosphate embedded in this matrix is hydroxyapatite, in particular crystalline hydroxylapatite.
  • Another object of the present invention relates to a process for the preparation of an inventive Materi ⁇ as for bone implants, comprising the steps of:
  • step (b) of the process OF INVENTION ⁇ to the invention are not particularly Be ⁇ restrictions and are known in the art.
  • the surface comprises or consists of PEEK
  • Step (b) of the method according to the invention the steps in any order:
  • linker molecule selected from the group consisting of a diamine linker, or a diamine linker and a succinic acid linker or UV gegrafteter polyacrylic acid (PAA), or a photokoppelbaren linker special into ⁇ a Azidoanilin- left to this activated upper ⁇ surface, and
  • any critiquenfol ⁇ ge that either first the coupling of the linker can be made to the activated surface followed by coupling of the product from activated surface and linker to the polysaccharide, or vice versa, so only the coupling the linker to the polysaccharide, and subsequently the coupling of the product from the linker and the polysaccharide at a k ⁇ tivêtêt surface.
  • a method for coupling of linker molecules to a entspre ⁇ accordingly activated PEEK surface or the activated polymer are also subject to no particular restrictions.
  • the covalent coupling of the photo ⁇ couplable linker, in particular the Azidoanilin linker, to the activated surface at a wavelength having a Be ⁇ ranging from 200 nm to 400 nm, preferably with a range of 200 nm to 300 nm, and most preferably with a range of 240 nm to 260 nm.
  • the covalent coupling of the photokop ⁇ pelbaren linker, in particular the Azidoanilin linker, to the activated surface at a wavelength of 254 nm. here ⁇ by a common method can quickly , reliable and easy to apply.
  • the polysaccharide having its carboxylic acid groups ⁇ is coupled overall even before the light-induced coupling to the photo ⁇ couplable linkers, in particular the Azidoanilin linker.
  • the covalent coupling of the carboxy-functionalized polysaccharide takes place by means of a, for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) -mediated amine and carboxy group coupling to the photo-couplable Lin- ker, in particular on the azidoaniline linker.
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • the coupling can be performed routinely and quickly by a standard method.
  • a method of mineralizing a polysaccharide containing matrix with calcium phosphates according to step (c) of the process according ⁇ invention are not particularly Beschränkun ⁇ gene.
  • amorphous calcium phosphate (ACP) is used, for example, incubating the upper surface with a Solution comprising calcium chloride, dipotassium hydrogen phosphate and a nucleation inhibitor.
  • This Nucle ⁇ tionation inhibitor is preferably a non-collagenous protein or protein analog, particularly preferably poly-aspartic acid and / or fetuin.
  • Hydroxylapat it is used, for example, include incubating the Oberflä ⁇ che with a solution comprising hydrogen phosphate, calcium chloride and dipotassium.
  • Another object of the present invention relates to a bone implant to the inventive Knochenim ⁇ plantatmaterial is applied.
  • Another object of the present invention relates to the use of the material according to the invention for a bone implant as a bone implant material.
  • the present invention was considered all relevant defi ⁇ nition, advantages and preferred embodiments that have been before ⁇ standing listed for the novel material for Knochenimplanta ⁇ te, in an analogous manner.
  • Another object of the present invention relates to the use of the inventive material for a bone ⁇ chenimplantat for example, for the treatment of KnochenC ⁇ .
  • Another object of the present invention relates to the use of the bone implant according to the invention in ⁇ example, for the treatment of bone damage. Also for this aspect of the present invention, all the relevant definitions, advantages and preferred exporting ⁇ insurance forms, which have been listed above for the novel material for bone implants apply analogously. Implants grow in the human body better, and be more stable attached to the body (among other ⁇ rem by increased accumulation of body cells), the better the implant surface corresponds to the natural bone. This is the goal of the present invention. Further, the coating should be covalently TIALLY to the surface of the implants ⁇ .
  • the bone implant materials of the invention have a higher biocompatibility, better healing in the natural bones and an increased mechanical belast ⁇ bility.
  • the surface modification according to the present invention aims, include bone-like structures covalently bonded to the surface of the bone implant materials réellebrin ⁇ gene which alphase an organic polysaccharide and Miner of natural bone. This should be the Assist healing of the implant in the bone.
