US20160106884A1

US20160106884A1 - Implant with controlled porosity comprising a matrix covered by a bioactive glass or by a hybrid material

Info

Publication number: US20160106884A1
Application number: US14/894,955
Authority: US
Inventors: Jonathan Claude Alexandre Lao; Joséphine Lacroix; Edouard Daniel Albert Jallot; Xavier Dieudonne
Original assignee: Centre National de la Recherche Scientifique CNRS; Universite Blaise Pascal Clermont Ferrand II
Current assignee: Centre National de la Recherche Scientifique CNRS; Universite Blaise Pascal Clermont Ferrand II
Priority date: 2013-06-03
Filing date: 2014-06-03
Publication date: 2016-04-21
Also published as: ES2767076T3; EP3003414B1; EP3003415A1; HK1223571A1; ES2682943T3; US20160114076A1; HK1223572A1; HUE040212T2; CA2914130C; PT3003415T; PT3003414T; HUE047500T2; FR3006195B1; FR3006195A1; US10149920B2; WO2014195862A1; TR201811285T4; CA2914130A1; EP3003415B1; WO2014195863A1

Abstract

The disclosure relates to an implant material for filling bone defects, for bone regeneration and for bone tissue engineering, to an implant comprising this material, and to a method for producing such an implant. The implant material comprises: a bioactive glass M based on SiO₂and CaO, optionally containing P₂O₅and/or optionally doped with strontium, and a biodegradable polymer P soluble in at least one solvent S1 and chosen from among the bioresorbable polysaccharides. The implant material has applications in the medical field.

