WO1993000935A1 - Materiaux pour implants - Google Patents

Materiaux pour implants Download PDF

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Publication number
WO1993000935A1
WO1993000935A1 PCT/GB1992/001247 GB9201247W WO9300935A1 WO 1993000935 A1 WO1993000935 A1 WO 1993000935A1 GB 9201247 W GB9201247 W GB 9201247W WO 9300935 A1 WO9300935 A1 WO 9300935A1
Authority
WO
WIPO (PCT)
Prior art keywords
material according
carrier
enzyme
materials
phosphatase
Prior art date
Application number
PCT/GB1992/001247
Other languages
English (en)
Inventor
Wouter Beersten
Theo Van Den Bos
Original Assignee
British Technology Group Ltd.
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
Application filed by British Technology Group Ltd. filed Critical British Technology Group Ltd.
Priority to JP5502108A priority Critical patent/JPH06508780A/ja
Priority to EP92915026A priority patent/EP0595863A1/fr
Publication of WO1993000935A1 publication Critical patent/WO1993000935A1/fr
Priority to US08/470,952 priority patent/US5674725A/en

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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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
    • C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
    • C12Y301/03001—Alkaline phosphatase (3.1.3.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A61L2300/254—Enzymes, proenzymes

Definitions

  • This invention relates to novel materials useful in the restoration and repair of the skeletal system, to processes for their production and to novel methods for the repair of the skeleton which utilise them.
  • alkaline phosphatase The possible role of the enzyme alkaline phosphatase in promoting the calcification of bone has been postulated for many years. Recent studies notably an in vitro study reported by Beertsen and Van Den Bos (Matrix Vol. 9 1989 pl59-171) have tended to support the proposition that alkaline phosphatase may be involved in the initiation of the calcification process apparently by virtue of its acting so as to raise the local concentration of phosphate ions.
  • USP 4,394,370 describes a bone graft material which comprises a complex of reconstituted collagen and either de ineralised bone particles or a solubiused bone morphogenetic protein fabricated as a sponge. These sponges may be complexed with bovine intestinal alkaline phosphatase. A concentration of 15mg per gram of collagen dispersion is said to eliminate all inflammatory responses to the graft material, accelerate the formation of osteoid in the graft material and aid the slow resorption of the graft enabling it to be more completely corticalised. There is no mention of any mineralisation having occurred.
  • USP 4,409,332 describes porous membrane structures based on collageneous materials which are complexed with alkaline phosphatase in order to reduce the inflammatory reaction produced when these membranes are introduced into the body.
  • novel materials useful in the repair of the skeleton may be produced by combining a biocompatible carrier material with a quantity of a phosphatase enzyme such as will promote mineralisation.
  • the level of enzyme activity is preferably at least 0.5 milliunits Apase per l.O ⁇ gm of hydroxyproline (where one unit is defined as I ⁇ mol p-nitrophenol released per minute from p-nitrophenyl phosphate at 37°C and pH 10.5 using the technique described by Beertsen and van den Bos in Matrix, Vol. 9/1989, pl ⁇ l).
  • Biocompatible carrier materials may themselves mineralise at least to some degree if used to repair the skeleton and allowed to remain in situ for an extended period. The materials of this invention promote mineralisation of the implant so that it can be readily detected within seven days and have practical utility in the repair of the skeleton.
  • the novel materials are stable products which when used to repair the skeleton undergo mineralisation and may serve to promote the growth of new bone. Accordingly, from one aspect this invention provides a novel material useful in the repair of the skeleton which comprises a phosphatase enzyme combined with a bio-compatible carrier material and having a level of enzyme activity as will promote mineralisation.
  • the phosphatase enzyme is preferably an alkaline phosphatase enzyme (hereinafter for convenience "APase").
  • APase is normally obtained by extraction from human or animal tissue.
  • the enzyme is a cell surface glycoprotein which is capable of hydrolysing a variety of monophosphate esters. Three main forms of APase are distinguished; liver/bone/kidney; placental and intestinal and all of these forms are useful in this invention.
  • the carrier material may comprise any biocompatible material which is capable of combining with the enzyme.
  • the combination is brought about by incubating the carrier with the enzyme in the presence of a coupling agent which is capable of covalently bonding with the carrier and with the enzyme.
  • Suitable coupling agents are those which are capable of bonding to the enzyme without significantly reducing its biological activity.
  • a wide variety of polyfunctional compounds may be useful.
  • the coupling agents used to form the preferred materials of this invention will be those which are capable of bonding to the carrier material. Examples of potentially useful coupling agents include biotin-avidin; glutaraldehyde and l-ethyl-3(3-dimethyl-aminopropyl) carbodiimide HC1.
  • the preferred coupling agents are those which do not produce an adverse reaction when introduced into the body in particular as part of a material according to this invention.
  • the most preferred coupling agents are the carbo-diimides and in particular the compound mentioned above.
  • a particularly preferred coupling agent is that known as SATA-MHS, which involves the use of a combination of succinimidyl-S-acetylthioacetate (SATA) and maleimidohexanoyl-N- hydroxysuccinimide (MHS).
  • SATA succinimidyl-S-acetylthioacetate
  • MHS maleimidohexanoyl-N- hydroxysuccinimide
  • the carrier is incubated with the SATA and the enzyme with the MHS. The products of these two incubation processes are combined and allowed to react to produce an implant material.
  • the carrier material may be of natural or synthetic origin.