  • These structures include a matrix of a polysaccharide which is eventually mineralized with calcium phosphate. Mineralization occurs with the help of non-collagenous proteins and their analogues, which act as nucleation inhibitors, so that mineralization is controlled and ectopic mineralization is avoided.
  • Such Nuk ⁇ leationsinhibitoren are for example poly-aspartic acid or fetuin.
  • Mineralization with octacalcium phosphate or hydroxyapatite is accomplished by incubating the polysaccharide matrix in a solution containing calcium ions or phosphate ions. By a slow and controlled addition of a solution of the respective complementary phosphate ions or Calciumi ⁇ ones octacalcium phosphate and / or hydroxyapatite may be intra ⁇ half of the polysaccharide precipitated. By re ⁇ tively disordered structure of the polysaccharide, the re ⁇ sultierende surface modification has woven bone like or kallusieri structure.
  • the bone cells could thus build up further disordered Kollagenstruktu ⁇ ren around the material during the healing of the material or directly connect the material further with the bone.
  • This disordered struc ⁇ ren can then finally in the natural Remodellie- approximately phase of bone healing are transformed into parent bone structural ⁇ tures.
  • the cells can not penetrate to the surface of the direct Implantatma ⁇ terials by the covalent attachment of the polysaccharides in the remodeling and thus always remain in a gewünsch ⁇ th matrix of extracellular proteins.
  • the Implantatmateri ⁇ al is thus masked for the cells to avoid adverse reactions in the healing of implants. Since the modifications only affect the surface of the implant materials, material properties are not changed.
  • the basic chemical reactions can be easily adapted for modification of various materials.
  • metal oxide surfaces can be covalently attached via established silane chemistry. This makes the surface coating of the invention also interesting for oxide Kera ⁇ mikmaterialien.
  • the common Implantatmateri ⁇ alien of titanium over the surface modification according to the invention silanes are accessible via silane chemistry.
  • a method was developed in which the gelatin functionalization of the bone implant plastic PEEK was established.
  • a method has now been developed to bind to the surface of PEEK, a network of Po ⁇ lysacchariden vegetable or bacterial origin, concretely hyaluronic acid, alginic acid derivatives and vollsyntheti ⁇ specific polymers covalently to the problems that a coating has animal-based, such as to bypass the post ⁇ setting of sterility and the lengthy approval process due to the potential endotoxin and Allergenpo- tentials.
  • Some patients opt for certain animal products for personal reasons, be it religious or ethical reasons. vegan, resp. synthetic functionalization could be interesting alternatives for these people ⁇ circle.
  • the applied coating with calcium phosphate, in particular hydroxyapatite be mineralized.
  • the reduced PEEK films can be further reacted to Bernstein Text ⁇ esters.
  • the esterification can be carried out by means of Bern ⁇ steinklad in acetone at room temperature:
  • Purified PEEK films could be reacted in pure diamine (ethylenediamine (EDA) and 1,3-diaminopropane). It comes to ei ⁇ ner forming imines (Schiff base) on the surface of PEEK. The reaction may take 3 h while refluxing the diamine and
  • the modified PEEK films were subjected to Kunststoffwinkelmes ⁇ solution.
  • the modified PEEK films were treated with phosphate buffer prior to measurement, rinsed with MilliQ and dried well.
  • the contact angle measurements can be made 5 seconds (s) after application of the drop.
  • Grewinkelmes ⁇ solutions with ultrapure water (MilliQ) imply while with ethylene diamine modified PEEK with a 6 6 ° markedly increased hydrophilicity compared to unmodified PEEK films (84, 5 °).
  • the contact angle with 7 0 ° has also become smaller, since the surface was also more hydrophilic. The increase in the hydrophilicity indicates a successful reaction during the reaction of PEEK with the diamines.
  • Untreated PEEK films can be coated with a grafting from poly ⁇ merisationsmethode with polyacrylic acid (UV light induced PEEK-modification):
  • the experimental procedure used can be carried out in one step. It can be worked with degassed aqueous solutions of distilled acrylic acid.
  • a UV light source is a OSRAM Vitalux 300 can be used without additional filter ver ⁇ spent.
  • the samples were used, which were polymerized for 30 minutes at 5 wt% acrylic acid fraction. Under these conditions the Beschich ⁇ tung was still thick enough to speak of a homogeneous coating (not shown), and at the same time can be assumed at this layer thickness that the mechanical properties of the bulk material egg ⁇ advertising does not adversely affect the.
