EP4153258A1 - Matériau de substitution osseux poreux - Google Patents
Matériau de substitution osseux poreuxInfo
- Publication number
- EP4153258A1 EP4153258A1 EP21726661.8A EP21726661A EP4153258A1 EP 4153258 A1 EP4153258 A1 EP 4153258A1 EP 21726661 A EP21726661 A EP 21726661A EP 4153258 A1 EP4153258 A1 EP 4153258A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- bone
- advantageously
- substitute material
- porous
- poly
- 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.)
- Pending
Links
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Classifications
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- 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
- A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
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- 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
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- 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
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/005—Ingredients of undetermined constitution or reaction products thereof
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/146—Porous materials, e.g. foams or sponges
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- 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
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
- A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- this natural self-healing process is insufficient: about one in ten times mechanical or biological problems prevent self-healing of a fracture.
- certain bone lesions encountered in victims of domestic or road accidents, terrorist attacks, certain pathologies (such as pseudo-arthritis) or surgical interventions (removal of tumors, cysts, infectious foci) can lead to significant losses of bone substance that natural osteogenesis will not suffice to fill. The reconstruction of the bone must then be assisted.
- Another solution considered to repair bone is to transplant a bone fraction from a donor.
- the bone replacement material must have two important properties:
- the present invention therefore relates to a porous bone substitute material comprising:
- the present invention also relates to the use of said porous bone substitute material in bone repair, preferably the repair of a cavitary bone defect and / or the repair of a segmental bone defect.
- a subject of the present invention is also a process for preparing a bone substitute material.
- bone substitute material is understood to mean a physical support on which osteoprogenitor cells can adhere, migrate, proliferate and differentiate into osteoblasts, cells responsible for bone formation, on the surface and on the surface. inside the bone substitute material.
- the bone substitution material according to the invention is a composite material comprising at least one porous elastomeric matrix and bone particles. decellularized, the individual properties of which combine to form a heterogeneous material (the bone substitute material) having greatly improved overall performance, properties which cannot be observed with the at least one elastomeric matrix or particles of decellularized bone, when used individually.
- the term “elastomeric matrix” is understood to mean a structure consisting of a porous elastomer system, said structure being capable of including particles of decellularized bone.
- at least one elastomeric matrix according to the present invention has good biodegradability, good biocompatibility and good mechanical properties.
- the isocyanate number of the elastomeric matrix is between 0.1 and 6.0.
- the isocyanate number is between 0.1 and 5.0, advantageously between 0.2 and 4.9, advantageously between 0.3 and 4.8, advantageously between 0.4 and 4.7, advantageously between 0.5 and 4.7, advantageously between 0.6 and 4.6, advantageously between 0.7 and 4.5, advantageously between 0.8 and 4.5, advantageously between 0.9 and 4.5, advantageously between 1 and 4.5, advantageously between 1.05 and 4.5, advantageously between 1.1 and 4.5, advantageously between 1.2 and 4.5, advantageously between 1.3 and 4.5, advantageously between 1.4 and 4.5, advantageously between 1.5 and 4.5, advantageously between 2.0 and 4.5, advantageously between 2.5 and 4.5, advantageously between 2.6 and 4.4, advantageously between 2.7 and 4.3, advantageously between 2.8 and 4.2, advantageously between 2.9 and 4.1, advantageously between 3.0 and 4.0.
- the term “elastomer” is understood to mean one or more crosslinked polymers exhibiting “rubbery elasticity” properties.
- the elastomer must be biocompatible and biodegradable.
- the Young's modulus in compression of the bone substitute material of the invention is between 10kPa and 1000kPa.
- biocompatible elastomeric matrix is understood to mean an elastomeric matrix which is advantageously both compatible for implantation in a patient, that is to say that this implantation presents a favorable benefit / risk ratio. from a therapeutic point of view, for example within the meaning of Directive 2001/83 / EC, ie a reduced or non-existent risk for the patient, versus the therapeutic benefit concerned; and compatible to include therein particles of decellularized bone, that is to say it allows the inclusion of particles of decellularized bone, that it does not or only slightly degrades the activity of the particles of decellularized bone included in the matrix, and which is suitable for bone reconstruction once the bone substitute material is implanted in a patient, human or animal.
- biodegradable elastomer matrix is understood to mean an elastomeric matrix which is bioresorbable and / or biodegradable and / or bioabsorbable, with a common goal of gradual disappearance, with one or more different or complementary degradation mechanisms, solubilization or absorption of the elastomeric matrix in the patient, human or animal, in which the material has been implanted.
- the at least one elastomeric matrix of the porous bone substitute material according to the invention comprises an elastomer based on poly (ester-urea-urethane), the ester being chosen from caprolactone oligomers (PCL), lactic acid oligomers (PLA), glycolic acid oligomers (PGA), hydroxybutyrate oligomers (PHB), hydroxyvalerate oligomers (PVB), dioxanone oligomers (PDO), oligomers of poly (ethylene adipate) (PEA), poly (butylene adipate) (PBA) oligomers or combinations thereof.
- PCL caprolactone oligomers
- PLA lactic acid oligomers
- PGA glycolic acid oligomers
- PHB hydroxybutyrate oligomers
- PVB hydroxyvalerate oligomers
- PDO dioxanone oligomers
- PDA oligomers of poly (ethylene adipate) (PEA), poly
- At least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane). In another particular embodiment, at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (hydroxybutyrate-urea-urethane). In another particular embodiment, at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (dioxanone-urea-urethane).
- At least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (ethylene adipate-urea-urethane). In another particular embodiment, at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (butylene adipate-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (hydroxyvalerate-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (hydroxybutyrate-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (butylene adipate-urea-urethane).
- At least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and poly (glycolic acid-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and poly (hydroxyvalerate-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and on poly (hydroxybutyrate-urea-urethane).
- at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and poly (dioxanone-urea-urethane).
- At least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and poly (ethylene adipate-urea-urethane).
- at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and poly (butylene adipate-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (glycolic acid-urea-urethane) and poly (hydroxyvalerate-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (glycolic acid-urea-urethane) and poly (hydroxybutyrate-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (glycolic acid-urea-urethane) and poly (butylene adipate-urea-urethane).
- At least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane) and poly (hydroxybutyrate-urea-urethane).
- at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane) and poly (dioxanone-urea-urethane).
- At least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane) and poly (ethylene adipate-urea-urethane).
- at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane) and poly (butylene adipate-urea-urethane).
- At least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (ethylene adipate-urea-urethane) and poly (butylene adipate-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), poly (lactic acid-urea-urethane) and poly (glycolic acid-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), poly (lactic acid-urea-urethane), poly (glycolic acid-urea-urethane), poly (hydroxyvalerate-urea-urethane), poly (hydroxybutyrate-urea-urethane) and poly (dioxanone-urea-urethane).
- the at least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), poly (lactic acid-urea-urethane), poly (glycolic acid-urea-urethane), poly (hydroxyvalerate-urea-urethane), poly (hydroxybutyrate-urea-urethane), poly (dioxanone-urea-urethane) and poly (butylene adipate-urea-urethane) .
- At least one elastomeric matrix of the porous bone substitute material is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane).
- This matrix comprising an elastomer based on poly (caprolactone-urea-urethane) also has the advantage of having an elastomeric character, giving it flexibility, having an interconnected porous structure and suitable osteo-induction properties. to bone reconstruction.
- the bone particles present in the porous bone substitute material are particles of decellularized bone.
- decellularized bone means the bone collagen matrix consisting exclusively of collagen, in particular type I collagen, of the mineral phase consisting of crystals of hydroxyapatite (crystallized calcium phosphate) and of calcium carbonate, and osteo-inductive proteins. The presence of collagen and osteoinductive proteins allows the increase in osteoconduction and osteoinduction.
- the decellularized bone is obtained from a natural spongy bone.
- the natural spongy bone can be a human femoral head.