  • a wide variety of synthetic polymers are potentially useful.
  • a particular group of synthetic materials which may be of use are those polymers which are known to be bioabsorbable.
  • the use of synthetic materials is also advantageous insofar as they may be flexible and capable of being formed into shaped pieces designed for particular applications.
  • a variety of natural materials may also be used as the carrier.
  • human or animal tissues such as bones and teeth may be useful.
  • Calcified tissues such as bones and teeth must be demineralised before they can be used as a carrier.
  • the materials obtained by demineralisation comprise a substantial proportion of fibrillar collagen.
  • Collagen is the major fibrous protein of many animals and may be extracted from many parts of the human or animal body.
  • Fibrillar collagen is a preferred carrier material for use in the present invention as are materials which comprise a substantial proportion of it.
  • An example of such a material is human or animal dura mater.
  • the carrier materials are preferably those which are sufficiently flexible to be formed into shaped pieces.
  • Those materials which are porous or comprise meshes of fibrillar or fibrous materials are also advantageous in that they have a larger surface area to which the enzyme may be bonded.
  • Useful carrier material may also be formed by incorporating collagen fibres into or onto a suitable supporting material always provided that the surface of the fibres remains exposed.
  • An example of a supporting material is natural or synthetic calcium phosphates which substances may usefully form part of the materials of this invention.
  • the carrier material will preferably be sufficiently flexible and sufficiently strong to be useful as an implant material.
  • the degree of flexibility or strength may vary according to the particular application for which the material is intended.
  • the material is preferably one which is capable of being handled and manipulated prior to and during the implantation operation.
  • the preferred implant materials comprise at least 200 units of phosphatase per cubic centimetre.
  • the preferred carrier materials are those which are capable of combining with this amount of enzyme. Useful materials may be produced by compression of a carrier or of a material produced by combination of a carrier and a phosphatase enzyme.
  • the preferred carrier materials are those having a relatively smooth surface and a densely organised fibrous structure. Such materials may exhibit osteoconductive properties, i.e. they appear to guide the migration of osteoblasts and thereby to encourage the growth of new bone.
  • the carrier has a tubular structure, i.e. one having a series of cracks or microfractures.
  • the enzyme is bound within these tubules and mineralisation may occur in them. This is advantageous insofar as the strength of the material increases as the mineralisation proceeds.
  • Mineralisation may be enhanced by pre-incubating the carrier (or the combined carrier - APase material) in a solution containing physiological concentrations of calcium and an organophosphate (e.g. a ⁇ -glycerophosphate solution) or an inorganic phosphate.
  • the pre-incubation appears to form nucleation centres within the carrier which after implantation in the body may grow rapidly and boost the rate of mineralisation.
  • the carrier material is preferably one which is free from any substance which might serve to inhibit its mineralisation. In the case of materials of natural origin it may be necessary to extract the material thoroughly in order to reduce the level of any inhibitor to an acceptable value.
  • Conveniently demineralisation of a calcified tissue may be effected by washing the cleaned tissue and placing it in an acid solution, e.g. of acetic or hydrochloric acid for an extended period.
  • the resulting demineralised material is further extracted with a chaotropic agent in the presence of a chelating agent.
  • the de ineralised material may contain residual quantities of non-collagenous proteins and insoluble phosphoproteins or dentinal phosphophoryns.
  • the presence of bound phosphoproteins or dentinal phosphophoryns has been discovered to be efficacious in promoting the remineralisation.
  • the preferred carrier materials are those which inherently comprise such phosphoproteins or phosphophoryns or those into which such phosphoproteins or phosphophoryns have been introduced and preferably covalently bound to the carrier.
  • the materials of this invention comprise at least 0.03 micrograms of phosphate per microgram of hydroxyproline most preferably in the form of phosphoproteins or phosphophoryns.
  • novel materials of this invention may be produced by incubating the carrier with the APase in the presence of the coupling agent and optionally in the presence of an organo- phosphorus compound.
  • the coupling reaction may conveniently be carried out by introducing the carrier and the APase into a solution of the coupling agent.
  • the reaction should be carried out under conditions which do not inactivate the APase. Conveniently allowing the reactants to stand at a temperature which is not greater than ambient and is preferably less than 10°C for periods which will in general be at least 1 hour and may conveniently be longer, say 24 hours, will be sufficient to produce a product according to the invention.
  • the amount of APase present in the novel materials may vary within wide limits.
  • the materials particularly those provided that it is sufficient to promote remineralisation in the intended application will exhibit a level of enzyme activity which is at least 1.0 milliunit Apase per l.O ⁇ gm of hydroxyproline.
  • the optimum amount of enzyme to be incorporated will vary with the nature of the component materials, the use to which the material is to be put, the age of the person or animal into which it is to be implanted and the concentration of inorganic phosphate present in the serum of the person or animal. Materials comprising lower amounts of enzyme may be useful in animals which are undergoing a period of relatively rapid growth. In mature animals the implants preferably contain a higher concentration of enzyme most preferably in conjunction with phosphoproteins and phosphophoryns.