Description

The invention relates to an implant material for filling bone defects, for bone regeneration and for bone tissue engineering, an implant comprising said material, a method for manufacturing such an implant.
The overall aging of the population and the disorders of the osteoarticular system that accompany this make it necessary to develop high-performance materials for replacing bone tissues. 18 billion Euros of health care costs are in fact expended each year in France for diseases of the osteoarticular system and dental diseases; musculoskeletal disorders are the commonest occupational pathologies in the industrialized countries, whereas osteoporosis develops in elderly patients; these facts delineate the contours of a major societal and economic challenge and explain the increasing demand for biomaterials, implants with increased lifetimes capable of making up for bone loss.
As recourse to grafts is limited, and materials of animal origin may pose problems of biocompatibility or risks of infection, research efforts aim to develop synthetic biomaterials capable of promoting bone regeneration.
In this case they are called bioactive implants: the material implanted is not simply intended to make up for bone loss passively, remaining as inert as possible, but on the contrary it has to stimulate and participate actively in the mechanism of bone regeneration. This is particularly important in the case of extensive bone defects, for which the self-repair mechanism no longer functions.
Currently the main bioactive materials used as bone substitutes are the bioactive “ceramics”, such as the calcium phosphates, and the bioactive glasses, also called “bioglasses”.
The first bioactive ceramics were developed by L. L. Hench (L. L. Hench et al., J. Biomed. Mater. Res. 1971, 2, 117-141; L. L. Hench et al., J. Biomed. Mater. Res. 1973, 7, 25-42).
The first bioactive glasses were prepared from SiO₂, P₂O₅, CaO and Na₂O. The oxides of silicon and of phosphorus are network formers that participate in the cohesion of the vitreous network. The alkali and alkaline-earth metals such as sodium and calcium do not display this capacity and modify the vitreous network by introducing chain breaks in it, which are the cause of the low melting point of these glasses, associated with increased structural disorder. Their presence results in greater reactivity of the bioactive glasses notably through their corrosion in an aqueous environment. This reactivity allows formation of hydroxyapatite in the physiological medium and therefore promotes bone reconstruction.
The bioglass that has received the most study is a soda-silico-phospho-calcium glass called Bioglass® or Hench Bioglass. Its basic composition is 45% SiO₂—24.5% CaO—24.5% Na₂O—6% P₂O₅, by weight relative to the total weight of the composition. The remarkable bioactive properties of this material require no further demonstration. Bioglass® is still one of the most interesting bioactive materials (inducing a specific response from the cells).
There have been numerous developments in the field of bioactive glasses since their discovery (M. Vallet-Regi et al., Eur. J. Inorg. Chem. 2003, 1029-1042), such as the incorporation of various atoms or the incorporation of active principles. The compositions of the bioactive glasses have been optimized so as to promote the proliferation of osteoblasts and the formation of bone tissues (WO 02/04606). Incorporation of silver has been proposed notably for endowing bioactive glasses with antibacterial properties (WO 00/76486).
In its turn, application WO 2009/027594 describes a bioactive glass in which strontium is introduced in amounts between 0.1 and 10% of the total weight of the bioactive glass.
A characteristic feature of these bioactive materials is that they are simultaneously biocompatible, capable of binding spontaneously to bone tissues, of promoting adhesion of bone cells and, finally, of being bioabsorbable, being gradually replaced with newly formed bone tissue as bone regrowth progresses.
However, despite this very satisfactory set of characteristics, the fragility of these materials limits their applications: in fact, although their rigidity is often greater than that of bone, their lack of flexibility and toughness means that the bioactive materials cannot be implanted in mechanically loaded sites.
To overcome this defect, an ingenious solution is to take inspiration from the particular structure of bone tissue. It is complex, consisting mainly of a composite weft intimately mixed with an inorganic phase, the bone mineral consisting of crystals of apatite (absorbable calcium phosphate), with an organic phase, which is predominantly collagen. Remarkably, this composite structure combines the initial rigidity of the inorganic part with the natural toughness and flexibility of the collagen fibers. To obtain implants with mechanical properties close to bone tissue, one strategy therefore consists of combining bioactive materials and biodegradable polymers within one and the same composite or hybrid matrix.
For filling extensive bone defects, in addition to the above characteristics, the implants must have a specific morphology: the latter takes inspiration from trabecular bone, namely a highly porous structure consisting of a three-dimensional network of interconnected macropores of several hundreds of microns. In fact, in the case of extensive bone defects, the bone cells need an extracellular “support” matrix capable of guiding and stimulating cellular adhesion, proliferation, and differentiation, while being compatible with the processes of vascularization and tissue invasion.
This macroporous structure is also required for the new applications envisaged in bone tissue engineering: it is a matter of manufacturing in the laboratory, starting from cells taken from the patient, new bone tissue that can later be re-implanted in the patient. For optimal tissue culture, it must also be supported on porous three-dimensional supports allowing good cellular adhesion, differentiation into mature cells as well as production of tissue and in particular biomineralization.
To summarize, although numerous materials and formulations have been developed for making up for bone loss, none fully meets the specifications describing an ideal implant, namely it should:
be biocompatible;
be bioactive: spontaneously induce the formation of a strong interfacial bond with the bone tissues, promote adhesion and cellular activity;
be bioabsorbable;
have a suitable morphology based on a three-dimensional matrix of interconnected macropores;
have good mechanical behavior;
be derived from a method of manufacture allowing easy and sufficiently flexible forming for adapting to the numerous geometries of defects.
“Suitable morphology based on a three-dimensional matrix of interconnected macropores” means that the size, shape and distribution of the pores as well as the size of the interconnections between these pores must be controlled.
The aim of the invention is to propose a material that responds perfectly to all these criteria and that can be manufactured by a method that allows the production of porous architectures made up of an inorganic part and an organic part, in contrast to the methods of the prior art.
For this purpose, the invention proposes a method for manufacturing an implant made of a material according to the invention for filling bone defects, for bone regeneration and for bone tissue engineering, characterized in that it comprises the following steps:
a) selecting a bioactive glass M based on SiO₂and CaO, optionally containing P₂O₅and/or optionally doped with strontium,
b) selecting a biodegradable polymer P that is soluble in a solvent S1 and insoluble in at least one solvent S,
c) selecting microspheres of a porogenic agent A having diameters and sizes corresponding to the desired diameters and sizes of the pores in an implant material, the material of this porogenic agent A being a polymer insoluble in the solvent S1 and soluble in the at least one solvent S,
the at least one solvent S in which the biodegradable polymer P is insoluble and the at least one solvent S in which the material of the porogenic agent A is soluble being identical,
d) putting at least 60 vol %, preferably at least 70% (and less than 100%) relative to the total volume of the mixture of biodegradable polymer P-porogenic agent A introduced into the mold, of microspheres of the porogenic agent A in a mold having the required shape and size for the implant, these microspheres forming a compact stack corresponding to the shape and size of the pores to be obtained in the implant material,
e) putting the biodegradable polymer P in the mold,
f) gelling the mixture obtained in step e) in the mold,
g) removing the mixture obtained in step f) from the mold,
h) removing the porogenic agent by washing with the at least one solvent S,
i) crosslinking the mixture obtained in step g),
j) coating the mixture obtained in step i) with the bioactive glass M or with a hybrid material H formed from a biodegradable polymer identical to or different than the biodegradable polymer P and from the bioactive glass M.
In a first embodiment of the method of the invention, step j) is carried out by impregnation of the mixture obtained in i) with a suspension, in a solvent, containing particles of the bioactive glass M or of the hybrid material H, and evaporation of the solvent.
In a second embodiment of the method of the invention, step j) is a step of coating the mixture obtained in step i) either with the bioactive glass M, or with the hybrid material H, and is carried out by immersion of the mixture obtained in step i) either in a sol containing the alkoxide precursors of the bioactive glass M, for a coating only with the bioactive glass M, or in a sol of the hybrid material, or in a sol of the alkoxide precursors of the bioactive glass M and of biodegradable polymer of the hybrid material H, for a coating with the hybrid material H, followed by a gelling step.
In all the embodiments, the method of the invention may further comprise a step j) of crosslinking of the material obtained in step i).
Moreover, in all the embodiments of the method of the invention, the biodegradable polymer P is selected from:
biodegradable polymers that are soluble in at least one solvent S1 and insoluble in at least one solvent S selected from:
bioabsorbable polysaccharides, preferably selected from dextran, hyaluronic acid, agar, chitosan, alginic acid, sodium or potassium alginate, galactomannan, carrageenan, pectin,
bioabsorbable polyesters, preferably polyvinyl alcohol or poly(lactic acid) (PLA),
biodegradable synthetic polymers, preferably a polyethylene glycol, or poly(caprolactone),
proteins, preferably gelatin or collagen,
the material of the porogenic agent A is selected from biodegradable polymers that are insoluble in the at least one solvent S1 and soluble in the at least one solvent S, preferably selected from C₁to C₄polyalkyl methacrylates, preferably polymethyl methacrylate or polybutyl methacrylate, polyurethane, polyglycolic acid, the various forms of polylactic acids, the copolymers of lactic-coglycolic acids, polycaprolactone, polypropylene fumarate, paraffin, naphthalene and acrylonitrile butadiene styrene (ABS),
the material of the porogenic agent A being different from the biodegradable polymer P.
More preferably, the biodegradable polymer P is a polymer of natural origin or a biodegradable synthetic polymer or a bioresorbable polyester.
When the biodegradable polymer P is coated with a hybrid material, preferably, the biodegradable polymer/bioactive glass M weight ratio in this hybrid material is between 10/90 and 90/10, inclusive, preferably between 20/80 and 80/20, inclusive, preferably between 30/70 and 70/30 inclusive.
Most preferably, the hybrid material consists of 70% by weight of biodegradable polymer and 30% by weight of bioactive glass.
The polymer of the hybrid material of the coating may be identical to or different than the biodegradable polymer P.
When the biodegradable polymer P is covered with the bioactive glass M alone, then, preferably, the biodegradable polymer P/bioactive glass M weight ratio is preferably between 50/50 and 90/10, preferably between 60/40 and 80/20.
Also preferably, the bioactive glass M is a glass based on SiO₂and CaO, the biodegradable polymer P is gelatin, the material of the microspheres of porogenic agent A is polymethyl methacrylate and the solvent S is acetone.
However, the preferred bioactive glass is a glass consisting of 75% by weight of SiO₂and 25% by weight of CaO or a glass consisting of 75% by weight of SiO₂, 20% by weight of CaO and 5% by weight of SrO.
The method of the invention may further comprise a step of introducing a coupling agent, preferably an organoalkoxysilane compound, more preferably 3-glycidoxypropyltrimethoxysilane (GPTMS) and even more preferably 3-glycidoxypropyltriethoxysilane (GPTES), in step e).
It may also further comprise, after step d), and before step e), a step of enlarging the interconnections, by infiltration of a solvent S of the material of the porogenic agent A, in the stack of the microspheres of porogenic agent A and/or by heating this stack.
The invention further proposes an implant material for filling bone defects, for bone regeneration and for bone tissue engineering, obtained by the method according to the invention,
characterized in that it comprises:

- a bioactive glass M based on SiO₂and CaO, optionally containing P₂O₅and/or optionally doped with strontium, and
- a biodegradable polymer P soluble in the at least one solvent S1 selected from:

bioabsorbable polysaccharides, preferably selected from dextran, hyaluronic acid, agar, chitosan, alginic acid, sodium or potassium alginate, galactomannan, carrageenan, pectin,
bioabsorbable polyesters, preferably polyvinyl alcohol or poly(lactic acid),
biodegradable synthetic polymers, preferably a polyethylene glycol, or poly(caprolactone), and
proteins, preferably gelatin or collagen,
and in that it consists of a matrix comprising at least the biodegradable polymer P covered with the bioactive glass M or with a hybrid material H formed from the bioactive glass M and from a biodegradable polymer which is identical to or different than the biodegradable polymer P, this matrix having at least 70% by number of pores having at least one interconnection with another pore and the shape of spheres or of polyhedra inscribed in a sphere, the diameter of the spheres being between 100 and 900 μm, preferably between 200 and 800 μm inclusive, with a difference between the diameter of the smallest or the largest sphere being at most 70%, preferably at most 50%, more preferably at most 30%, relative to the arithmetic mean diameter of the set of spheres of the implant and the interconnections between the pores having their smallest dimension between 25 μm and 250 μm inclusive.
The invention finally proposes an implant for filling bone defects, for bone regeneration and for bone tissue engineering, characterized in that it comprises a material according to the invention or obtained by the method for manufacturing an implant according to the invention.