- a decellularized bone particle comprises, relative to the total weight of the particle:
- the calcium / phosphorus ratio being advantageously from 1 to 2.2.
- the particles of decellularized bone of the porous bone substitute material can be obtained from natural bone.
- the natural bone particles can be obtained from allogeneic or xenogeneic bone, of human or animal origin.
- the particles of decellularized bone of the porous bone substitute material can be obtained from natural bone according to one of the methods described in patents FR2798294 or EP0502055.
- the particles of decellularized bone of the porous bone substitute material according to the invention are obtained from natural bone of human or animal origin.
- the particles of decellularized bone of the porous bone substitution according to the invention are obtained from a natural spongy bone.
- the natural spongy bone can be a human femoral head.
- the particles of decellularized bone according to the invention have a diameter of between 1nm and 1mm.
- the diameter of the particles of decellularized bone is between 1nm and 1mm, advantageously between 10 nm and 900 pm, advantageously between 100 nm and 800 pm, advantageously between 100 nm and 700 pm, advantageously between 100 nm and 600 pm, advantageously between 100 nm and 500 pm, advantageously between 1pm and 800 pm, advantageously between 1pm and 700 pm, advantageously between 10 pm and 600 pm, advantageously between 100 pm and 550 pm, advantageously between 200 pm and 500 pm, advantageously between 300 pm and 450 pm, advantageously between 300 pm and 400 pm.
- the diameter of the particles of decellularized bone is between 300 ⁇ m and 400 ⁇ m.
- decellularized bone By way of example of decellularized bone, mention may in particular be made of Allodyn® and Osteopure® (OST Développement, Clermont Ferrand) for bone of human origin, or the product Laddec®, (OST Développement, Clermont -Ferrand) for bone of animal origin.
- Allodyn® and Osteopure® OST Développement, Clermont Ferrand
- Laddec® OST Développement, Clermont -Ferrand
- the porous bone substitute material according to the invention comprises:
- elastomeric matrix comprising an elastomer based on poly (ester-urea-urethane), the ester being chosen from oligomers of caprolactone (PCL), oligomers of lactic acid (PLA), oligomers of acid glycolic (PGA), hydroxybutyrate oligomers (PHB), hydroxyvalerate oligomers (PVB), dioxanone oligomers (PDO), poly (ethylene adipate) oligomers (PEA), poly (butylene adipate) oligomers ) (PBA) or combinations thereof, and
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
- the porous bone substitute material according to the invention comprises: - at least one elastomeric matrix comprising an elastomer based on poly (lactic acid-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (glycolic acid-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (glycolic acid-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and poly (glycolic acid-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), on poly (lactic acid-urea-urethane) and on poly (glycolic acid-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (hydroxybutyrate-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (dioxanone-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (ethylene adipate-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (butylene adipate-urea-urethane), and
- the porous bone substitute material according to the invention consists only of:
- elastomeric matrix comprising an elastomer based on poly (ester-urea-urethane), the ester being chosen from oligomers of caprolactone (PCL), oligomers of lactic acid (PLA), oligomers of acid glycolic (PGA), oligomers of hydroxybutyrate (PHB), oligomers of hydroxyvalerate (PVB), oligomers of dioxanone (PDO), oligomers of poly (ethylene adipate) (PEA), oligomers of poly (butylene adipate) (PBA) or combinations of these, and
- the porous bone substitute material according to the invention consists of:
- elastomeric matrix comprising an elastomer based on poly (ester-urea-urethane), the ester being chosen from oligomers of caprolactone (PCL), oligomers of lactic acid (PLA), oligomers of acid glycolic (PGA), hydroxybutyrate oligomers (PHB), hydroxyvalerate oligomers (PVB), dioxanone oligomers (PDO), poly (ethylene adipate) oligomers (PEA), poly (butylene adipate) oligomers ) (PBA) or combinations thereof, and
- the decellularized bone particles can be obtained from natural bone of human or animal origin or from synthetic bone.
- the particles of decellularized bone having a diameter between 1 nm and 1 mm, advantageously between 300 ⁇ m and 400 ⁇ m.
- the porous bone substitute material according to the invention comprises:
- At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
- the inventors have demonstrated that the specific combination of particles of decellularized bone and of at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), gives the porous bone substitute material a better biocompatibility of the material due to the presence of hydroxyapatite.
- the degradation of at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) produces a slightly acidic environment, resulting in a decrease in cell proliferation.
- the addition of particles of decellularized bone helps neutralize this acidity, thanks to the presence of hydroxyapatite.
- the inventors have also demonstrated that the specific combination of particles of decellularized bone and of at least one elastomeric matrix comprising an elastomer based on of poly (caprolactone-urea-urethane), allows an increase in osteo-induction compared with the use of the elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) alone.
- the addition of particles of decellularized bone leads to an increase in cell attachment and mineralization without the addition of exogenous factors, due to changes in the topography of the surface of the porous bone substitute material and / or the release. calcium ion.
- porous bone substitute material consists only of:
- At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
- porous bone substitute material consists of:
- At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
- the porous bone substitute material according to the invention comprises:
- particles of decellularized bone having been obtained from natural bone of human or animal origin or from synthetic bone.
- porous bone substitute material consists of:
- At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
- particles of decellularized bone having been obtained from natural bone of human or animal origin or from synthetic bone.
- the porous bone substitute material according to the invention comprises:
- the porous bone substitute material according to the invention comprises:
- particles of decellularized bone having a diameter of between 1nm and 1mm, advantageously between 300pm and 400pm, said particles of decellularized bone having been obtained from a natural bone of human origin or animal or from synthetic bone.
- the particles of decellularized bone represent at least 10% by weight of the porous bone substitute material.
- the particles of decellularized bone represent at least 11% by weight of the porous bone substitute material, advantageously at least 12%, advantageously at least 13%, advantageously at least 14%, advantageously at least 15%, advantageously at least 16 %, advantageously at least 17%, advantageously at least 18%, advantageously at least 19%, advantageously at least 20%, advantageously at least 21%, advantageously at least 22%, advantageously at least 23%, advantageously at least 24%, advantageously at least 25%, advantageously at least 26%, advantageously at least 27%, advantageously at least 28%, advantageously at least 29%, advantageously at least 30%, advantageously at least 31%, advantageously at least 32%, advantageously at less 33%, advantageously at least 34%, advantageously at least 35%, advantageously at least 36%, advantageously at least 37%, advantageously at least 38%, advantageously at least 39%, advantageously at least 40%,
- the particles of decellularized bone represent between 10% and 50% by weight of the porous bone substitute material.
- the particles of decellularized bone represent between 11% and 50%, advantageously between 12% and 50%, advantageously between 13% and 50%, advantageously between 14% and 50%, advantageously between 15% and 50%, advantageously between 16% and 50%, advantageously between 17% and 50%, advantageously between 18% and 50%, advantageously between 19% and 50%, advantageously between 20% and 50%, advantageously between 21% and 50%, advantageously between 22% and 50%, advantageously between 23% and 50%, advantageously between 24% and 50%, advantageously between 25% and 50%, advantageously between 26% and 50%, advantageously between 27% and 50%, advantageously between 28% and 50%, advantageously between 29% and 50%, advantageously between 30% and 50%, advantageously between 31% and 50%, advantageously between 32% and 50%, advantageously between 33% and 50%, advantageously between 34% and 50%, advantageously between 35% and 50%, advantageously between 36% and 50%, advantageously between 37% and 50%, advantageously between 38% and 50%, advantageously, advantageous
- the particles of decellularized bone represent 33% by weight of the porous bone substitute material. In another particularly advantageous embodiment of the invention, the particles of decellularized bone represent 50% by weight of the porous bone substitute material.
- the porous bone substitute material has a multiscale pore size of between 50 ⁇ m and 2000 ⁇ m.
- pore size and “pore diameter” can be used interchangeably.