  • the polyacrylic acid layers prepared at higher acrylic acid concentrations are not suitable for targeting as a bone graft material because of the thick gel pad of up to 5 millimeters (mm) because a gel pad on the surface greatly degrades mechanical contact with the surrounding tissue.
  • the polyacrylic acid has formed linear structures with the beads.
  • the off ⁇ formation of these lines could be drying method due to his (vacuum furnace) may also the hydrophobicity of the surface PEEK owed.
  • the dif ⁇ founding to the active site acrylic acid molecules have a higher affinity for a growing polyacrylic acid, as for the hydro ⁇ phobe PEEK surface. This could explain the line structures consisting of PAA balls.
  • the average globule -size in under these reaction conditions is 1.7 pm and is therefore again about half as large as at 60 min polymerisation ⁇ tion. Coating results were verified by ATR-IR spectra (not shown).
  • the coatings which have been prepared at 5% by weight of acrylic acid and 30 minutes of UV treatment have proven particularly suitable.
  • the PEEK can be thin ⁇ be coated so that no too much gel pad was deposited under these conditions.
  • the UV-induced graft ing polymer ion is thus very well suited for the coating of PEEK with polyacrylic acid, since significant amounts of PAA on the PEEK surface could be detected.
  • the polyacrylic acid layer can be modified by the coupling of Dia ⁇ minlinkern so that later can be formed with organic acids amide bonds.
  • the coupling of the diamine species to the carboxyl groups can by means of the mo ⁇ ern coupling reagent 4- (4, 6-dimethoxy-l, 3, 5-triazin-2-yl) -4-methylmorpholinium Chloride performed (DMT-MM) ⁇ the , Activation and coupling can be performed with DMT-MM at a buffered pH of 9:
  • the fluorescence intensity can be used to determine the concentration of the dye in solution and thus to draw conclusions about the amount of surface amino groups.
  • TMDA tetramethylenediamine
  • alginic acid shown as structural sections of alginic acid with the various poly-G, poly-M and alternating blocks, depending on the source of alginic acid, the ratio of G and M is different
  • Unmodified hyaluronic acid consists of a D-glucuronic acid and an N-acetyl-glucosamine unit. It therefore possesses one free carboxyl function and one acetylated amine function per disaccharide monomer.
  • the deacetylation can be carried out in aqueous hydrazine solution with Hyd ⁇
  • the purple solution was in the sheath ⁇ funnel extracted five times with 25 mL of diethyl ether until the aqueous phase was colorless.
  • the pH of the solution was adjusted to 7-7.5 with 0.2 M NaOH solution.
  • the polymer was precipitated in 1 volume equivalent of ethanol, dissolved in H 2 O and evaporated dialyzed deionized water.
  • the dialysis water was day ⁇ Lich changed two times. After three days of dialysis, the Lö ⁇ solution was freeze-dried and obtain the deacetylated hyaluronic acid as a product.
  • the free amino groups could be used as anchor groups for coupling to the carboxyl groups of the PEEK-PAA surface.
  • the polymer was examined by NMR spectroscopy to determine the degree of deacetylation (not shown).
  • the free carboxyl groups of hyaluronic acid may be suitable for various modification possibilities of the polymer.
  • the literature e.g. reported by amidation, ester formation or Ugi condensation.
  • HMDA hyaluronic acid amidated hexamethyl ⁇ endiamin
  • the coupling of the amine can proceed via the classic EDC / NHS coupling (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / N-hydroxysuccinimide coupling) in an aqueous medium.
  • the reaction is divided into an activation phase in slightly acidic and a coupling phase in slightly basic.
  • the pH value of the reaction had to be continuously monitored and adjusted:
  • ADH adipic dihydrazide
  • a sodium hyaluronate solution containing 3 - was prepared by dissolving 500 mg of sodium hyaluronate in 170 mL H2O. Based on the amount of carboxyl groups in the polymer, a 40-fold molar excess of adipic dihydrazide (ADH, 52.8 mmol, 9.2 g) was added. It was waited until the ADH was completely dissolved (15 min). The pH of the reaction mixture was adjusted to 4 using 1 M HCl solution. Ethanol (50 mL, 50% v / v) was added and stirred for 30 minutes. There were 4 eq. EDC-HC1 (5.3 mmol, 0.9 g) was added. The pH value for 2 h using 1 M HCl supported ⁇ th. To about 4.8 After 2 h the reaction was stopped neutralization of
  • alginic acid can also be functionalized with HMDA.