The invention will be better understood and other features and advantages of the invention will become clearer on reading the explanatory description that follows, which refers to the appended figures in which:

FIG. 1 shows a sectional view, taken with a scanning electron microscope, of the implant of the invention obtained in example 1, at a magnification of ×70,

FIG. 2 is a schematic representation of the implant material according to the invention,

FIG. 3 shows a photograph, taken with a scanning electron microscope, of an implant of the invention, the matrix of which consists of gelatin covered with a bioactive glass, at a magnification of ×100,

FIG. 4 shows a photograph, taken with a scanning electron microscope, at a magnification of ×50, of a section of an implant material of the prior art prepared by a lyophilization method, described in Kim et al. “Hydroxyapatite and gelatin composite foams processed via novel freeze-drying and crosslinking for use as temporary hard tissue scaffolds” J Biomed Mater Res 72A: 136-145, 2005,

FIG. 5 shows a photograph, taken with a scanning electron microscope at a magnification of ×200, of an implant material of the prior art prepared by a method of thermally induced phase separation, described in Blaker et al. “Mechanical properties of highly porous PDLLA/Bioglass® composite foams as scaffolds for bone tissue engineering” Acta Biomater 2005, 1, 643-52,

FIG. 6 shows a photograph, taken with a scanning electron microscope at a magnification of ×50, of a hybrid implant material with gelatin/glass weight ratio of 70/30, obtained by a method comprising a step of increasing the size of the interconnections between pores by infiltration with an acetone-ethanol mixture at 30 vol % of acetone, relative to the total volume of the mixture for 5 minutes by infiltration with the mixture in the stack of microspheres of porogenic agent, alone,

FIG. 7 is a photograph, taken with a scanning electron microscope at a magnification of ×50, of the same implant material as shown in FIG. 6 but after infiltration with an acetone-ethanol mixture at 30 vol % of acetone, relative to the total volume of the mixture, for 15 minutes, with the mixture in the stack of microspheres of porogenic agent, alone,

FIG. 8 is a photograph, taken with a scanning electron microscope at a magnification of ×50, of the material shown in FIG. 6 and FIG. 7 obtained by the method of the invention after increasing the size of the interconnections between pores by infiltration of the acetone-ethanol mixture at 30 vol % of acetone, relative to the total volume of the mixture, for 30 minutes, with the mixture in the stack of microspheres of porogenic agent, alone,

FIG. 9 is a curve representing the increase in the size of the interconnections between pores by infiltration with an acetone-ethanol mixture at 30 vol % of acetone, relative to the total volume of the mixture, as a function of the infiltration time,

FIG. 10 is a photograph, taken with a scanning electron microscope at a magnification of ×100, of a hybrid implant material consisting of 70% of gelatin and 30% of glass, by weight, according to the invention obtained by the method of the invention after increasing the size of the interconnections of the pores by heating the stack of microspheres of porogenic agent, alone, at 125° C. for 15 minutes, under air,

FIG. 11 is a photograph, taken with a scanning electron microscope at a magnification of ×100, of the implant material shown in FIG. 10 but after increasing the size of the interconnections of pores by heating the stack of microspheres of porogenic agent, alone, at 125° C. for 1 hour, before infiltration with the hybrid material consisting of 70% of gelatin and 30% of glass, by weight,

FIG. 12 is a photograph, taken with a scanning electron microscope at a magnification of ×100, of the same composition of the implant material according to the invention as shown in FIGS. 10 and 11, obtained by a method after increasing the size of the interconnections of pores by heating the stack of microspheres of porogenic agent, alone, at 125° C., for 2 hours, and

FIG. 13 shows the curve of the variation in size of the interconnections between pores as a function of the time of heating the stack of microspheres of porogenic agent, alone, at 125° C.