- multiscale pore size is meant a variable distribution of pore sizes, that is to say comprising both pores of several microns and pores of smaller sizes, in varying proportions.
- a bone substitute material having a multiscale pore size of between 50 ⁇ m and 2000 ⁇ m means that the bone substitute material comprises both and in the same bone substitute material, pores having variable sizes, between 50 ⁇ m and 2000 ⁇ m.
- a bone replacement material having a multiscale pore size of between 50 ⁇ m and 2000 ⁇ m means that the bone replacement material comprises both and in the same bone replacement material, pores for example having a size of 50 ⁇ m, pores having a size of 100 ⁇ m, pores having a size of 500 ⁇ m, pores having a size of 1500 ⁇ m, pores having a size 2000 ⁇ m.
- the size of the multiscale pores of the porous bone substitute material is between 50 ⁇ m and 2000 ⁇ m, advantageously between 50 ⁇ m and 1500 ⁇ m, advantageously between 50 ⁇ m and 1000 ⁇ m, advantageously between 50 ⁇ m and 800 ⁇ m, advantageously between 100 ⁇ m and 1500 ⁇ m, advantageously between 100 ⁇ m and 1000 ⁇ m, advantageously between 100 ⁇ m and 800 ⁇ m.
- the pores of the bone substitute material have a rough surface.
- macroporosity when the size of the pores is greater than 50nm, of microporosity, when the size of the pores is less than 2nm and of mesoporosity, when the size of the pores is between 2nm and 50nm.
- the porous bone substitute material exhibits macroporosity.
- the porous bone substitute material has a total porosity greater than or equal to 60%.
- total porosity is understood to mean the ratio of the volume of empty spaces of material to the overall volume of the porous bone substitute material.
- the total porosity of the porous bone substitute material is greater than or equal to 60%, advantageously greater than or equal to 61%, advantageously greater than or equal to 62%, advantageously greater than or equal to 63%, advantageously greater than or equal to 64% , advantageously greater than or equal to 65%, advantageously greater than or equal to 66%, advantageously greater than or equal to 67%, advantageously greater than or equal to 68%, advantageously greater than or equal to 69%, advantageously greater than or equal to 70%, advantageously greater than or equal to 71%, advantageously greater than or equal to 72%, advantageously greater than or equal to 73%, advantageously greater than or equal to 74%, advantageously greater than or equal to 75%, advantageously greater than or equal to 76%, advantageously greater than or equal to 77%, advantageously greater than or equal to 78%, advantageously greater than or equal to 79%, advantageously greater than or equal to 80%, advantageously greater than or equal to equal to 81%, advantageously greater than or equal to 82%, advantageously greater than or equal to 83%,
- the total porosity of the porous bone substitute material is between 60% and 95%, advantageously between 61% and 89%, advantageously between 62% and 88%, advantageously between 63% and 87%, advantageously between 64% and 86 %, advantageously between 65% and 85%, advantageously between 66% and 84%, advantageously between 67% and 83%, advantageously between 68% and 82%, advantageously between 69% and 81%, advantageously between 70% and 80%.
- the porous bone substitute material has a total porosity of between 70% and 90%.
- the porous bone substitute material exhibits an interconnectivity between the pores of between 60% and 100%.
- the interconnectivity between the pores is between 65% and 100%, advantageously between 70% and 100%, advantageously between 75% and 100%, advantageously between 80% and 100%, advantageously between 85% and 100%, advantageously between 90% and 100%, advantageously between 91% and 100%, advantageously between 92% and 100%, advantageously between 93% and 100%, advantageously between 94% and 100%, advantageously between 95% and 100%, advantageously between 96 % and 100%, advantageously between 97% and 100%, advantageously between 98% and 100%, advantageously between 99% and 100%.
- the interconnectivity between the pores is greater than 65%, advantageously greater than 70%, advantageously greater than 75%, advantageously greater than 80%, advantageously greater than 85%, advantageously greater 90%, advantageously greater than 91%, advantageously greater than 92%, advantageously greater than 93%, advantageously greater than 94%, advantageously greater than 95%, advantageously greater than 96%, advantageously greater than 97%, advantageously greater than 98 %, advantageously greater than 99%.
- the porous bone substitute material exhibits 100% inter-pore interconnectivity.
- the porous bone substitute material according to the invention has a multiscale pore size of between 50 ⁇ m and 2000 ⁇ m, a total porosity of between 60% and 95% and interconnectivity between the pores. between 60% and 100%.
- the porous bone substitute material according to the invention has a multiscale pore size of between 50 ⁇ m and 2000 ⁇ m, a total porosity of between 70% and 85% and an interconnectivity between the pores of 100%.
- the porous bone substitute material comprising at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and particles of decellularized bone, has a multiscale pore size between 50 ⁇ m and 2000 ⁇ m, a total porosity between 60% and 95% and an interconnectivity between the pores between 60% and 100%.
- the porous bone substitute material comprising at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and particles of decellularized bone, has a multiscale pore size of between 50 ⁇ m and 2000.
- the porous bone substitution material comprising at least one elastomeric matrix comprising an elastomer based on poly ( caprolactone-urea-urethane) and particles of decellularized bone is particularly suited to cell migration and bone formation within said porous bone substitute material.
- the multi-scale pore size between 50 ⁇ m and 2000 ⁇ m and the interconnectivity between the pores of 100% allow to regulate angiogenesis and osteogenesis even inside the porous bone substitute material according to invention. Indeed, the interconnected porous network helps guide attachment and cell growth, and therefore the growth of newly formed bone.
- the porous bone substitute material comprising at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and particles of decellularized bone therefore allows the migration of progenitor cells and their differentiation into osteoblasts, which in fact an osteo-conductive material.
- the size of the porous bone substitute material is dependent on the size and thickness of the bone to be reconstructed.
- the porous bone substitute material has a size of between 10 mm and 20 cm and a thickness of between 100 ⁇ m and 4 cm.
- the size of the porous bone substitute material is between 10 mm and 20 cm, advantageously between 50 mm and 20 cm, advantageously between 100 mm and 20 cm, advantageously between 500 mm and 20 cm, advantageously between 1 cm and 20 cm , advantageously between 2 cm and 20cm, advantageously between 3 cm and 20 cm, advantageously between 4 cm and 20 cm, advantageously between 5 cm and 20 cm, advantageously between 6 cm and 20 cm, advantageously between 7 cm and 20 cm, advantageously between 8 cm and 20 cm, advantageously between 9 cm and 20 cm, advantageously between 10 cm and 20 cm, advantageously between 11 cm and 20 cm, advantageously between 12 cm and 20 cm, advantageously between 13 cm and 20 cm, advantageously between 14 cm and 20 cm, advantageously between 15 cm and 20 cm.
- the size of the porous bone substitute material is 10 cm, in particular when the bone to be reconstructed is a long bone.
- the thickness of the porous bone substitution material is between 100 ⁇ m and 4 cm, advantageously between 200 ⁇ m and 4 cm, advantageously between 500 ⁇ m and 4 cm, advantageously between 1 mm and 4 cm, advantageously between 1 cm and 4 cm. cm, advantageously between 1 cm and 3 cm.
- the thickness of the porous bone substitute material is between 1 cm and 3 cm, in particular when the bone to be reconstructed is a long bone.
- the thickness of the porous bone substitute material is between 100 ⁇ m and 1 cm, in particular when the bone to be reconstructed is a flat bone.
- the porous bone substitute material has a volume of at least 0.1 cm 3 .
- the porous bone substitution material has a volume of at least 0.2 cm 3 , advantageously at least 0.3 cm 3 , advantageously at least 0.4 cm 3 , advantageously at least 0.5 cm 3 , advantageously at least.
- the bone substitute material can be in different forms, advantageously in cylindrical, planar or prismatic forms.
- the bone substitute material may be in the form of a flexible porous sponge, in the form of a flexible porous membrane, in the form of a flexible porous film.
- the bone replacement material according to the invention is used alone.