  • the coupling can for a pre ⁇ writing to Octylaminfunktionalmaschine of alginic acid SUC th:
  • the reaction can be carried out at a constant pH of 9 and the reaction vessel between activation and coupling must not be changed.
  • the coupling at pH 9 is significantly faster compared to the coupling to the NHS ester at pH 7.3, since the amines at pH 9 are largely free amine, which is important for nucleophilic attack on the activated carbonyl center.
  • the NHS clutch can not be performed by ⁇ at such high pH values, as the NHS ester to otherwise fast h is hydrolysed in the aqueous solution:
  • the imine-functionalized PEEK surface can be reacted with native hyaluronic acid and alginic acid under identical reaction conditions.
  • Alginic acid 0.05 mg / mL. It was washed three times with MilliQ of water):
  • Table 2 Overview of the polysaccharide couplings to PEEK substrates.
  • reaction schemes associated with each reaction are as follows: ATR-IR spectra demonstrated successful functionalization (not shown).
  • PEEK-PA film An established synthetic route for hydroxyapatite can be removed and used for the mineralization of PEEK-PA films.
  • the PEEK-PA film can be placed in 0.3 M calcium chloride solution at a buffered pH of 9 and for
  • Simpler variants of mineralization can also be performed.
  • PEEK-PAA samples were incubated for 72 h in diammonium hydrogen phosphate (phosphate pre-structuring, 6 mL vials with 1 M aqueous (NH 4) 2 HPO 4 solution) or calcium nitrate Cal (6 mL vials with 1 M aqueous Ca (NO 3) 2 solution). After this rest period, the samples were added to the other solution (0.6 M (NH 4 ) 2HPC> 4 or 0.6 M Ca (NO 3) 2 solution) and left for one week to allow the counterions ⁇ chen also to diffuse into the gel.
  • diammonium hydrogen phosphate phosphate pre-structuring, 6 mL vials with 1 M aqueous (NH 4) 2 HPO 4 solution) or calcium nitrate Cal (6 mL vials with 1 M aqueous Ca (NO 3) 2 solution).
  • the samples were added to the other solution (0.6 M (NH 4 ) 2HPC> 4 or
  • azido-functionalized hyaluronic acid was attached to a PEEK surface by means of light-induced coupling.
  • the reaction sequence of light-induced coupling of azidoanilines with hyaluronic acid to PEEK could proceed as follows:
  • So Azidoanilin phenomenon were at the carboxy group of polysaccharides, such as alginic or hyaluronic acid, angekop ⁇ pelt (see below).
  • the coupling product of polysaccharide and azidoaniline linker was then ligated to the PEEK surfaces with light.
  • hyaluronic acid for example, would be a split in the hyaluronic acid ⁇ how something enzymatically or by ultrasound, in Be ⁇ costume.
  • the hyaluronic acid is cleaved into fragments of about 15 kilodaltons (kD) and in the ultrasound treatment into fragments of about 300 kD.
  • the substrates containing Hya-US-N3 are slightly darker in color than the substrates with Hya-Enz-N3.
  • the hyaluronic acid ring or spot can be detected in the SEM examination. Fitting for this are signals in the EDX analysis of carbon and oxygen. Depending ⁇ but is not (e) resistant to washing (s) or film deposition on the Hyaluronsaurebe Anlagenung to recognize and detect no calcium or phosphorus in the EDX analysis, which could include a mineralization.
  • the hyaluronic acid coating is a ring (as with all previous ones) Samples with enzymatically split hyaluronic acid) and not completely, but partially covered by the deposited material.
  • the deposits show no preference for hyaluronic acid coating or PEEK, but they appear to be inhomogeneously distributed throughout (not shown).
  • the hyaluronic acid coating is a filled-in spot (as in all previous samples by means of ultrasound cleaved hyaluronic acid) and very tightly covered by the material from ⁇ divorced. There is evidence of preferential mineralization of the hyaluronic acid coating and lower coverage of the uncoated PEEK area (not shown).
