WO1994026322A1 - Utilisation d'un materiau poreux a base de carbonate de calcium comme support pour un facteur de croissance dans la preparation d'un implant bioresorbable - Google Patents

Utilisation d'un materiau poreux a base de carbonate de calcium comme support pour un facteur de croissance dans la preparation d'un implant bioresorbable Download PDF

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Publication number
WO1994026322A1
WO1994026322A1 PCT/FR1994/000565 FR9400565W WO9426322A1 WO 1994026322 A1 WO1994026322 A1 WO 1994026322A1 FR 9400565 W FR9400565 W FR 9400565W WO 9426322 A1 WO9426322 A1 WO 9426322A1
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Prior art keywords
implant
growth factor
use according
cells
bone
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PCT/FR1994/000565
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English (en)
French (fr)
Inventor
Jean-Louis Patat
Jean-Pierre Ouhayoun
Original Assignee
Inoteb
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 FR9305783A external-priority patent/FR2705235B1/fr
Application filed by Inoteb filed Critical Inoteb
Priority to AU67887/94A priority Critical patent/AU676056B2/en
Priority to AT94916275T priority patent/ATE194922T1/de
Priority to US08/360,801 priority patent/US5711957A/en
Priority to DE69425358T priority patent/DE69425358T2/de
Priority to CA002139864A priority patent/CA2139864C/fr
Priority to DK94916275T priority patent/DK0650374T3/da
Priority to JP6525071A priority patent/JP2957281B2/ja
Priority to EP94916275A priority patent/EP0650374B1/de
Publication of WO1994026322A1 publication Critical patent/WO1994026322A1/fr
Priority to GR20000402357T priority patent/GR3034667T3/el

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    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0068—General culture methods using substrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1825—Fibroblast growth factor [FGF]
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/12—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
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00179—Ceramics or ceramic-like structures
    • A61F2310/00293—Ceramics or ceramic-like structures containing a phosphorus-containing compound, e.g. apatite
    • 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
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/10—Mineral substrates
    • C12N2533/18—Calcium salts, e.g. apatite, Mineral components from bones, teeth, shells