  • Methods of treatment of the skeleton in order to repair it which comprise the introduction of an implant material as hereinbefore described form another aspect of this invention.
  • Methods of treatment further comprise an increase of the level of phosphates in the locality of the implant from a preferred aspect.
  • the amount of coupling agent employed will simply be that required to bind the desired amount of APase.
  • the coupling agent will be present in the solution in a large excess over the quantity required by stoichio etry.
  • the presence of such excess quantities of coupling agent may act so as to cross-link the surface of the carrier.
  • Such cross-linking may be useful in improving the mechanical properties of a carrier material. It may also be useful in regulating the biodegradability of the implant.
  • the implant should retain its mechanical integrity during the mineralisation but may usefully degrade thereafter.
  • the materials of this invention find use in a variety of surgical procedures.
  • the carrier material will preferably be formed into an appropriate shape prior to it being coupled to the APase.
  • the material finds use as an internal wound dressing to stabilise and facilitate the healing of fractures or defects of the skeleton. Following implantation it mineralises and hardens.
  • the novel materials may also be used as a substitute for bone and used to repair fractures by fixing the material into position and allowing it to mineralise and harden in situ. The treatment of fractures in these ways provides a further aspect of this invention.
  • the materials also find use in treatment processes which involve what has been termed "guided tissue regeneration". Such procedures involve the insertion of a membrane to help regenerate supportive connective tissues in areas of the body which have been damaged by disease.
  • the membranes currently used in this application are often not biodegradable and must be removed in a second surgical operation.
  • the materials of this invention are advantageous in this application insofar as they are biocompatible and may be allowed to remain in situ thus avoiding the need for further surgical intervention.
  • Example 1 The invention is illustrated by the following examples.
  • Example 1 The invention is illustrated by the following examples.
  • Demineralised dentin slices were prepared by soaking in 0.5M acetic acid or 0.6M hydrochloric acid for four weeks. Sections were cut by means of a cryotome set at 30 ⁇ m. They were then further extracted with 4M guanidine.HCl and 0.4M EDTA (pH 7.5) for three days at 4°C. Before use the DDS were washed in double-distilled water for one hour and placed in double-distilled water supplemented with antibiotics at 4 ⁇ C overnight. DDS contained 0.04 ⁇ g P0 4 per ⁇ g hydroxyproline. Bindin g of APase. Bovine intestinal Apase was covalently bound to the dentinal collagen sheets by using the coupling agents glutaraldehyde or carbodiimide.
  • Glutaraldehvde coupling The DDS were incubated in PBS containing 0.1% glutaraldehyde for 2h at 25°C in the presence of
  • Wistar rats (about 200g each) were anaesthetized with Hypnorm and an incision was made through the skin covering the skull following the sagittal suture. The skin was retracted so as to expose the right and left temporal muscles. A pouch was then created on either side by cutting through the insertion of the exposed muscle. DDS slices of 30 ⁇ m thickness and 1cm in width, 2cm in length were inserted into the pouches: APase-treated ones on the right side and controls on the left side. Care was taken that only a narrow rim of the implant was in contact with the muscle; its greater part (90%) was in direct contact with the der is. The skin wound was closed with nylon sutures and allowed to heal for time periods varying from one to four weeks.
  • a series of implant materials were prepared using the materials and techniques described in Example 1.
  • the coupling agent was l-ethyl-3(3-dimethylaminopropyl)carbodiimide.
  • Forty female Wistar rats (body weight, ca. 200g) were anesthetized with Hypnorm.
  • An incision was made through the skin parallel to the sagittal suture.
  • the skin covering the right and left parietal bones was reflected so as to expose the cranial vault from the frontal to the occipital region.
  • a periosteal flap was raised on either side following incisions along the sagittal, frontal and occipital sutures.
  • the wounds were covered with a graft, one on either side of the skull, each measuring 0.5cm in width and 0.8cm in length.
  • On the right side an APase-containing one was implanted, on the left side a control one (no enzyme).
  • the periosteum and skin were closed.
  • the animals were killed by decapitation at the following time intervals post surgery: 3 weeks, 6 weeks, 9 weeks and 12 weeks.
  • the calvariae were dissected out and immersed in a solution of 4% paraformaldehyde and 1% glutaraldehyde in 0.1 mol/L Na-cacodylate buffer (pH 7.4) for 24h.
  • the specimens were postfixed in 1% OsO ⁇ and embedded in epoxy resin.
  • Each skull half was oriented on the microtome so as to section the two wounds in the same plane, perpendicular to the cranial vault. Sections were stained with methylene blue or according to the Von Kossa method. From each Specimen one methylene blue stained section was taken from the central area of the two defects and used for histomorphometric analysis.
  • Ultrathin sections were cut with a diamond knife, stained with uranyl acetate and lead citrate and examined in a Zeiss EM 10C electron microscope.
  • APase-activity in the enzyme- treated implants was bound to the wall of the dentinal tubules and the outer aspects of the sheets. The distribution of the activity was uniform, in that along the entire length of the sheets the same staining pattern was seen. Sections of control sheets that were incubated with the crosslinking agent in the absence of APase did not show any histochemical staining. Based on the conversion rate of p-nitrophenylphosphate, the enzyme-treated collagen sheets contained 0.95 ⁇ 0.24 mU of enzyme per ⁇ g hydroxyproline.
  • SATA succinimidyl-S-acetylthioacetate, Pierce