  • the deposited materials appear to be rather coarse at RT, while a temperature of 37 ° C appears to promote the formation of fine deposits.
  • a temperature of 37 ° C appears to promote the formation of fine deposits.
  • significant deposits were seen after one day at pH8 (eg IS019 and IS025) and pH9 (eg IS033 and IS039), whereas at RT (IS022, IS036, IS028, IS042) after one day below Conditions nothing until hardly anything was deposited.
  • a longer insertion time should increase the amount of deposited material or, in the case of very slow deposition, allow deposition over ⁇ . Contrary to this expectation, the largest amounts of deposits were observed in the samples with a 24-hour loading time. It may be that length ⁇ rer Open time processing or diffusion processes take place which reduce the visible deposits compared to samples with shorter laying times. Depth analyzes could provide more detailed information on elemental distribution in the mineralized substrate.
  • the polyacrylic acid was investigated with different surface analysis methods such as attenuated total reflection, scanning electron microscopy and confocal laser scanning microscopy to get spectro ⁇ scopic information about the surface and to obtain an accurate picture of the topography (not ge ⁇ shows). It has been modified by the development of Ankupp- Diaminlinkern so later with organic acids ⁇ rule amide bonds can be formed, the polyacrylic acid layer. To quan ⁇ titative statements about the degree of endurenfunktionalisie- tion meet with amino groups, the cleavable fluorescent dye C-coumarin was synthesized with the amino groups accessible indirectly quanti ⁇ fied left on the surface. The quantification was successful for the samples which were directly imin-functionalized with diamines.
  • Hyaluronic acid with adipic dihydrazide and hexamethylenediamine and alginic acid was modified only with the diamine in order to couple amine linkers for subsequent anchorages on the various polyether ether ketone substrates.
  • Hyalur ⁇ oic acid was deacetylated to introduce in this way amine functionalities on the polysaccharide.
  • the modified polysaccharides have been characterized by NMR and ATR-infrared spectroscopy Metho ⁇ (not shown).
  • the numerous modified and unmodified polysaccharides were coupled to the complementary PEEK substrates.
  • the coupled samples were analyzed using ATR-infrared spectroscopy ⁇ , scanning electron microscopy and partly with thermo- mogravimetrie examined (not shown).
  • azidoaniline groups have been coupled to the carboxy groups of polysaccharides, such as alginic or hyaluronic acid, and then attached to a PEEK surface with light.
  • a coating of the polyetheretherketone with azido-functionalized hyaluronic acid was successfully demonstrated. Further ⁇ th strong evidence could be found that a Mineralisie ⁇ tion of the coupled with hyaluronic acid derivatives PEEK surface takes place.
  • a very sensitive surface analysis method is X-ray photoelectron spectroscopy (XPS, narrow X-Ray Photo-electron Spectroscopy).
  • XPS X-ray photoelectron spectroscopy
  • the investigation of the swelling behavior of the polyacrylic acid layers on the polyether ether ketone substrate could be an approach to optimize the coupling conditions so that polysaccharide detection would be possible even with simple analytical methods.
  • Couplings in non-aqueous media would also be conceivable, but are certainly also problematic because of the poor solubility of the polysaccharides. Should also be made to deposit further attempts Hydroxylapat it in the polyacrylic acid, as Hyd ⁇ roxylapat it-coating has been shown to have a positive effect on the acceptance in the organism.

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Abstract

L'invention concerne un matériau pour implant osseux, comprenant : a) une structure de support présentant une surface qui comprend au moins un matériau biocompatible, (b) une matrice liée de façon covalente à cette surface et (c) du phosphate de calcium intercalé dans cette matrice. Un matériau médicalement sûr, à haute tolérance et polyvalent peut être obtenu si la matrice comporte au moins un polysaccharide (formule (I)).
EP17811852.7A 2016-11-25 2017-11-24 Matériau pour implant osseux et procédé de fabrication d'un tel matériau Withdrawn EP3544644A1 (fr)

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CN113425911B (zh) * 2021-07-21 2022-09-09 郑州大学第一附属医院 具有长效抗菌和自润滑功能的3d打印支架的制备方法
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CA2582705C (fr) * 2004-10-06 2014-03-11 Bayco Tech Limited Dispositif d'implantation osseuse recouvert d'acide hyaluronique
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