Throughout this text, the following terms have the following definitions:
“interconnection(s) between pores”: opening(s) allowing passage from one pore to another,
“aqueous medium” or “aqueous solvent”: any liquid medium containing water, or water alone,
“biodegradable”: degradable in a physiological fluid, for example a buffered saline solution (SBF),
“bioabsorbable”: removable from a physiological medium containing biological cells,
“arithmetic mean diameter of the set of pores”: sum of the diameters of the pores/number of pores,
“spherical pore” or “sphere”: pore or sphere for which the ratio of the smallest diameter to the largest diameter is 0.9±0.1,
“polyhedron inscribed in a sphere”: polyhedron inscribed in a sphere having the same diameter at all points, the differences between the different diameters of the polyhedron inscribed in this sphere being at most±15% of the diameter of the sphere in which they are inscribed,
“compact stack of microspheres of porogenic agent A”: stack of microspheres of porogenic agent A in which at least 60% by number, more preferably at least 70% by number, of microspheres are in contact with one another, in the absence of the biodegradable polymer P, and remain in contact with one another when the mixture of biodegradable polymer P-porogenic agent A is in the mold.
Said compact stack of microspheres of porogenic agent A may be obtained by centrifugation of the mixture of microspheres of porogenic agent A-biodegradable polymer P or else by applying a negative pressure (vacuum) or positive pressure (above atmospheric pressure) on the mixture of microspheres of porogenic agent A-biodegradable polymer P introduced into the mold, before and during gelation of this mixture.
The implant material for filling bone defects, for bone regeneration and for bone tissue engineering of the invention will be described with reference to FIGS. 1 and 2.
As can be seen in FIGS. 1 to 3, the implant material of the invention comprises a matrix, designated 1 in FIGS. 1 and 2, of a material that comprises an organic part and an inorganic part.
This material is biocompatible, bioactive, bioabsorbable and, as can be seen in FIGS. 1 to 3, it has a very regular morphology, in terms of distribution of pores, designated 2 in FIGS. 1 to 3, and in terms of shape of pores, in contrast to the materials of the prior art, which have a chaotic pore distribution, size and shape, as can be seen in FIGS. 4 and 5, which show respectively photographs taken with the scanning electron microscope, of implant materials obtained by a lyophilization method (FIG. 4) and a method of thermally induced phase separation (FIG. 5).
In particular, this material has pores in the form of spheres whose diameter, designated 3 in FIG. 2, is preferably identical in every respect, such that the ratio of the smallest diameter to the largest diameter is 0.9±0.1, or else in the form of polyhedra inscribed in such a sphere, the differences between the diameters at different points of the polyhedron inscribed in this sphere being at most approximately 15% of the diameter of the sphere in which they are inscribed.
At least 70% by number of the pores of the implant material of the invention have these shapes.
The implant materials of the invention may have pore sizes that are in a very wide range from 100 μm to 900 μm, preferably 200 μm to 800 μm inclusive, with a difference between the diameter of the smallest or the largest sphere being at most 70%, preferably at most 50%, more preferably at most 30%, relative to the arithmetic mean diameter of the set of spheres of the implant in association with the interconnections, designated 4 in FIGS. 1 to 3, between pores whose smallest dimension is between 25 μm and 250 μm, inclusive.
Thus, this form and distribution of pore sizes as well as these sizes of interconnections between pores are very favorable for conduction of the cells, for bone regrowth and for tissue invasion, as was demonstrated by Karageorgiou et al., “Porosity of 3D biomaterial scaffolds and osteogenesis”. Biomaterials 2005, 26, (27), 5474-5491.
However, in the case of this article, these pore shapes had been obtained on an implant made entirely of bioactive ceramic, i.e. of a calcium phosphate (hydroxyapatite).
Now, such ceramics have the drawback that they do not have the required flexibility for a bone implant. Their method of manufacture cannot be applied to a material comprising an organic part, like that of the invention, as it involves a step of sintering at temperatures of the order of 800° C., at which the organic part disintegrates.
Such size distributions are never achieved in implant materials comprising an organic part and an inorganic part derived from the methods of the prior art, for which the pores generally have sizes well below 200 μm with interconnections of far smaller sizes.
There are plenty of implant materials derived from the methods of foaming, but these then have very wide, uncontrolled size distributions of pores and interconnections, with a pore size that may even reach a millimeter, which is unfavorable for the mechanical behavior of the implant.
WO 2013/023064 describes two methods for obtaining a composite matrix having pores whose size allows cell infiltration and internal growth of bone. In the first method, a fibrous matrix (which therefore does not have spherical pores, with a controlled size distribution) is obtained. In the second method, which is a solvent molding method, the porosity can be increased by adding a porogenic agent. However, example 1B describing this method, when reproduced, did not make it possible to obtain an implant, as is shown in the comparative example given in what follows.
As will be seen later, thanks to the method for manufacturing implants of the invention, it is possible to control the dispersion of the set of sizes of pores and of interconnections of the matrix, which was not possible in the methods of the prior art, where the porosity generated is distributed randomly in their respective ranges.
The matrix 1 consists of an organic phase and an inorganic phase.
The inorganic phase is a bioactive glass M.
Bioactive ceramics and bioactive glasses are familiar to a person skilled in the art and are described in particular in L. L. Hench et al., J. Biomed. Mater. Res. 1971, 2, 117-141; L. L. Hench et al., J. Biomed. Mater. Res. 1973, 7, 25-42 for bioactive ceramics and in M. Vallet-Regi et al., Eur. J. Inorg. Chem. 2003, 1029-1042 and WO 02/04606, WO 00/76486 and WO 2009/027594, in particular. In the invention, only a bioactive glass is used.
The organic part of the implant material of the invention is a biodegradable polymer P selected from:
bioabsorbable polysaccharides, preferably selected from dextran, hyaluronic acid, agar, chitosan, alginic acid, sodium or potassium alginate, galactomannan, carrageenan, pectin,
bioabsorbable polyesters, preferably polyvinyl alcohol or poly(lactic acid),
biodegradable synthetic polymers, preferably a polyethylene glycol, or poly(caprolactone), and
proteins, preferably gelatin or collagen.
Of course, when the porogenic agent A is made of poly(lactic acid) or of poly(caprolactone), the biodegradable polymer P will be made of a different polymer.
The matrix 1 may consist of the bioactive glass M and the biodegradable polymer P, which form a composite material, i.e. the two phases bioactive glass M and biodegradable polymer P coexist in the architecture of the matrix. This is not the case in the invention.
The matrix 1 may also consist of the bioactive glass M and of the biodegradable polymer P that form a hybrid material, i.e. form a single phase. In this case, the hybrid material is obtained by forming a sol containing all the alkoxide precursors of the bioactive glass, by adding the biodegradable polymer required for the hybrid material H to this sol and by gelling the solution thus obtained by a succession of polymerization reactions (sol-gel polymerization of the inorganic phase) (condensation of the alkoxides). A hybrid mixture is then obtained, intimately associating the mineral phase and the organic phase. This is not the case in the invention.
The hybrid material therefore differs from the composite material by intimate integration between the two phases, organic and inorganic, these two phases being indiscernible (except at the molecular scale) in the case of a hybrid mixture. This, once again, is not the case in the invention.