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La combinaison d'une phosphatase avec un materiau porteur biocompatible permet d'obtenir des matériaux susceptibles de favoriser la réparation squelettique ainsi qu'une croissance osseuse renouvelée. La combinaison comprend de préférence un accouplement covalent entre l'enzyme et le porteur. Les matériaux porteurs préférés comprennent un collagène fibrillaire et peuvent être obtenus par l'intermédiaire d'une déminéralisation de tissus calcifiés. Les matériaux peuvent comprendre des phosphoprotéines ou des phosphophorynes de dentine qui peuvent être résiduelles ou ajoutées au cours de la préparation des matériaux. L'addition d'autres organophosphates et de phosphates inorganiques peut améliorer le taux de minéralisation, en particulier chez des animaux plus âgés.
PCT/GB1992/001247 1991-07-11 1992-07-09 Materiaux pour implants WO1993000935A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP5502108A JPH06508780A (ja) 1991-07-11 1992-07-09 移植片材料
EP92915026A EP0595863A1 (fr) 1991-07-11 1992-07-09 Materiaux pour implants
US08/470,952 US5674725A (en) 1991-07-11 1995-06-06 Implant materials having a phosphatase and an organophosphorus compound for in vivo mineralization of bone

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP91306305.3 1991-07-11
EP91306305 1991-07-11

Publications (1)

Publication Number Publication Date
WO1993000935A1 true WO1993000935A1 (fr) 1993-01-21

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ID=8208343

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1992/001247 WO1993000935A1 (fr) 1991-07-11 1992-07-09 Materiaux pour implants

Country Status (3)

Country Link
EP (1) EP0595863A1 (fr)
JP (1) JPH06508780A (fr)
WO (1) WO1993000935A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005456A1 (fr) * 1993-08-13 1995-02-23 Rijksuniversiteit Te Groningen Composition pharmaceutique comportant la phosphatase ou son derive
WO1998047547A1 (fr) * 1997-04-22 1998-10-29 Washington Research Foundation Proteses et greffons osseux revetus de phosphatase acide resistant aux tartrates
WO2003070290A1 (fr) * 2002-02-19 2003-08-28 National Institute Of Advanced Industrial Science And Technology Biomateriau composite contenant de la phospholine
WO2005016368A2 (fr) * 2003-08-19 2005-02-24 University Of Pittsburgh Of The Commonwealth System Of Higher Education Methode permettant d'induire la biomineralisation, methode permettant d'induire la regeneration osseuse et methodes associees
US7053051B2 (en) 2003-10-28 2006-05-30 Medtronic, Inc. Methods of preparing crosslinked materials and bioprosthetic devices
US9266191B2 (en) 2013-12-18 2016-02-23 Aeroprobe Corporation Fabrication of monolithic stiffening ribs on metallic sheets