- the material substitution can further be used in combination with an active agent.
- the active agent is placed inside the pores of the bone replacement material according to the invention, partially or completely covering the pores of the bone replacement material.
- the active agent can be added by one of the following methods: covering the bone substitute material with the active agent, immersion of the bone substitute material in the active agent, spraying of the active agent on the material of bone substitution, vaporization of the active agent on the bone substitution material or any other technique well known to those skilled in the art making it possible to fill and / or fill the pores of said bone substitution material.
- the active agent can be any therapeutic or pharmaceutically active agent (including, but not limited to nucleic acids, proteins, lipids and carbohydrates) which possesses desirable physiological characteristics for application to the site. implantation.
- Therapeutic agents include, without limitation, anti-infectives such as antibiotics and antiviral agents; chemotherapeutic agents (eg, anticancer agents); anti-rejection agents; analgesics and analgesic combinations; anti-inflammatory agents; hormones such as steroids; growth factors (including, but not limited to cytokines, chemokines and interleukins), coagulation factors (factors VII, VIII, IX, X, XI, XII, V), albumin , fibrinogen, von Willebrand factor, thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensives, antimicrobials, antibiotics , surface glycoprotein receptor inhibitors, antiplatelet agents
- the active agent is a combination of therapeutic agents, and in particular a combination of antibiotics and growth factors.
- Another aspect of the invention relates to the porous bone substitute material according to the invention for its use in bone repair.
- the term “bone repair” is understood to mean the reconstruction by induction of osteogenesis of an injured bone.
- the porous bone substitute material of the invention can be useful in repairing a variety of orthopedic injuries.
- the porous bone replacement material according to the invention can be used for the repair of a cavitary bone defect and / or the repair of a segmental bone defect.
- the porous bone replacement material according to the invention can be used for the repair of a cavitary bone defect.
- the porous bone replacement material according to the invention can be used for the repair of a segmental bone defect.
- the porous bone replacement material according to the invention can be used for the repair of a maxillofacial bone defect.
- the term “cavitary bone defect” is understood to mean a loss of bone exhibiting a volume of at least 0.1 cm 3 without loss of continuity with respect to the total surface of the bone not exhibiting. default.
- the loss of bone without loss of continuity has a volume of at least 0.1 cm 3 .
- the porous bone substitution material has a volume of at least 0.2 cm 3 , advantageously at least 0.3 cm 3 , advantageously at least 0.4 cm 3 , advantageously at least 0.5 cm 3 , advantageously at least.
- the term “segmental bone defect” is understood to mean a loss of bone in the length of the bone of at least 10 mm with loss of continuity with respect to the bone which does not exhibit any defect.
- the loss of bone with loss of continuity is at less 10 mm, advantageously at least 50 mm, advantageously at least 100 mm, advantageously at least 500 mm, advantageously at least 1 cm, advantageously at least 2 cm, advantageously at least 3 cm, advantageously at least 4 cm, advantageously at least 5 cm , advantageously at least 6 cm, advantageously at least 7 cm, advantageously at least 8 cm, advantageously at least 9 cm, advantageously at least 10 cm, advantageously at least 11 cm, advantageously at least 12 cm, advantageously at least 13 cm, advantageously at least 14 cm, advantageously at least 15 cm.
- porous bone replacement material according to the invention can be used as a remodeling implant or prosthetic bone replacement, for example in orthopedic surgery, including hip revisions, replacement of bone loss, for example in traumatology, remodeling in maxillofacial surgery or filling of periodontal defects and tooth extraction sockets, including ridge augmentation and sinus elevation.
- the porous bone replacement material according to the invention can thus be used to correct any number of bone defects at a bone repair site.
- the porous bone substitute material according to the invention can be used to repair any type of bone, of human or animal origin.
- the porous bone substitute material according to the invention can be used to repair long bone. Examples of long bones include the humerus, femur, tibia, fibula, radius and ulna.
- the porous bone substitute material according to the invention can be used to repair short bone. Examples of short bones include the vertebrae, kneecap, carpal bone, and tarsal bone.
- the porous bone substitute material according to the invention can be used to repair flat bone. Examples of flat bone include the ribs, skull bone, iliac bone, scapula, and breastbone.
- the porous bone substitute material according to the invention can be used to repair maxillofacial bone.
- the bone repair is greater than or equal to 5% by volume of the volume of the bone to be repaired.
- the bone repair is greater than or equal to 6% by volume of the volume of the bone to be repaired, advantageously greater than or equal to 7%, advantageously greater than or equal to 8%, advantageously greater than or equal to 9%, advantageously greater than or equal to 10%, advantageously greater than or equal to 11%, advantageously greater than or equal to 12%, advantageously greater or equal to 13%, advantageously greater than or equal to 14%, advantageously greater than or equal to 15%, advantageously greater than or equal to 16%, advantageously greater than or equal to 17%, advantageously greater than or equal to 18%, advantageously greater than or equal at 19%, advantageously greater than or equal to 20%, advantageously greater than or equal to 21%, advantageously greater than or equal to 22%, advantageously greater than or equal to 23%, advantageously greater than or equal to 24%, advantageously greater than or equal to 25 %, advantageously greater than or equal to 26%,
- the porous bone substitute material according to the invention can be used for bone repair in humans or animals.
- the animal can be a horse, a pony, a dog, a cat, a rat, a mouse, a pig, a sow, a cow, an ox, a bull, a calf, a goat, a sheep, a ram, a lamb, a lamb, a donkey, a camel, a dromedary, the list not being exhaustive.
- the bone repair kit comprises the porous bone replacement material comprising at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and particles of decellularized bone according to the invention and a fixing element.
- the term “fixing element” is understood to mean a metal plate or a tubular, circular, internal or external fastener intended for keeping the porous bone substitute material according to the invention in place on the bone to be repaired while it consolidates.
- the fixator can be a locked plate with screw holes provided with a thread, allowing the placement of counter-screws, preventing any retreat of the screws, such as the Surfix® fixator.
- the fixer may be a polyetheretherketone (PEEK) plate from the company RiSystem or a steel plate.
- the porous bone substitute material according to the invention is obtained by the poly-HIPE method (formation and polymerization / crosslinking of high internal phase emulsions).
- High internal phase emulsions or HIPE consist of liquid / liquid immiscible dispersed systems, in which the volume of the internal phase, also called the dispersed phase, occupies a volume greater than about 74 - 75% of the total volume of the emulsion, that is to say a volume greater than what is geometrically possible for the compact packaging of monodisperse spheres.
- the process for preparing a porous bone substitute material comprises the following steps: a) preparing an organic phase comprising the compounds necessary for the synthesis of poly (ester-urea-urethane), b) adding water and the particles of bone decellularized in the organic phase of step a) to form an emulsion, c) polymerize / crosslink the emulsion containing the particles of bone decellularized in step c) to obtain said material porous bone substitution material, d) washing said porous bone substitution material obtained in step c), and e) drying said porous bone substitution material obtained in step d).
- step a) consists in preparing an organic phase comprising the compounds necessary for the synthesis of poly (ester-urea-urethane).
- the organic phase further comprises an oligoester, an organic solvent for the oligoester, a crosslinking agent, a catalyst and a surfactant.
- the organic phase comprises toluene, the polycaprolactone triol oligomer, the Span80 surfactant, the hexamethylene diisocyanate crosslinking agent (HMDI) and the dibutyltin dilaurate (DBTDL) catalyst.
- HMDI hexamethylene diisocyanate crosslinking agent
- DBTDL dibutyltin dilaurate
- step a) comprises a first step a1) consisting in dissolving in toluene, the polycaprolactone triol oligomer and the Span80 surfactant, then a second step a2) consisting in adding the crosslinking agent HMDI and the DBTDL catalyst in the solution of step a1) to form the organic phase.
- a first step a1) consisting in dissolving in toluene, the polycaprolactone triol oligomer and the Span80 surfactant
- a second step a2) consisting in adding the crosslinking agent HMDI and the DBTDL catalyst in the solution of step a1) to form the organic phase.