In fact, in the invention, the matrix 1 is formed from the biodegradable polymer P alone, a polymer that is covered with bioactive glass M, for example by impregnation of the matrix 1 in biodegradable polymer P in a suspension of the bioactive glass M or, when the matrix 1 is covered with the hybrid material H, by immersing the matrix 1 formed only of the biodegradable polymer P in a sol of the hybrid material or in a sol of the alkoxide precursors of the bioactive glass M and of the biodegradable polymer of the hybrid material H.
In both cases, the matrix 1 will then be dried to allow deposition of the particles of the bioactive glass M or gelation of the sol, as appropriate.
The implant material of the invention is obtained by a method employing a porogenic agent A that consists of microspheres of a polymer soluble in at least one solvent S, in which the biodegradable polymer P is not soluble.
Thus, the method of the invention consists of stacking microspheres of porogenic agent A of a polymer material, different from the biodegradable polymer P, in a mold having the shape and size corresponding to the geometry of the bone defect to be filled or of the defect where bone regeneration is desired. This stack is a compact stack as defined previously.
These microspheres of porogenic agent A make it possible to obtain, finally, pores whose size and distribution will correspond as a negative to the stack of microspheres of porogenic agent A initially produced.
Moreover, at least 70% by number of pores formed will have the shape of perfect spheres, i.e. will have in every respect an equal diameter or will have a ratio of the smallest diameter to the largest diameter of 0.9±0.1, or for the largest pores, will have the shape of a polyhedron inscribed in a sphere having the same diameter at all points, the differences between the diameters at different points of the polyhedron inscribed in this sphere being at most approximately 15% of the diameter of the sphere in which they are inscribed.
In fact, the material intended to constitute the matrix 1 will then be infiltrated in the stack of beads of microspheres of porogenic agents A, then solidified so that it can be removed from the mold without changing the shape and size of the stack of the desired implant. The porogenic agent A will then be removed, allowing the implant material of the invention to be obtained.
As can be seen, this method does not use any high-temperature thermal treatment for sintering the bioactive glass M, the only heating required being the temperature of evaporation of the solvent used.
In the method of the invention, the matrix 1 consists only of the biodegradable polymer P and is then covered either with the bioactive glass M or with a hybrid material consisting of a biodegradable polymer and the bioactive glass M.
As will become clear, the invention is based on a judicious combination of the choice of three materials: the material constituting the biodegradable polymer P, the material constituting the porogenic agent A and the solvent S of the porogenic agent A, which must not dissolve the biodegradable polymer P.
The material of the biodegradable polymer P that forms part of the implant material must be a biocompatible polymer.
For its part, the material of the porogenic agent A must be a material, for example a polymer, for which the solvent S is a nonsolvent of the biodegradable polymer P.
It will then be understood that the choice of one of the three elements of the trio “biodegradable polymer P-porogenic agent A-solvent S of the porogene” cannot be made independently of the choice of the others.
The biodegradable polymers P must be soluble in at least one solvent S1 and insoluble in at least one solvent S.
The solvent S1 may be water, an aqueous medium or an organic solvent. The same applies to the solvent S.
The biodegradable polymers P that can be used include:
bioabsorbable polysaccharides, preferably selected from dextran, hyaluronic acid, agar, chitosan, alginic acid, sodium or potassium alginate, galactomannan, carrageenan, pectin,
bioabsorbable polyesters, preferably polyvinyl alcohol, or poly(lactic acid),
biodegradable synthetic polymers, preferably a polyethylene glycol, or poly(caprolactone), and
proteins, preferably gelatin or collagen.
All these polymers are soluble in at least one solvent S1 and insoluble in at least one solvent S.
In the case of polyethylene glycols, these polymers are soluble in water and in numerous organic solvents, except for diethyl ether and hexane.
The material constituting the porogenic agent A must be soluble in the at least one solvent S in which the biodegradable polymer P is insoluble.
Examples of such materials are C₁to C₄polyalkyl methacrylates, preferably polymethyl methacrylate (PMMA) or polybutyl methacrylate, polyurethane, polyglycolic acid, the various forms of polylactic acids, the copolymers of lactic-coglycolic acids, polycaprolactone, polypropylene fumarate, paraffin and naphthalene and acrylonitrile butadiene styrene (ABS).
Examples of polymers which make up the composition of the hybrid material H intended to coat the biodegradable polymer P in the embodiments of the method of the invention are the same as those mentioned for the biodegradable polymer P. However, this polymer and the biodegradable polymer P may be identical to or different than one another.
The material of the porogenic agent A must also be different than the biodegradable polymer P.
In all cases, the solvent of the material of the porogenic agent A will not have to be a solvent for the material selected to serve as biodegradable polymer P.
The solvents S are in particular acetone, ethanol, chloroform, dichloromethane, hexane, cyclohexane, benzene, diethyl ether, hexafluoroisopropanol.
In the invention, preferably, the biodegradable polymer P will be gelatin, the microspheres of porogenic agent A will be made of polymethyl methacrylate, the solvent S will be acetone and the solvent S1 will be water.
In the method for manufacturing implant material of the invention, the microspheres may be placed in the mold before introduction of the biodegradable polymer P.
However, it is also possible to put the biodegradable polymer P in the mold first, and then pour in the microspheres of porogenic agent A.
To obtain a material in which at least 70% by number of pores have at least one interconnection with another pore, the amount of porogenic agent A added to the biodegradable polymer P must represent at least 60 vol % and preferably at least 70 vol % of the total volume of the biodegradable polymer P-porogenic agent A mixture introduced into the mold.
The size of the interconnections is related to the size of the point of contact between porogenic spheres in the stack of spheres produced. The size of the interconnections generated, at constant pore diameter, can be increased by adding a step consisting of partial fusion of the porogenic spheres in the stack initially produced, so as to increase the size of their point of contact.
This fusion may be done by infiltration of a solvent of the material of the invention on the stack of the porogenic agent A, or else by heating the stack of microspheres of porogenic agent produced, or else both at the same time, so as to produce superficial dissolution of the spheres and allow their partial fusion.
FIGS. 6 to 8 show the effect of increasing the size of these interconnections by infiltration of an acetone-ethanol mixture at 30 vol % of acetone, relative to the total volume of the mixture, after 15 min, 30 min and 1 hour of infiltration.
This infiltration takes place directly on the stack of microspheres of porogenic agent, before introduction of the bioactive glass M and/or of the biodegradable polymer P.
FIG. 9 shows the effect of this increase in the form of a curve.
FIGS. 10 to 12 show the effect of increasing the size of these interconnections by heating the stack of microspheres of porogenic agent at 125° C., before introduction of the bioactive glass M and/or of the biodegradable polymer P, for 15 min, 1 hour and 2 hours.
FIG. 13 shows the effect of this increase in the form of a curve.
For better understanding of the invention, several embodiment examples will now be described, purely for illustration, and nonlimiting.