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2055848A (en) * 1979-08-01 1981-03-11 Eni Ente Naz Idrocarb Immobilised biologically active materials
US4394370A (en) * 1981-09-21 1983-07-19 Jefferies Steven R Bone graft material for osseous defects and method of making same
US4409332A (en) * 1982-01-12 1983-10-11 Jefferies Steven R Collagen-enzyme conjugates that exhibit no inflammatory response and method for making the same
NL8902155A (nl) * 1989-08-25 1991-03-18 Stichting Biomat Met bloed compatibel kunststofprodukt.

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2055848A (en) * 1979-08-01 1981-03-11 Eni Ente Naz Idrocarb Immobilised biologically active materials
US4394370A (en) * 1981-09-21 1983-07-19 Jefferies Steven R Bone graft material for osseous defects and method of making same
US4409332A (en) * 1982-01-12 1983-10-11 Jefferies Steven R Collagen-enzyme conjugates that exhibit no inflammatory response and method for making the same
NL8902155A (nl) * 1989-08-25 1991-03-18 Stichting Biomat Met bloed compatibel kunststofprodukt.

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, vol. 97, no. 10, 6 September 1982, (Columbus, Ohio, US), see page 425, abstract no. 78947m, & JP,A,8289867 (K. MIURA) 4 June 1982, see abstract *
Journal of Dental Research, vol. 70, no. 3, March 1991, W. BEERTSEN et al.: "Alkaline phosphatase induces the deposition of calcified layers in relation to dentin: an in vitro study to mimic the formation of afibrillar acellular cementum", pages 176-181, see discussion *
Matrix, vol. 9, no. 2, March 1989, Gustav Fischer Verlag, (Stuttgart, DE), W. BEERTSEN et al.: "Calcification of dentinal collagen by cultured rabbit periosteum: the role of alkaline phosphatase", pages 159-171, see summary (cited in the application) *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005455A1 (fr) * 1993-08-13 1995-02-23 Rijksuniversiteit Te Groningen Composition pharmaceutique comportant la phosphatase ou son derive
AU698331B2 (en) * 1993-08-13 1998-10-29 Pharmaaware Ip B.V. Pharmaceutical composition comprising phosphatase or a derivative thereof
WO1995005456A1 (fr) * 1993-08-13 1995-02-23 Rijksuniversiteit Te Groningen Composition pharmaceutique comportant la phosphatase ou son derive
US7353830B2 (en) 1997-04-22 2008-04-08 Washington Research Foundation TRAP-coated bone grafts and prostheses
WO1998047547A1 (fr) * 1997-04-22 1998-10-29 Washington Research Foundation Proteses et greffons osseux revetus de phosphatase acide resistant aux tartrates
US6190412B1 (en) 1997-04-22 2001-02-20 Washington Research Foundation Trap-coated bone grafts and prostheses
US6508838B2 (en) 1997-04-22 2003-01-21 Washington Research Foundation Compositions for medical implantation
WO2003070290A1 (fr) * 2002-02-19 2003-08-28 National Institute Of Advanced Industrial Science And Technology Biomateriau composite contenant de la phospholine
EP1477191A1 (fr) * 2002-02-19 2004-11-17 National Institute of Advanced Industrial Science and Technology Biomateriau composite contenant de la phospholine
EP1477191A4 (fr) * 2002-02-19 2009-07-22 Nat Inst Of Advanced Ind Scien Biomateriau composite contenant de la phosphophoryne
WO2005016368A2 (fr) * 2003-08-19 2005-02-24 University Of Pittsburgh Of The Commonwealth System Of Higher Education Methode permettant d'induire la biomineralisation, methode permettant d'induire la regeneration osseuse et methodes associees
WO2005016368A3 (fr) * 2003-08-19 2005-05-26 Univ Pittsburgh Methode permettant d'induire la biomineralisation, methode permettant d'induire la regeneration osseuse et methodes associees
US7053051B2 (en) 2003-10-28 2006-05-30 Medtronic, Inc. Methods of preparing crosslinked materials and bioprosthetic devices
US9266191B2 (en) 2013-12-18 2016-02-23 Aeroprobe Corporation Fabrication of monolithic stiffening ribs on metallic sheets

Also Published As

Publication number Publication date
EP0595863A1 (fr) 1994-05-11
JPH06508780A (ja) 1994-10-06

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