- 7 ml of toluene is used, 1.3 g of polycaprolactone triol oligomer, 1.3 g of Span80 surfactant, 1.04 ml of HMDI crosslinking agent and 12 drops of DBTDL catalyst. are used.
- step b) of the process consists of adding water to the organic phase to form the emulsion, then adding particles of decellularized bone to the emulsion.
- the water and the particles of decellularized bone are introduced gradually and concomitantly with stirring, until an emulsion is obtained.
- the water is sterilized distilled water.
- the amount of water added is 34m L.
- step c) of the process consists in polymerizing / crosslinking the emulsion obtained in step b) to obtain said porous bone substitute material.
- the polymerization / crosslinking is carried out in a mold to give the porous bone substitute material the desired shape.
- the emulsion obtained in step b) is placed at a temperature of between 30 ° C and 80 ° C for 10 to 30 hours.
- the emulsion obtained in step b) is placed at a temperature between 35 ° C and 65 ° C, advantageously at a temperature between 40 ° C and 60 ° C, advantageously at a temperature between 45 ° C and 65 ° C, advantageously at a temperature between 50 ° C and 60 ° C, advantageously at a temperature of 55 ° C.
- the emulsion obtained in step b) is placed at a temperature between 30 ° C and 80 ° C for 10 to 30 hours, advantageously for 11 to 29 hours, advantageously for 12 to 29 hours, advantageously for 13 to 28 hours, advantageously for 14 to 27 hours, advantageously for 15 to 27 hours, advantageously for 16 to 27 hours, advantageously for 17 to 27 hours, advantageously for 18 to 26 hours, advantageously for 19 to 25 hours, advantageously for 20 to 24 hours, preferably for 22 hours.
- a person skilled in the art will know adapt the temperature according to the pore size desired for the porous bone substitute material.
- the porous bone substitute material obtained in step c) is annealed prior to step d).
- the porous bone substitute material obtained in step c) is annealed for at least 1 hour at a temperature of at least 50 ° C.
- the porous bone substitute material obtained in step c) is annealed for 2 hours at a temperature of 100 ° C.
- the washing step of step d) makes it possible to remove the reagents necessary for the synthesis of the poly (ester-urea-urethane) which have not reacted during the polymerization as well as the surfactant and catalyst still present.
- the washing of step d) is carried out using one of the following products: dichloromethane, dichloromethane / hexane, hexane, water, a mixture of these products or the successive application of these products.
- the washing of step d) is carried out by bringing the dried porous bone substitute material into contact with dichloromethane for at least 24 hours, followed by a washing step with dichloromethane / hexane (50% vol / 50 % vol) for at least 24 hours, followed by a washing step with hexane for at least 24 hours, then a final wash with distilled water for at least 24 hours.
- the method according to the invention may further comprise a drying step between step c) and step d).
- this drying step can be carried out by drying in the open air or in an oven.
- a person skilled in the art will know how to adapt the temperature of the oven according to the material to be dried.
- the drying is carried out by drying in the open air for at least 7 days.
- the drying of step e) can be carried out by drying in the open air or in an oven.
- a person skilled in the art will know how to adapt the temperature of the oven according to the material to be dried.
- the drying is carried out by drying in the open air for at least 15 days.
- the method according to the invention may further comprise a step f) of sterilization after step e) of washing said porous bone substitute material.
- step f) of sterilization can be carried out directly on the dry porous bone substitute material or after washing the biomaterial under vacuum in an aqueous medium.
- the sterilization is carried out after washing under vacuum in an aqueous medium.
- the sterilization step f) is carried out as follows: f1) contacting the porous bone substitute material in sterile water for one hour under vacuum, f2) replacing the sterile water and contacting the porous bone substitute material in sterile water replaced for 4 hours under vacuum, f3) contacting the porous bone substitute material from step f2) in 70% ethanol for 1 hour under vacuum, f4) replacing the 70% ethanol with water sterile and bringing the porous bone replacement material from step f3) into contact in sterile water, overnight at ambient pressure, f5) sterilization by autoclave of the porous bone replacement material from step f4) in the water.
- step f) of sterilization can be performed by gamma radiation.
- step f) of sterilization can be performed by beta radiation.
- the dose of beta and / or gamma radiation can be between 15 and 45 kGy.
- the dose of beta and / or gamma radiation is 25 kGy.
- the dose of beta and / or gamma radiation is 15 kGy.
- step f) sterilization can be performed by contacting the bone substitute material with ethylene oxide.
- step f) of sterilization can be carried out by contacting the bone substitute material with a plasma phase derived from a gas.
- step f) of sterilization can be performed by irradiating the bone substitute material with an electron beam (E-beam, E-beam).
- the electron beam irradiation treatment has the following advantages: shorter processing time, improved supply chain efficiency, less risk of embrittlement of the elastomeric matrix, less oxidative damage in the material substitution, no color change of the processed bone substitute material, making it clean and safe.
- the electron beam irradiation treatment is an environmentally friendly treatment.
- the method according to the invention can also comprise a step g) of conservation of said porous bone substitute material after step e) of sterilization.
- step g) of conservation of said material of Porous bone substitution is achieved by contacting porous bone substitution material in 70% ethanol until use.
- the process for preparing a porous bone substitute material comprising the following steps: a) preparing an organic phase comprising the compounds necessary for the synthesis of poly (ester-urea-urethane) , b) add water and the particles of decellularized bone to the organic phase of step a) to form an emulsion, c) polymerize / crosslink the emulsion obtained in step b) to obtain said material of porous bone substitution, and d) washing said porous bone substitution material obtained in step c), e) drying said porous bone substitution material obtained in step d), f) sterilization of the porous bone substitution material obtained from step e), and g) optionally, conservation of the porous bone substitute material.
- the process for preparing a porous bone substitute material comprising the following steps: a) preparing an organic phase comprising the compounds necessary for the synthesis of poly (ester-urea-urethane) , b) concomitantly add water and the particles of decellularized bone to the organic phase of step a) to form an emulsion, c) polymerize / crosslink the emulsion obtained in step b) to obtain said porous bone replacement material, and d) washing said porous bone replacement material obtained in step c) e) drying said porous bone replacement material obtained in step d) f) sterilization of the porous bone replacement material obtained of step e), and g) optionally, conservation of the porous bone substitute material.
- the process for preparing a porous bone substitute material comprising the following steps: a) preparing an organic phase comprising the compounds necessary for the synthesis of poly (ester-urea-urethane), said step a) comprising a first step a1) consisting in dissolving in toluene, the polycaprolactone triol oligomer and the surfactant Span80 , then a second step a2) consisting in adding the crosslinking agent HMDI and the DBTDL catalyst in the solution of step a1) to form the organic phase, b) adding water and the particles of decellularized bone to the organic phase of step a) to form an emulsion, c) polymerize / crosslink the emulsion obtained in step b) to obtain said porous bone substitute material, and d) wash said porous bone substitute material obtained by 'step c) e) drying said porous bone substitution material obtained in step d) for at least 15 days, f) sterilization of the
- Figure 1 shows the allogeneic bone granules distributed homogeneously inside and on the surface of the porous bone substitute material according to the invention.
- the images were obtained by 3D microscopy (VHX Keyence) of the porous bone substitute material according to the invention after washing without staining of the bone granules, the arrows indicating the presence of bone granules (A, B)
- Figure 2 shows the analysis by Fourier Transform Infrared Spectroscopy (FTIR) of the bone granule alone, of the poly (caprolactone-urea-urethane) elastomer matrix alone and of the porous bone substitute material according to the invention (composite).
- FTIR Fourier Transform Infrared Spectroscopy
- Figure 3 shows the stress - deformation curves of the poly (caprolactone-urea-urethane) elastomer matrix alone and of the porous bone substitute material according to the invention (composite) during compression tests (left: full curves; right: enlargement at the start of the curves).