Definitions

  • the subject of the invention is the use of a material based on calcium carbonate as a support for a growth factor in the preparation of a bioresorbable implant intended to be placed in a living organism.
  • Such a material can be used in particular as an osteoforming implant. It is known that bone surgery often requires the placement of bone grafts or implants constituting artificial substitutes for such grafts. The production of allografts raises objections, for obvious reasons of public health, taking into account the risks of transmission of certain serious viral diseases or diseases caused by non-conventional transmissible agents or "prions".
  • biocompatible materials such as tricalcium phosphate, hydroxyapatite, plaster, coral, polymers based on poly (lactic acid) and / or poly (acid glycolic), etc.
  • Some of these materials, including calcium carbonate, are bioresorbable and allow the progressive formation of newly formed bone tissue at the expense of the material implanted in the process of resorption; see in particular European patent 0 022 724.
  • a material based on porous calcium carbonate such as coral, can serve as a support for osteoinductive factors, and more generally for growth factors, in the preparation of bioresorbable implants and that the presence collagen is neither necessary nor desirable in the case where the implant is intended to be used as an osteoforming implant.
  • the present invention therefore relates to the use of a porous material based on calcium carbonate as a support for at least one growth factor in the preparation of a bioresorbable implant intended to be placed in a living animal organism, in particular in a vertebrate animal, including humans, said support being free of collagen in the case where said growth factor is an osteoinductive factor.
  • the growth factors are osteoinductive factors
  • the implants can be used as osteoforming implants.
  • these implants may contain, in addition to osteoinductive factors, other growth factors.
  • the implants thus obtained can either be placed as progressively absorbable bone filling pieces for the benefit of a newly formed tissue, or implanted in a non-bone site, for example a connective tissue, where they will give rise to bone tissue which can later be used as bone autograft material.
  • the calcium carbonate support When the calcium carbonate support is loaded with a non-osteoinductive growth factor, it can be used in particular as a support for the in vivo culture of living cells.
  • the implant after placement, can serve in particular as a support for obtaining new tissue at the location of implantation. This newly formed tissue can be used as a replacement for failing organ parts (pancreas-intestine connection, urethra, bladder, pericardium, etc.).
  • the implant of the invention can also be used as an in vivo culture support for genetically modified cells, in particular by insertion of an appropriate gene, in a manner known per se, to remedy a genetic defect.
  • the modified cells can possibly come from an autologous sample.
  • the implants thus obtained constitute an "organoid" serving as a therapeutic treatment device, the installation of which makes it possible to replace a failing organ, and in particular to remedy certain dysfunctions of genetic origin. It is therefore a new mode of implementation of gene therapies.
  • a hollow piece of coral can be produced, provided with an opening which can be closed by a plug, screwed or fitted, also made of coral.
  • ⁇ implantation in humans it can be a hollow cylinder having 2 to 10 cm of the eu 1 to 3 cm in external diameter and 0.5 to 2 cm in internal diameter.
  • the inner wall can be impregnated with collagen loaded with growth factors like TGF beta.
  • the outer wall can be impregnated with a solution of an angiogenic factor (FGF).
  • FGF angiogenic factor
  • the autologous cells (for example fibroblasts) modified are previously cultured in vitro on a solid support such as a network of collagen fibers or coral granules. The culture of modified cells, with its solid support, is introduced into the hollow part of the implant.
  • the implanted cells are organized into vascularized tissue surrounded by connective tissue replacing the coral as it is absorbed.
  • the cells introduced into the implant can be undifferentiated cells whose differentiation is effected by endogenous or exogenous cytokines.
  • the calcium carbonate-based material which can be used as a support for the growth factors is preferably aragonite.
  • One of the advantages of using the coral skeleton is that it contains communicating pores, which promotes neovascularization as well as invasion of the material by bone cells or by other cells previously introduced or recruited. in situ.
  • the porosity that is to say the volume proportion of the pores relative to the total volume of the material, is generally between 20 and 80%, for example between 40 and 60%.
  • Materials of this type can be obtained by using in particular the coral of the genera Porites, Acropora, Goniopora, Lobophyllia, Simphyllia and Millipora.
  • growth factors are polypeptides which act locally on certain cells by influencing their proliferation, their migration and / or their differentiation or which stimulate the production of other growth factors.
  • the growth factors having an osteoinductive effect are known and their effects have been studied in particular in vitro on cultures of various bone cells.
  • DBM Demineralized Bone Matrix
  • BP Bone Protein
  • BMP Bone Morphogenetic Protein
  • Another active protein is osteogenin.
  • growth factors influencing cellular growth in general including bone cell growth
  • IGF Insulin-like Growth Factor
  • PDGF Plateelet-Derived Growth Factor
  • FGF Fibroblast Growth Factor
  • BDGF II or beta-2-microglobulin
  • TGF Transforming Growth Factor
  • TGF beta or bTGF
  • the doses of growth factors that can be used are known or can be determined by routine experiments in animal models. Generally, growth factors, whose action is local, are used at doses of a few micrograms or a few tens of micrograms.
  • the invention also relates to the preparation of porous calcium carbonate supports loaded with growth factors. These can be incorporated:
  • binding agent in particular a binding agent capable of forming a gel.
  • binding agents are known. These are, for example, collagen or cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc. These products are biocompatible. They are commercially available.
  • a fibrin precursor for example fibrinogen or a biological glue (cryoprecipitate) can also be used as binding agents.
  • the binding agent notably has the effect of promoting the fixation of the growth factor and possibly its gradual release.
  • the binding agent is gradually absorbed as the implant is rehabilitated by a newly formed tissue.
  • Bovine BP having a protein concentration of 1.52 mg / ml is used as the osteoinductive factor.
  • the BP is diluted so as to obtain doses of 10, 35 and 100 micrograms of active principle in a volume of 20 microliters.
  • Each coral disc is impregnated with 20 microliters of one of the solutions obtained. After infiltration of the solution into the pores, the discs are frozen quickly and then subjected to lyophilization.
  • subcutaneous implants are produced in the ventral region in rats.
  • Three groups of five animals which each receive a coral implant impregnated with 10, 35 or 100 micrograms of BP, respectively.
  • the animals are administered, subcutaneously, a dose of
  • the implants are extracts, weighed, photographed and fixed in methanol.
  • the samples are coated in poly (methyl methacrylate) for histological examination.
  • the samples are cut and stained with the Rapid Bone Stain reagent and with Van Gieson micro-fuchsin. The sections are examined under a microscope.
  • the weights of the coral discs before implantation and after explantation are indicated in the following table 1, in which the results are expressed in the form of an average ⁇ standard deviation.
  • group I microscopic examination shows formation of still immature bone and hematopoietic marrow throughout the implant, as well as bone formation on the surface. Bone is formed and conduction by the material allows bone to grow. There is a harmony between osteoinduction and osteoconduction.
  • the mineralization is good throughout the implant, the newly formed bone is mature and lines the coral.
  • the osteoinduction dominates the osteoconduction and the bone is more important around the periphery of the implant.
  • the samples have a thick outer edge of mature bone with hematopoietic marrow in the center. In several cases, cartilage and cartilage in the process of mineralization are observed after a few weeks.
  • EXAMPLE 2 A trepanation is carried out on rats by ablation of a circular flap 8 mm in diameter on the top of the skull. In the window thus obtained, a disk of coral 8 mm in diameter. The coral discs are impregnated, in a manner analogous to that described in the previous example, by the osteoinductive factor (recombinant human BMP-2), at the rate of 0.5 micrograms of BMP-2 per 1 mg of coral. The day of the operation, intramuscular injection of calcein at a rate of 20 mg / kg. On the 27th day, orange xylenol (90 mg / kg) is injected intramuscularly.
  • the osteoinductive factor recombinant human BMP-2
  • part of the skullcap, including the implant is removed and fixed in 10% neutral formalin for histological study after inclusion in methyl methacrylate on non-demineralized sections stained with Giemsa dye. -Paragon. Microradiographs highlight the mineralization.
  • the sections show bone formation from the edges of the bone lesion and extending over the edges of the coral disc
  • Bilateral and symmetrical trepanation of the skull is performed on rabbits at the level of the parietal bones, by removal of two circular flaps 10 mm in diameter. Five batches of rabbits are made up: four test groups and one control group. Only one side of the individuals in each test group is treated.
  • Group 1 (Symbol MF): 50 microliters of methylcellulose gel containing 1 ⁇ g of TGF beta is applied in one of the windows.
  • Group 2 (Symbol BF): 100 ⁇ l of biological glue is applied to one of the windows to which 1 ⁇ g of TGF beta has been added.
  • Group 3 50 microliters of a mixture similar to that applied to the BF group are applied, but also containing 70 mg of Porites coral granules, marketed under the name BIOCORAL 450 by the company INOTEB.
  • Group 4 (Symbol BC): the same mixture is applied as for group 3, but without growth factor.
  • the diameter of the treated side is less than the diameter of the control side.
  • the diameter of the control side is less than the diameters observed in the control group.
  • VTO volume of the bone spans
  • the BCF group has the highest VTO, followed by the BC group.
  • the addition of the growth factor increases the speed of remineralization.
  • a piece of coral (porosity: 50%) is covered with a murine type I collagen gel containing an angiogenic growth factor (bFGF).
  • bFGF angiogenic growth factor
  • the coral pieces thus treated are implanted in a subcutaneous site in mice. Macroscopic and histological observation of the implants is carried out for one year.
  • the coral In a few months, the coral is absorbed. It gives way to a connective tissue of the same size and shape as the implant. After three months, there is a strong vascularization and the absence of any inflammatory cell compared to the coral residues.
  • the connective tissue is made up of sparse mesenchymal cells.
  • the collagen was replaced by carboxymethylcellulose or fibrinogen.
  • a network of collagen fibers containing autologous fibroblasts genetically modified by insertion of a gene using a retro viral vector is introduced.
  • the external wall of the cylinder was impregnated with a type I collagen gel associated with heparin.
  • the coral thus pretreated is incubated in the presence of a factor ar2iogenic growth (bFGF).
  • bFGF factor ar2iogenic growth
  • the implant After 45 days, the implant is removed. The vascularization of the latter is important and includes large caliber vessels. The resorption of the coral is initiated. The modified cells are viable and express the inserted gene. They are organized in vascularized tissue. A similar experiment was carried out on mice deficient in beta-glucuronidase and having a lysosomal overload disease. A human cDNA encoding beta-glucuronidase is inserted into a retroviral vector which is then used to modify mouse (autologous) cells. The modified cells are introduced into a network of collagen fibers and the whole is introduced into a coral cylinder treated in a similar manner to that described above. The implants thus prepared are inserted into the mesentery of the deficient mice.
  • the modified implanted cells are capable of secreting the missing enzyme which passes into the general circulation, thus causing the regression of the physiological consequences of the genetic defect, and in particular the correction of the hepatic and spleen lesions.