EXAMPLE 1

Manufacture of an implant made of a gelatin composite material, as biodegradable polymer P, and a bioactive glass consisting of 75% of SiO₂and 25% of CaO, by weight, relative to the total weight of the glass, as bioactive glass M (not part of the invention)
Gelatin was selected as the material for the biodegradable polymer P because it is a natural, biocompatible biopolymer that is inexpensive and readily available. Moreover, gelatin is derived from collagen, which is present naturally in bones. Furthermore, it is already used in the context of clinical applications, dressings, adhesives and encapsulation of pharmaceuticals.
A bioactive glass was selected on account of its great capacity for inducing mineralization, the possibility of shaping its textural and morphological properties (porosity, size and therefore specific surface area) at the nanometric scale, the wide range of bioactive compositions that it is possible to formulate, for example by adding anti-inflammatory, or osteoinducing elements, and finally it is the combination of their properties of bioactivity and bioabsorbability that makes them the most promising biomaterials for bone regeneration, notably relative to calcium phosphates (bioactive ceramics), which are generally either less bioactive, or less absorbable.
The microspheres are microspheres of polymethyl methacrylate. This material was selected as it can easily be dissolved by numerous solvents.
Moreover, if residues of polymethyl methacrylate not removed were to remain in the implant material, the good biocompatibility of this polymer with human tissues is a good guarantee that the implant will not present any risk of cytotoxicity.
The porogenic agent was in the form of spherical particles, namely beads of polymethyl methacrylate.
Their diameters may be selected between several tens and several hundreds of microns, depending on the applications. The porosity of the implant material of the invention that will finally be obtained can be controlled for these two points; firstly the diameter of the pores that will be obtained depends directly on the diameter of the initial porogenic particles. It is therefore sufficient to adjust the granulometry of the initial microspheres of polymethyl methacrylate to obtain the desired porosity very simply. Secondly the size of the interconnections between pores depends directly on the size of the contact zone between the polymer beads in the initial stack. The size of this contact zone can be modified by fusing the initial polymer particles together, by means of a solvent S, or by a preliminary thermal treatment. This procedure has already been described by Descamps et al., “Manufacture of macroporous beta-tricalcium phosphate bioceramics”. Journal of the European Ceramic Society 2008, 28, (1), 149-157 and “Synthesis of macroporous beta-tricalcium phosphate with controlled porous architectural”. Ceramics International 2008, 34, (5), 1131-1137.
In this example, the biodegradable polymer and the bioactive glass were used for obtaining a composite matrix.
Thus, for this example, the first step consisted of placing particles of porogenic agents consisting of microspheres of polymethyl methacrylate in a mold with the size and shape required for the implant.
In a second step, the powder of bioactive glass was introduced.
The granulometry of the powder of bioactive glass plays an important role in obtaining a homogeneous composite matrix. Preferably, the granulometry of the powder of bioactive glass must be well below 50 μm. Ideally, the powder particle size must be of the order of a micrometer, or even of the order of a nanometer to a few hundred nanometers. Such fineness can be obtained with a planetary ball mill, for example.
In a third step, gelatin, previously dissolved in lukewarm water, is introduced. The composite mixture is then homogenized.
In a fourth step, the mixture obtained in the third step is gelled for several hours, in the mold, partial dehydration of the gelatin ensuring setting of the mixture.
This operation is carried out at a temperature between 0° C. and 60° C. inclusive, so as not to degrade the matrix.
In a fifth step, the microspheres of polymethyl methacrylate porogenic agent are removed by washing with acetone.
Acetone offers several advantages: firstly, the polymethyl methacrylate beads are easily dissolved in acetone, whereas gelatin is insoluble in acetone.
In addition, acetone makes it possible to continue dehydration of the gelatin, if required.
Finally, it is a solvent in very common use, relatively economical, readily available, without any serious risks of toxicity.
After several washing steps, the initial imprint of the microspheres of polymethyl methacrylate is removed completely and the final material is obtained, in the form of a bio-composite macroporous block of bioactive glass/gelatin.
The biodegradability of this implant material in a living environment and its mechanical behavior may, moreover, easily be adjusted by crosslinking the gelatin in a final step of immersion in a solution of a crosslinking agent, for example genipin, carbodiimide, glutaraldehyde, formaldehyde.
However, this step is optional.
The structures obtained can be washed without any damage in baths of ethanol, in order to remove any undesirable residues, such as chlorides, acetone, etc.
In this example, an implant material was obtained comprising 60 wt % of bioactive glass and 40 wt % of gelatin, relative to the total weight of the implant.

EXAMPLE 2

Manufacture of an implant material according to the invention with a matrix of hybrid material (not part of the invention)
This started with the step of stacking the microspheres of porogenic agent polymethyl methacrylate in a mold having the geometry required for the implant.
In a second step, the hybrid mixture was poured into the mold containing the stack of beads.
Centrifugation or infiltration under pressure or infiltration under vacuum may be used to ensure that the hybrid mixture fills the interstices between the microspheres of polymethyl methacrylate.
The hybrid material was obtained by a sol-gel technique.
In this technique, a sol containing all the alkoxide precursors of the bioactive glass is caused to undergo gelation by a succession of polymerization reactions.
In the present example, gelatin (the biodegradable polymer P) was added before gelation of the sol, so as to obtain a hybrid mixture.
For making the hybrid material, a major difficulty is that thermal treatments at high and moderate temperature, i.e. above 150° C., are to be avoided.
Now, in the methods described in the prior art and notably in Lin, S. et al., “Nanostructure evolution and calcium distribution in sol-gel derived bioactive glass”. Journal of Materials Chemistry 2009, 19, (9), 1276-1282, these thermal treatments are indispensable for obtaining a homogeneous vitreous network, notably for incorporating calcium in the silicate network.
The use of an alkoxide precursor for calcium makes it possible to incorporate calcium in the inorganic phase without thermal treatment.
However, the very great reactivity of the calcium alkoxides with respect to reactions of hydrolysis/condensation in the presence of water means that the sol obtained is very unstable, sol-gel polymerization taking place extremely rapidly, which to date has made it impossible to manipulate it for making a porous implant, and moreover has not allowed good incorporation of calcium in the silicate network. Thus, the inventors discovered that by limiting addition of water to the sol to the maximum extent and by using an alkoxide precursor different from that used in the literature (Ramila A. et al., “Synthesis routes for bioactive sol-gel glasses: alkoxides versus nitrates”. Chemistry of Materials 2002, 14, (12), 542-548) (namely calcium methoxyethoxide), it is possible to increase the stability of the sol considerably. The reactions of hydrolysis/condensation are then slow enough to allow homogeneous incorporation of calcium in the silicate network, while remaining fast enough to allow polymerization of the inorganic phase. In the example, the alkoxide precursors of silicon and calcium are mixed together in a lightly acidified alcoholic solution. Preferably, the alkoxide precursors are tetraethoxysilane and calcium ethoxide. Then the gelatin, previously dissolved, is added to this mixture to obtain a hybrid sol. Water is only supplied via the acid and the gelatin solution: this is sufficient to allow the reactions of hydrolysis/condensation while limiting them strongly so as to have a sol that is stable and can be manipulated for between some minutes and some hours depending on the proportions of the reactants.
The implant material is then obtained by applying the fourth and fifth steps as carried out in example 1.
Whether during preparation of the composite mixture or of the hybrid mixture, it may be advantageous to add a coupling agent, such as an organo-alkoxysilane, to the mixture.
For example, this may simply be added to the aqueous solution of the biodegradable polymer P, in this case gelatin. The role of the coupling agent is to functionalize the gelatin, to allow the establishment of covalent bonds with the inorganic phase (silicate network of the bioactive glass). In the case of a composite mixture, coupling makes it possible to obtain particles of bioactive glass bound at the surface to the gelatin. In the case of a hybrid mixture, a true organo-mineral copolymer is obtained. The advantage is to be able to tailor the degradability of the composite or hybrid implant as well as its mechanical behavior, simply by acting on the degree of affinity between organic and inorganic phases.
An example of coupling agent used successfully in the invention is GPTMS (3-glycidoxypropylmethoxysilane), which is soluble in an aqueous solution of gelatin.

EXAMPLE 3

Manufacture of an implant material according to the invention with a matrix of biodegradable polymer P covered with bioactive glass
In this example, the porogenic agent A was PMMA microspheres with a diameter of 200 to 400 μm which represented 70 vol % of the total volume of the mixture introduced into the mold.
The procedure as in example 2 was then followed, except that in the second step, only gelatin was added, and after the fifth step, removal of the microspheres of polymethyl methacrylate by washing, the biodegradable polymer P, in this case gelatin, was crosslinked in a solution of glutaraldehyde.
In this case, the solvent S1 is water and the solvent S is acetone.
Then the matrix of biodegradable polymer P is immersed in a suspension of the bioactive glass M or else immersed in a sol containing all the alkoxide precursors of the bioactive glass M.
In both cases, the matrix 1 is then dried to allow deposition of the particles of bioactive glass M or gelation of the sol, as appropriate.
The biodegradable polymer P/bioactive glass weight ratio was 70/30.