- Figure 4 shows the loss of mass of the poly (caprolactone-urea-urethane) elastomer matrix alone and of the porous bone substitute material according to the invention (composite) during in vitro degradation at 37 ° C and accelerated at 90 ° C.
- Figure 5 represents the cellular activity determined by MTT test after incubation with the extraction media of the poly (caprolactone-urea-urethane) elastomer matrix alone and of the porous bone substitute material according to the invention (composite) .
- the "Blank” represents the result for control cells under normal conditions, and the "positive control” represents the result for cells in the presence of a cytotoxic molecule (chosen here as being HMDI).
- Figure 6 shows the cell viability determined by staining with trypan blue during an indirect cytotoxicity test of the poly (caprolactone-urea-urethane) elastomer matrix alone and of the porous bone substitute material according to the invention (composite ).
- "Blank” represents the result for control cells under normal conditions, and the "positive control” represents the result for cells in the presence of a cytotoxic molecule (chosen here as HMDI).
- Figure 7 shows the migration of mesenchymal stromal cells obtained from canine adipose tissue from day 10 (D 10) to day 40 (D40) within the poly (caprolactone-urea-urethane) elastomer matrix alone and porous bone substitute material according to the invention (composite).
- Figure 8 shows a critical size segmental defect on a rat femur.
- Figure 9A shows the cylinders of the porous bone substitute material according to the invention before implantation in a conditioning medium.
- Figure 9B shows the cylinders of the porous bone substitute material according to the invention after acquisition by microtomography.
- Figure 10A represents the radiological follow-up of a segmental femoral defect maintained by an osteosynthesis plate, with partial reconstruction after 61 days.
- Figure 10B represents the radiological follow-up of a segmental femoral defect maintained by an osteosynthesis plate, with the appearance of system failure after 31 days.
- Figure 11 represents the concentrations of red blood cells and blood platelets for the control batches (Non-operated (Non-op)), Control (Empty default), poly (caprolactone-urea-urethane) elastomer matrix alone (Elastomer), material of bone substitution according to the invention (Composite), decellularized bone and positive control (C pos) (non-critical) at the different study times.
- Figure 12 represents the concentrations of white blood cells and lymphocytes for the control batches (Non-operated (Non-op)), Control (Empty default), elastomer matrix poly (caprolactone-urea-urethane) alone (Elastomer), bone substitute material according to the invention (Composite), decellularized bone and positive control (C pos) (non-critical) at the various study times.
- Figure 13 represents the concentrations of serum markers of bone metabolism (CTX: bone resorption; P1PN and Oc: bone synthesis) for the control batches (Non operated (Non op)), Control (Empty defect), poly elastomer matrix (caprolactone-urea-urethane) alone (Elastomer), bone substitute material according to the invention (Composite), decellularized bone and positive control (C pos) (non-critical) at the different study times.
- CX serum markers of bone metabolism
- P1PN and Oc bone synthesis
- Figure 14A represents the amount of bone formed after 1 or 3 months inside the area of the bone defect for the control (Unoperated (Non Op)), Control (Empty defect), poly elastomer matrix batches. (caprolactone-urea-urethane) alone (Elastomer), bone substitute material according to the invention (Compo) and positive control (C pos) (non-critical) at the various study times.
- Figure 14B represents the quantity of bone / initial volume ratio of the bone defect for the control batches (Not operated), Control (Empty defect), poly (caprolactone-urea-urethane) elastomer matrix alone (Elastomer), material of bone substitution according to the invention (Compo) and positive control (C pos) (non-critical) at the different study times.
- Figure 15A represents the surface of the bone formed after 1 or 3 months inside the area of the bone defect for the control (Unoperated), Control (Empty defect), poly (caprolactone- urea-urethane) alone (Elastomer), bone substitute material according to the invention (Compo) and positive control (C pos) (non-critical) at the different study times.
- Figure 15B represents the bone surface / initial volume ratio of the bone defect for the control (Unoperated), Control (Empty defect), poly (caprolactone-urea-urethane) elastomer matrix alone (Elastomer), material of bone substitution according to the invention (Compo) and positive control (C pos) (non-critical) at the different study times.
- Figure 16 represents the bone defect which remained empty after 3 months for the “Control” batch, ((A): top view in 3D microtomography and (B): lateral view in 3D microtomography).
- FIG. 17A represents the bone defect of non-critical size for the “Positive control” batch, in top view in 3D microtomography after 3 months.
- FIG. 17B represents the bone defect of non-critical size for the “Positive control” batch, in lateral view in 3D microtomography after 3 months.
- FIG. 17C represents the bone defect of non-critical size for the “Positive control” batch, in histological section with Masson's trichrome staining (magnification x5) after 1 month.
- FIG. 17D represents the detail of the central zone of the bone defect for the “Positive control” batch (image insert C, magnification x40).
- FIG. 18A represents the bone defect of critical size for the poly (caprolactone-urea-urethane) elastomer matrix batch alone, in top view in 3D microtomography after 1 month.
- FIG. 18B represents the bone defect of critical size for the poly (caprolactone-urea-urethane) elastomer matrix batch alone, in top view in 3D microtomography after 3 months.
- FIG. 18C represents the bone defect of critical size for the poly (caprolactone-urea-urethane) elastomer matrix batch alone, in histological section with Sudan black staining (magnification x2.5) after 1 month.
- Figure 18D shows the detail of the central zone of the bone defect for the poly (caprolactone-urea-urethane) elastomer matrix batch alone (inset image C, magnification x40), with Masson's trichrome staining after 1 month.
- Figure 19 represents the bone defect after 3 months for the poly (caprolactone-urea-urethane) elastomer matrix batch alone ((A): lateral view in 2D microtomography, (B): lateral view in 3D microtomography and (C ): lower view in 3D microtomography).
- Figure 20 represents the bone defect after 3 months for the “decellularized bone” batch, in lateral view in 3D microtomography.
- Figure 21A shows the critical size bone defect for the porous bone substitute material batch according to the invention "Composite”, in top view in 3D microtomography after 1 month.
- FIG. 21 B represents the bone defect of critical size for the batch of porous bone substitute material according to the “Composite” invention, in top view in 3D microtomography after 3 months.
- Figure 21 C represents the bone defect of critical size for the batch of porous bone substitute material according to the invention “Composite”, in histological section with Masson's trichrome staining after 1 month (magnification x2, 5) .
- Figure 21 D shows the detail of the central zone of the bone defect for the batch porous bone substitute material according to the invention "Composite" (insert image C, magnification x40).
- Figure 21 E shows the bone defect of non-critical size for the batch of porous bone substitute material according to the invention “Composite”, in histological section with Masson's trichrome staining after 1 month (magnification x2, 5 ).
- Figure 21F shows the detail of the external zone of the bone defect for the batch porous bone substitute material according to the invention "Composite" (insert image C, magnification x40).
- Example 1 Formulation and synthesis of the porous bone substitute material according to the invention
- the allogenic material Allodyn® (decellularized bone) was ground to produce granules with a diameter ranging from 50 to 500 ⁇ m.
- the mixture of granules obtained after grinding is sieved using a sieve (Fisher AS 200 TAP).
- the granules could be separated according to particle sizes of between 50 to 100 ⁇ m, 100 to 200 ⁇ m, 200 to 300 ⁇ m and 300 to 400 ⁇ m. Granules larger than 400 ⁇ m have not been considered here.
- compositions are:
- Bone substitute material A with a 100% elastomeric matrix / allogeneic bone ratio (1 g / 1 g), i.e. a bone mass fraction of 50% and particle size between 300 and 400 m,
- Bone substitute material B with a 50% elastomeric matrix / allogeneic bone ratio (1 g / 0.5g), i.e. a bone mass fraction of 33% and particle size between 300 and 400 ⁇ m.
- a proportion of more than 50% bone results in structural loss of the bone substitute material.