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PCT/FR1994/000565 1993-05-13 1994-05-11 Utilisation d'un materiau poreux a base de carbonate de calcium comme support pour un facteur de croissance dans la preparation d'un implant bioresorbable WO1994026322A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU67887/94A AU676056B2 (en) 1993-05-13 1994-05-11 Use of a calcium carbonate based porous material as support for a growth factor in the preparation of a bioabsorbable implant
AT94916275T ATE194922T1 (de) 1993-05-13 1994-05-11 Verwendung eines porösen materials aus kalziumcarbonat als träger für einen wachstumsfaktor in der herstellung eines resorbierbaren implantates
US08/360,801 US5711957A (en) 1993-05-13 1994-05-11 Use of a porous calcium carbonate based material as support of a growth factor in the preparation of a bioabsorbable implant
DE69425358T DE69425358T2 (de) 1993-05-13 1994-05-11 Verwendung eines porösen materials aus kalziumcarbonat als träger für einen wachstumsfaktor in der herstellung eines resorbierbaren implantates
CA002139864A CA2139864C (fr) 1993-05-13 1994-05-11 Utilisation d'un materiau poreux a base de carbonate de calcium comme support pour un facteur de croissance dans la preparation d'un implant bioresorbable
DK94916275T DK0650374T3 (da) 1993-05-13 1994-05-11 Anvendelse af et porøst materiale på basis af calciumcarbonat som bærer for en vækstfaktor ved fremstillingen af et bioreso
JP6525071A JP2957281B2 (ja) 1993-05-13 1994-05-11 生体吸収性移植片の製造に、成長因子のための支持体として、多孔性の炭酸カルシウムに基づく物質を使用する方法
EP94916275A EP0650374B1 (de) 1993-05-13 1994-05-11 Verwendung eines porösen materials aus kalziumcarbonat als träger für einen wachstumsfaktor in der herstellung eines resorbierbaren implantates
GR20000402357T GR3034667T3 (en) 1993-05-13 2000-10-23 Use of a calcium carbonate based porous material as support for a growth factor in the preparation of a bioabsorbable implant.