EXAMPLE 4

Manufacture of a Hybrid Material (Not Part of the Invention)
Products Used:

- Tetraethyl orthosilicate TEOS
- Calcium ethoxide Ca(OEt)₂
- 3-Glycidoxypropyltrimethoxysilane GPTMS
- 2M HCl and 10 mM HCl
- Absolute ethanol
- Gelatin type B
- Acetone

Protocol:

- 1. Fill a polyethylene tube with height of 32 mm and diameter of 9 mm with PMMA beads to a height of about 10 mm.
- 2. Mix 7.80 g of TEOS and 6.39 g of ethanol in a bottle.
- 3. Stir for 15 min using a magnetic stirrer.
- 4. Add 1.35 mL of 2M HCl to the Ethanol+TEOS mixture.
- 5. Stir for 30 min.
- 6. Weigh 6.39 g of ethanol in another bottle.
- 7. Add 1.74 g of calcium ethoxide.
- 8. Stir for 15 min.
- 9. Add the sol containing TEOS to the solution of calcium ethoxide.
- 10. Stir for at least 1 hour.
- 11. Dissolve 1.26 g of type B gelatin and 0.63 g of GPTMS in 8.74 g of 10 mM HCl in a water bath at 60° C.
- 12. Take 3 g of bioglass sol and add 7 g of GPTMS grafted gelatin sol to a bottle.
- 13. Stir for a few minutes, with a magnetic stirrer.
- 14. Add the hybrid sol to the PMMA beads.
- 15. Centrifuge for 1 min.
- 16. Leave to gel at a temperature between 0° C. and 60° C., for at least 24 hours.
- 17. Remove the hybrid block obtained from the mold.
- 18. Dissolve the PMMA beads in a bottle filled with acetone, renewing the acetone after 24 hours. This operation is to be repeated twice.
- 19. Recover the porous block obtained and put it in a stove to dry at 60° C. for 24 hours.

EXAMPLE 5

Preparation of Composite Porous Implants with 60% of Bioglass (75% SiO₂—25% CaO) and 40% of Gelatin (wt %) (Not Part of the Invention)

1) Synthesis of the Glass Powder by the Sol-Gel Route
13.48 mL of water and 13.48 mL of ethanol are mixed with 2.25 mL of 2N HCl and then 13.94 mL of TEOS is added. After stirring for 30 minutes, 5.2637 g of Ca(NO₃)₂.4H₂O is added. The sol is stirred for 1 hour, put in a stove at 60° C. in Teflon containers for 24 h and then put in the air at 125° C. for 24 h. The powder thus obtained is then calcined for 24 hours at 700° C. (heating from 25 to 700° C. carried out in 2 hours).
The powder is then ground for 30 minutes and then sieved, only keeping the fraction below 50 μm.
2) Preparation of the Composite
Porcine gelatin powder (type A) is added to distilled water heated to 35° C. in a ratio of 0.1 g/mL of water; the mixture is stirred for 10 minutes. In parallel, an amount of 0.025 g of glass powder is mixed with 0.2 g of PMMA beads. 0.15 mL of gelatin solution in water is then added, and the mixture obtained is poured into a tube, in which it is compacted.
After drying for 1 day in the ambient air, the glass cylinder+beads+gelatin is taken out of the mold and immersed in acetone for 6 hours with stirring; the acetone is then renewed and dissolution is allowed to continue for 24 hours, still with stirring. The porous glass-gelatin composite block obtained is then rinsed with acetone and dried in the ambient air.

EXAMPLE 6

In Vitro Evaluation of the Implants Obtained in Examples 1 to 5
The bioactivity of the implant materials obtained in examples 1 to 3 was evaluated in vitro by immersing them in a physiological solution (SBF) having an ion composition identical to that of blood plasma (ISO-23317 test).
Then the great bioactivity that is typical of the bioactive glasses used in the implant materials was verified: these implant materials were found to be very prompt in inducing mineralization in contact with the physiological medium: after 1 h of interaction with the medium, some of the calcium ions derived from the vitreous matrix have migrated to the surface of the composite, where phosphate ions derived from the physiological medium have been incorporated to form a layer of calcium phosphate about ten microns thick, which coats the surface of the pores.
This constitutes the first step of the bioactivity process.
It was verified that subsequently this layer of calcium phosphate continues to grow, to form an apatite layer similar to bone mineral.
Crosslinking of the gelatin does not diminish the bioactivity of the implant, but makes it possible to increase its resistance to dissolution in the physiological medium.
It was also noted that the SBF medium is quickly (after 1 day) exhausted of phosphorus, and to a less extent of calcium, these elements being incorporated at the surface of the implants and therefore withdrawn from the medium to form a biomimetic layer of calcium phosphate.
Crosslinking of the gelatin does not in any way alter the chemical reactivity of the implants, but offers the advantage of making it possible to adjust their biodegradability in a living environment.
Thus, all the materials manufactured in examples 1 to 5 prove to be prompt at inducing formation of bone mineral in contact with physiological fluids.
However, it is noted there are differences between these materials.
Firstly, the materials in which gelatin has been crosslinked have a slower biodegradability, which is manifested by slower dissolution of silicon. The formation of calcium phosphates is also slower.
Next, it can be seen that formation of calcium phosphates on the surface of the material is slower with the composite material than with the material consisting of the biodegradable polymer P coated with the bioactive glass M according to the invention.
This is a definite advantage.
With these two materials, as expected, formation of calcium phosphates and in particular of apatite only occurs on the surface of the material.
In contrast, with the hybrid material, formation of calcium phosphates takes place not only on the surface but also in the bulk, which represents a disadvantage when the bone defect to be filled requires slower integration.

EXAMPLE 7

The procedure was carried out as in example 3, except that the matrix of biodegradable polymer P was immersed in a sol of the alkoxide precursors of the bioactive glass M and of the biodegradable polymer of the hybrid material H obtained in step 13 of example 4.
The material of the invention thus obtained was evaluated in vitro as described in example 6.
This material has the advantage of a very rapid growth of calcium phosphates not only at the surface, but also in the body of the material of the invention.