- Example 2 Physicochemical and mechanical properties of the bone substitute material according to the invention.
- FTIR Fourier transform infrared spectroscopy
- the bone substitute material B having a bone mass fraction of 33%, and comprising bone particles with a diameter of 300 to 400 ⁇ m.
- the density of the bone substitute material was evaluated by pycnometry.
- a bone mass fraction of 31% is found after washing, by comparison with the mass fraction of 33% introduced at the start into the emulsion.
- the particles of decellularized bone appear to be homogeneously distributed within and on the surface of the bone substitute material ( Figure 1).
- EDX (Table 1) and IRTF ( Figure 2) analyzes confirm the presence of calcium and phosphorus due to particles of decellularized bone in the porous bone substitute material.
- decellularized alone, poly (caprolactone-urea-urethane) elastomer matrix alone and bone substitute material according to the invention (composite) ( 1 nitrogen not taken into account for comparison with experimental limited by sensitivity of the device).
- Elemental analysis shows a good correlation between the expected theoretical values according to the quantity of bone incorporated during the synthesis of the material, and the experimental values of the material after washing. This again proves the presence of the bone particles in the elastomeric matrix.
- the chemical structure of the elastomer matrix has not been modified since we find all the peaks associated with this matrix ( Figure 2). 2.3. Mechanical properties
- the Young E modulus of the porous material can be defined on the first linear part of the curve.
- a value of 228 kPa was found for the bone substitute material according to the invention, which is in the range of elastomeric foams (1 ⁇ E ⁇ 1000 kPa).
- the Young's modulus E of the non-porous material when the pores are all crushed, can be defined.
- a value of 19 MPa was found for the bone substitute material according to the invention. The values are greater than those found for the poly (caprolactone-urea-urethane) elastomer matrix alone.
- the particles of decellularized bone participate in a slight increase in the moduli of the bone substitute material according to the invention, while retaining the elastomeric character of the polymer matrix.
- the poly (caprolactone-urea-urethane) elastomeric matrix alone is stable for 14 days at 90 ° C.
- the "rule of ten” giving the relation between the increase in the rate of degradation when the temperature is elevated by ten degrees and taking a Q10 factor of 2-2.5 [ASTM F 1980 - 02: Standard Guide for Accelerated Aging of Sterile Medical Device Packages urea-urethane) alone at 37 ° C is estimated to be between 19.4 and 63.4 months.
- the life at 90 ° C is 10 days which leads to an estimate of the life at 37 ° C between 13.0 and 42.3 months. This stability is suitable for use of the bone substitute material as a support for bone regeneration.
- Example 3 Interactions between the porous bone substitute material according to the invention and the mesenchymal stromal cells obtained from canine adipose tissue (MSC)
- the bone substitute material as obtained in Example 1 and the poly (caprolactone-urea-urethane) elastomer matrix alone are incubated in standard culture medium for 24 hours at 37 ° C. Then this extraction medium is deposited on a CSM mat at 80% confluence. After 24 hours of incubation, the metabolic activity of the cells is measured by an MTT test.
- the standard sets a cell viability limit of 70% for a product to be considered non-cytotoxic.
- the results are shown in ( Figure 6).
- the cell viability obtained is greater than 80% and comparable between the control and the cells placed in the presence of the poly (caprolactone-urea-urethane) elastomer matrix alone or of the bone replacement material according to the invention (composite).
- the indirect cell-scaffold interaction does not generate cytotoxic compounds in the culture medium after 24 h.
- Colonization tests with canine MSCs were carried out in order to test the "attraction" power of the bone substitute material according to the invention (composite) and of the poly (caprolactone-urea-urethane) elastomer matrix alone.
- the bone substitute material according to the invention (composite) and the poly (caprolactone-urea-urethane) elastomer matrix alone are respectively deposited on a CSM mat at 80% confluence. The migration of the cells is determined on D 10, D20, D30 and D40.
- a count of the cells present on and inside the bone substitute material according to the invention (composite) and of the poly (caprolactone-urea-urethane) elastomer matrix alone are carried out after detachment of the cells by enzymatic treatment.
- the results obtained show that the cells are capable of migrating in materials.
- Example 4 In vivo study of the repairing power of the bone substitute material (composite) on a rat model of segmental defect.
- the segmental bone defect model consists of removing a section of bone removing all continuity between the two bone segments obtained, and not allowing spontaneous repair.
- the critical size of this bone defect is defined as being equal (at least) to 1.5 to 2 times the diameter of the bone concerned.
- a "control batch” (Non op.) Corresponds to non-operated animals, but having undergone anesthesia and analgesia.
- the rat model of segmental bone defect consists in making a section in the femoral shaft that does not allow spontaneous repair.
- the critical size of this bone defect here is 5 to 6 mm, a length well established in this rodent model.
- the bone is cut at the level of the shaft and the two bone ends are stabilized by a fixator adapted to the femur of the rat ( Figure 8). This fixator is held on the upper surface of the femur by 4 stainless steel screws 1.1 mm (Synthes).
- Anesthesia / Analgesia Anesthesia Ketamine / Medetomidine 60 / 0.5 mg / kg intraparentally.
- Awakening Atipamezole, 1 mg / kg intramuscularly
- Analgesia Buprenorphine 0.05 mg / kg postoperatively (waking up then 3 times a day for 3 days), subcutaneously (SC).
- Post-operative care analgesia by subcutaneous route during awakening then for 3 days (3 times a day).
- the animals use their operated limb as soon as they wake up.
- the animals are monitored daily: the wounds are clean and no external signs of inflammation, lameness or changes in behavior have been noted when the osteosynthesis system is stable. Weight curves are similar for all batches throughout the study, with a recovery phase of approximately 15 days after surgery.
- the biomaterials (bone substitute material according to the invention (composite) and the poly (caprolactone-urea-urethane) elastomer matrix alone) are cylinders 10 to 15 mm long and 4 mm in diameter (FIG. 9A). They are prepared the day before implantation in a sterile manner in conditioning medium and incubated in an oven at 37 ° C and 5% C0 2 . They are cut when they are placed in the bone defect to have dimensions adapted to each animal. Certain batches of composites were scanned by microtomography in order to verify the size and the homogeneity of the distribution of the granules (FIG. 9B) before implantation.
- the conditioning medium used contains DMEM (Dulbecco's Modified Eagle Medium)
- Radiological monitoring is carried out with an irradiator (SARRP) in imager mode at 1, 3, 6, 12 days then every 10 to 15 days, and makes it possible to check the integrity of the osteosynthesis system and the appearance of bone mineralized inside the bone defect ( Figure 10A).
- SARRP irradiator
- Figure 10B where the most distal screw is loosening after 31 days, the animals are euthanized and the femurs recovered for analysis.
- Blood is taken on EDTA-K3 by intracardiac puncture on anesthetized rats in anticipation of sacrifice, to perform a blood count (Procyte DX-IDEXX veterinary hematology machine), in order to detect abnormal inflammation, or a possible effect of biomaterials on blood count. Serum was also prepared from blood taken without anticoagulant and centrifuged at 1500 g for 10 minutes for assaying bone repair markers by ELISA test.
- the direct markers of remodeling testify to an activity of synthesis (Oc, P1NP) and bone resorption (CTX1).
- Oc, P1NP activity of synthesis
- CX1 bone resorption
- the interpretation of their dosages is however delicate in animals, their levels being able for example to be dependent on the diurnal / nocturnal cycles.
- P1NP procollagen 1 type N-terminal propeptide
- CX1 bone resorption
- the values of the batches implanted with the different biomaterials at 3 months are similar to those found for the positive controls (625.65 ⁇ 41.15 ng / mL) where complete reconstruction is in progress. These values are 3 times higher than those observed for the control batch (empty defect) for which no reconstruction was observed (221, 40 ⁇ 19.50 ng / mL).