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FR9305783A FR2705235B1 (fr) 1993-05-13 1993-05-13 Utilisation de particules d'un sel de calcium biocompatible et biorésorbable comme ingrédient actif dans la préparation d'un médicament destiné au traitement local des maladies déminéralisantes de l'os.
FR93/05783 1993-05-13
FR93/13740 1993-11-17
FR9313740A FR2706768B1 (de) 1993-05-13 1993-11-17

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Cited By (13)

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Publication number Priority date Publication date Assignee Title
EP0729325A1 (de) * 1993-11-16 1996-09-04 Intermedics Orthopedics/Denver, Inc. Osteogenisches produkt und verfahren
EP0729325A4 (de) * 1993-11-16 2000-08-02 Intermedics Orthopedics Denver Osteogenisches produkt und verfahren
EP0758550A1 (de) * 1995-08-14 1997-02-19 Biomat Beschichtungsmaterial für Prothesen
FR2737850A1 (fr) * 1995-08-14 1997-02-21 Biomat Produit de revetement pour prothese
FR2737851A1 (fr) * 1995-08-14 1997-02-21 Biomat Produit de revetement pour prothese
US6322592B2 (en) 1996-01-15 2001-11-27 Universite De Rennes Macro-porous composite support for medicinal substance(s) that can be used as a bone reconstitution material and a method of producing it
FR2743496A1 (fr) * 1996-01-15 1997-07-18 Univ Rennes Composite macroporeux support de substance(s) medicamenteuse(s) utilisable comme materiau de reconstitution osseuse et procede d'elaboration
WO1997026024A1 (fr) * 1996-01-15 1997-07-24 Universite De Rennes 1 Composite macroporeux support de substance(s) medicamenteuse(s) utilisable comme materiau de reconstitution osseuse et procede d'elaboration
WO1997031661A1 (en) * 1996-02-29 1997-09-04 Lindholm T Sam An osteogenic device and a method for preparing the device
US7186811B2 (en) 1996-02-29 2007-03-06 Bioactive Bone Substitutes Oy, Ab Osteogenic device and a method for preparing the device
WO2009066283A2 (en) * 2007-11-19 2009-05-28 Ben Gurion University Of The Negev Research And Development Authority Calcium-mediated effects of coral and methods of use thereof
WO2009066283A3 (en) * 2007-11-19 2009-11-05 Ben Gurion University Of The Negev Research And Development Authority Calcium-mediated effects of coral and methods of use thereof
US8932581B2 (en) 2007-11-19 2015-01-13 Ben Gurion University Of The Negev Research And Development Authority Calcium-mediated effects of coral and methods of use thereof

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CA2139864A1 (fr) 1994-11-24
CA2139864C (fr) 2003-07-15
US5711957A (en) 1998-01-27
EP0650374B1 (de) 2000-07-26
ES2150492T3 (es) 2000-12-01
AU6788794A (en) 1994-12-12
FR2706768B1 (de) 1995-12-01
EP0650374A1 (de) 1995-05-03
DE69425358T2 (de) 2001-03-29
DE69425358D1 (de) 2000-08-31
ATE194922T1 (de) 2000-08-15
DK0650374T3 (da) 2000-11-06
JPH08503157A (ja) 1996-04-09
PT650374E (pt) 2000-12-29
JP2957281B2 (ja) 1999-10-04
AU676056B2 (en) 1997-02-27
FR2706768A1 (de) 1994-12-30

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