COMPARATIVE EXAMPLE

Manufacture of an Implant According to WO 2013/023064
Porcine gelatin powder (type A) is added to distilled water heated to 35° C. in a ratio of 0.1 g/mL of water; the mixture is stirred for 10 minutes. An amount of 0.75 g of glass powder is mixed with 57.38 g of NaCl particles, then 4.5 mL of the gelatin solution is added, in such a way that the volume of porogene represents 90% of the total volume of the mixture, as stated in WO 2013/023064. The mixture obtained is poured into a tube. The mold and its mixture then undergo freezing, and then lyophilization under vacuum for 1 day. After lyophilization, the composite block is removed from the mold and immersed in distilled water in order to dissolve the porogene (NaCl).
Unfortunately, the amount of porogene (90% of the total volume) proved to be much too great relative to the amount of composite mixture: dissolution of the porogene led to immediate destruction of the composite structure, and no implant could be obtained by this production protocol.
Characterization of the Sphericity of the Macropores Obtained
The synthesis route proposed makes it possible to obtain spherical pores. In fact, measuring two perpendicular diameters for each pore, the ratio of the smallest diameter to the largest diameter is on average 0.9±0.1.
Thus, it can clearly be seen that thanks to the method of the invention, implants having all the properties of porosity, in terms of pore sizes, sphericity of these pores, distribution of this pore size over a very wide range between 100 and 900 μm, preferably between 200 and 800 μm inclusive, with a difference between the diameter of the smallest or the largest sphere being at most 70%, preferably at most 50%, more preferably at most 30%, relative to the arithmetic mean diameter of the set of spheres of the implant, can be obtained, in conjunction with interconnections between pores for which the smallest dimension is between 25 and 250 micrometers inclusive, which had never been obtained previously.

Claims

1. A method for manufacturing an implant for filling bone defects, for bone regeneration, and for bone tissue engineering, comprising the following steps:

a) selecting a bioactive glass M based on SiO₂and CaO, optionally containing P₂O₅and/or optionally doped with strontium,

b) selecting a biodegradable polymer P that is soluble in at least one solvent S1 and insoluble in at least one solvent S,

c) selecting microspheres of a porogenic agent A having diameters and sizes corresponding to the desired diameters and sizes of the pores in an implant material, the material of this porogenic agent A being a polymer insoluble in the at least one solvent S1 and soluble in the at least one solvent S, the at least one solvent S in which the biodegradable polymer P is insoluble and the at least one solvent S in which the material of the porogenic agent A is soluble being identical,

d) putting at least 60 vol %, preferably at least 70 vol % relative to the total volume of the mixture of biodegradable polymer P-porogenic agent A introduced into the mold, of microspheres of the porogenic agent A in a mold having the required shape and size for the implant, these microspheres forming a compact stack corresponding to the shape and size of the pores to be obtained in the implant material,

e) putting the biodegradable polymer P in the mold,

f) gelling the mixture obtained in step e) in the mold,

g) removing the mixture obtained in step f) from the mold,

h) removing the porogenic agent by washing with the at least one solvent S,

i) crosslinking the mixture obtained in step g), and

j) coating the mixture obtained in step i) with the bioactive glass M or with a hybrid material H formed from a biodegradable polymer identical to or different than the biodegradable polymer P and from the bioactive glass M.

2. The method as claimed in claim 1, wherein step j) is carried out by impregnation of the mixture obtained in step i) with a suspension, in a solvent, containing particles of the bioactive glass M or of the hybrid material H, and evaporation of the solvent.

3. The method as claimed in claim 1, wherein step j) is a step of coating the mixture obtained in step i) either with the bioactive glass M, or with the hybrid material H, and is carried out by immersion of the mixture obtained in step i) either in a sol containing the alkoxide precursors of the bioactive glass M, for a coating only with the bioactive glass M, or in a sol of the hybrid material, or in a sol of the alkoxide precursors of the bioactive glass M and of the biodegradable polymer of the hybrid material H, for a coating with the hybrid material H, followed by a gelling step.

4. The method as claimed in claim 1, wherein the biodegradable polymer P is selected from:

biodegradable polymers that are soluble in a solvent S1 and insoluble in at least one solvent S selected from:

bioabsorbable polysaccharides, preferably selected from dextran, hyaluronic acid, agar, chitosan, alginic acid, sodium or potassium alginate, galactomannan, carrageenan, pectin,

bioabsorbable polyesters, preferably polyvinyl alcohol or poly(lactic acid),

biodegradable synthetic polymers, preferably a polyethylene glycol, or poly(caprolactone), or

proteins, preferably gelatin or collagen,

and in that the material of the porogenic agent A is selected from biodegradable polymers that are insoluble in the at least one solvent S1 and soluble in the at least one solvent S, preferably selected from C₁to C₄polyalkyl methacrylates, preferably polymethyl methacrylate or polybutyl methacrylate, polyurethane, polyglycolic acid, the various forms of polylactic acids, the copolymers of lactic-coglycolic acids, polycaprolactone, polypropylene fumarate, paraffin and naphthalene and acrylonitrile butadiene styrene (ABS),

the material of the porogenic agent A being different from the biodegradable polymer P.

5. The method as claimed in claim 1, wherein the weight ratio biodegradable polymer P/bioactive glass M is between 90/10 and 50/50, inclusive, and preferably between 80/20 and 60/40, inclusive.

6. The method as claimed in claim 1, wherein the bioactive glass M is a glass based on SiO₂and CaO, the biodegradable polymer P is gelatin, the material of the microspheres of porogenic agent A is polymethyl methacrylate, the solvent S is acetone, and the solvent S1 is water.

7. The method as claimed in claim 1 further comprising a step of introducing a coupling agent, preferably an organoalkoxysilane compound, more preferably 3-glycidoxypropyltrimethoxysilane (GPTMS), and even more preferably 3-glycidoxypropyltriethoxysilane (GPTES), in step e).

8. The method as claimed in claim 1 comprising after step d), and before step e), a step of enlarging the interconnections (4), by infiltration of a solvent of the material of the porogenic agent A, into the stack of the microspheres of porogenic agent A and/or by heating this stack.

9. An implant material for filling bone defects, for bone regeneration, and for bone tissue engineering, obtained by the method as claimed in claim 1, comprising:

a bioactive glass M based on SiO₂and CaO, optionally containing P₂O₅and/or optionally doped with strontium, and

a biodegradable polymer P soluble in at least one solvent S1 selected from:

bioabsorbable polyesters, preferably polyvinyl alcohol or poly(lactic acid),

biodegradable synthetic polymers, preferably a polyethylene glycol, or poly(caprolactone), and

proteins, preferably gelatin or collagen,

and a matrix comprising at least the biodegradable polymer P covered with the bioactive glass M or with a hybrid material H formed from the bioactive glass M and from a biodegradable polymer identical to or different than the biodegradable polymer P, this matrix having at least 70% by number of pores having at least one interconnection with another pore and the shape of spheres or of polyhedra inscribed in a sphere, the diameter of the spheres being between 100 and 900 μm, preferably between 200 and 800 μm inclusive, with a difference between the diameter of the smallest or the largest sphere being at most 70%, preferably at most 50%, more preferably at most 30%, relative to the arithmetic mean diameter of the set of spheres of the implant, and the interconnections between the pores having their smallest dimension between 25 μm and 250 μm inclusive.

10. An implant for filling bone defects, for bone regeneration and for bone tissue engineering, comprising a material as claimed in claim 9.

11. An implant for filling bone defects, for bone regeneration, and for bone tissue engineering, comprising a material obtained by the method of claim 1.