- CTX1 type 1 carboxy-terminal telopeptide of collagen
- CTX1 is a marker of the level of bone resorption via the cathepsin K pathway, the predominant pathway of bone remodeling.
- This concentration is equivalent to that of non-operated animals when the poly (caprolactone-urea-urethane) elastomer matrix alone, the porous bone substitute material according to the invention (composite) or the decellularized bone are implanted after one and three months, signifying that remodeling of the newly formed mineralized tissue is in progress.
- femurs While the femurs are fixed in Burckhardt's solution for subsequent histological analyzes, they are analyzed by microtomography (Skyscan 1174) with the following parameters: 50 kV; 800 mA to visualize and quantify the bone neo-mineralization at the level of the segmental defect.
- a rapid acquisition (40 to 70 min) is carried out on the complete femurs with their fixator with a resolution of 50 to 60 ⁇ m, then, depending on the level of mineralization and the "solidity" observed at the time of the removal, the fixators are removed and a finer acquisition is carried out (resolution of 14 to 20 ⁇ m, 2 to 3 hours) for the analyzes.
- the measurement area corresponds to the area of the initial bone defect.
- the data acquired are processed by quantification software (CTan, Skyscan), and make it possible to visualize and quantify bone reconstruction at the level of the bone defect.
- CTan quantification software
- BV / TV ratio Bridge Volume / Tissue Volume
- FIG. 14A makes it possible to quantify the bone present in the area of the bone defect. This remains 3 times lower at one month and at three months for the control animals compared to the non-operated animals (31.11 mm 3 ), when the defect is left empty. This reflects the absence of bone synthesis and therefore of repair of this model.
- the poly (caprolactone-urea-urethane) elastomer matrix alone is implanted, this value is equivalent to that of the control animals at one month (10.8 ⁇ 1, 1 mm 3 ), but is equivalent (24.75 ⁇ 7, 29 mm 3 ) to that of non-operated animals after 3 months.
- the placement of the bone substitute material according to the invention results in a quantity of bone formed at three months 2.5 times greater (68.60 ⁇ 26.02 mm 3 ) than that of animals not operated. This value is close to that found for the positive controls where the synthesis is here 3 times greater (80.03 ⁇ 23.99 mm 3 ).
- the mirror image of the bone surface ratio (BS) to the bone defect volume (BV) (BS / BV) reflects the level of structure of the bone formed ( Figures 15A and 15B).
- the high ratio (15.10 ⁇ 5.49 mm 1 ) reflects a rather fine and spreading mineralized structure, while for the positive controls, a lower value represents a more compact bone (5.26 ⁇ 0 , 36 mm 1 ).
- TM Masson's trichrome
- RS Sirius Red
- the bone defect remains empty, no reconstruction was observed inside the defect during the 3 months of the study ( Figure 16). Bone formed at the edges only and a rough bone synthesis was observed for a few animals under the fixator ( Figure 16). The defect is filled with fibrous tissue. This confirms the critical size of the bone defect.
- the size of the bone defect here is not critical and is representative of a simple fracture. After 3 months, almost complete reconstruction is observed when this size is approximately 2 mm (Figure 17A). Very active zones of mineralization, indicated by the arrows in figure 17C, are found at the level of the bone margins after 1 month, as well as zones of endochondral ossification in the center of the defect (figure 17D), probably linked to a certain “ elasticity ”of the system. In fact, rats are active and dynamic, and this area is subjected to significant mechanical stresses.
- the level of reconstruction is low one month post-implantation (figure 18A) and localized only at the level of the bony margins.
- a black coloration Sudan makes it possible to visualize the poly (caprolactone-urea-urethane) elastomer matrix alone located in the center of the defect and partly integrated in neosynthesized bone (FIG. 18C).
- the bone defect was filled with a cylindrical Allodyn® rod with a diameter of 2 mm.
- the implant was carefully cut during placement so that it completely fills the defect and is in contact with the two bony margins. No reconstruction was observed after 3 months ( Figure 20).
- a rough resorption is noted for the biomaterial.
- Moderate bone synthesis around the ends of the fixative was observed for a few samples, at a level similar to that observed with the poly (caprolactone-urea-urethane) elastomer matrix alone. No reactions of rejection or infection were recorded.
- decellularized bone in the form of granules into the poly (caprolactone-urea-urethane) elastomer matrix modifies the reconstruction process. Indeed, after a month, bone forms on the bony edges, identifiable by a trichrome staining of Masson, with numerous osteoid zones at this level (figures 21C and 21 D). However, the area of the bone defect always appears empty; the granules of decellularized bone are clearly visible and are grouped together more or less eccentric with respect to this zone (FIG. 21A). However, there is an intense “delocalized” bone synthesis, with the fixatives which are covered with a mineralized layer.
- Bone formation typically takes place around biomaterials and to a lesser extent within them.
- the multiscale porosity of the porous bone substitute material according to the invention seems to be a positive factor since several foci of ossification are detected inside it, highlighting the fact that differentiated and active cells have been able to migrate into it. this area, probably accompanied by blood vessels.
- porous bone substitute material according to the invention makes it possible to visualize the porous bone substitute material according to the invention inside the bone defect: it appears fragmented and partly included in the mineralized tissue, demonstrating a degradation and a bio-integration compatible with the bones. repair kinetics.
- the in vivo lifetimes of the porous bone substitute material according to the invention are estimated to be 13 to 42 months. This lifespan is compatible with clinical use.
- the histological analyzes confirm the osteoconductive nature and the degradation of the porous bone substitute material according to the invention, visible from the first month of implantation, as well as the formation of bone. All the results indicate that the porous bone substitute material according to the invention has good mechanical properties, good biocompatibility and a degradation suitable for the reconstruction of bone tissue. It presents interesting performances in vivo by inducing intense bone synthesis, up to the restoration of tissue continuity between two bone fragments.
- the presence of decellularized bone in the porous bone substitute material according to the invention increases the production of mineralized tissue, which is three times greater than that obtained with the poly (caprolactone-urea-urethane) elastomer matrix alone after three month. This intense production, however, is not localized only inside the bone defect, and also takes place around the fixators. Several zones of mineralization were detected between the bone tissue and the surrounding muscle.
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IE70665B1 (en) | 1989-11-22 | 1996-12-11 | Whitbread & Co Plc | Carbonated beverage container |
FR2654625B1 (fr) | 1989-11-22 | 1992-02-21 | Transphyto Sa | Procede de fabrication d'un materiau pour osteoplastie a partir d'un tissu osseux naturel et materiau obtenu par ce procede. |
FR2798294B1 (fr) | 1999-09-10 | 2001-10-12 | Ost Dev | Procede de fabrication d'un materiau de prothese osseuse par traitement d'un tissu osseux naturel |
ES2541909T3 (es) * | 2003-02-04 | 2015-07-28 | Warsaw Orthopedic, Inc. | Poliuretanos para osteoimplantes |
US9333276B2 (en) * | 2008-10-30 | 2016-05-10 | Vanderbilt University | Bone/polyurethane composites and methods thereof |
US20150283182A1 (en) * | 2008-10-30 | 2015-10-08 | Vanderbilt University | INJECTABLE ALLOGRAFT PUR COMPOSITE CARRYING rhBMP2 |
-
2020
- 2020-05-20 FR FR2005385A patent/FR3110386A1/fr active Pending
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2021
- 2021-05-20 JP JP2022571178A patent/JP2023525930A/ja active Pending
- 2021-05-20 WO PCT/EP2021/063493 patent/WO2021234103A1/fr unknown
- 2021-05-20 CN CN202180036569.1A patent/CN115715204A/zh active Pending
- 2021-05-20 EP EP21726661.8A patent/EP4153258A1/fr active Pending
Also Published As
Publication number | Publication date |
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CN115715204A (zh) | 2023-02-24 |
FR3110386A1 (fr) | 2021-11-26 |
WO2021234103A1 (fr) | 2021-11-25 |
JP2023525930A (ja) | 2023-06-19 |
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