# US 12,599,703 B2 · Hybrid heterogeneous hydrogel, manufacturing method and use as an in-situ non-degradable filler implant > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,599,703 B2 - Document ID: US12599703B2 - Status: Granted - Kind: B2 - Application number: 17/912,184 - Filed: 2021-03-17 - Published: 2023-06-01 - Granted: 2026-04-14 - Earliest claimed: 2020-03-17 - Assignees: Neurobiomat - Applicants: Neurobiomat - Inventors: Stéphane Woerly - Web page: https://patentgrep.com/patent/US12599703B2 ## CPC - A61L 27/52: Hydrogels or hydrocolloids - A61L 27/14: Macromolecular materials - A61L 27/16: obtained by reactions only involving carbon-to-carbon unsaturated bonds - A61L 27/18: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds - A61L 2400/06: Flowable or injectable implant compositions - A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K) ## Abstract A filler implant includes a support of hybrid heterogeneous hydrogel which is formed by a copolymer including: a dendrimer monomer which is functionalised by an ethylene radical, an acryl amide compound which is selected from an N-substituted methacrylamide and N-substituted acrylamide, a cross-linking agent and a bioactive copolymerisable material. The support is formed by microbeads which have a diameter between 1.5 micrometres and 10 micrometres and it predominantly contains by weight the acrylamide compound. The microbeads are assembled to form aggregates which contain between 5 and 50 microbeads. The aggregates are connected by cross-linking points in order to define a penetrating porous network which defines three-dimensional percolating paths. The penetrating porous network is formed by pores, the majority of the volume of which has a diameter between 10 and 30 micrometres. The support has a viscoelastic nature with a modulus of elasticity between 1 and 200 kPa. ## Claims ### Claim 1 A hybrid heterogeneous hydrogel prepared from a copolymer derived from a reaction mixture comprising the following monomers: a dendrimer monomer comprising a plurality of branches and in which only a single branch is functionalized with an unsaturated ethylene radical, an acrylamide compound chosen from an N-substituted methacrylamide and an N-substituted acrylamide, and a cross-linking agent, wherein the hybrid heterogeneous hydrogel is formed by a plurality of microbeads having a diameter of more than 1.5 microns and less than 10 microns, wherein the microbeads are assembled to define a through porous array defining three-dimensional percolating paths, wherein the through porous array further defines pores, a majority thereof having a diameter of between 10 and 30 microns, and a fraction of pores in the through porous array having a diameter between 30 and 300 microns is more than 20%, wherein the microbeads contain closed non-communicating micropores having a size that is smaller than 20 nm, the microbeads are assembled to one another to form aggregates containing between 5 and 50 microbeads, wherein the aggregates have weakly cross-linked areas connecting the aggregates to each other which allow shifting of the aggregates in relation to each other, and wherein the hybrid heterogeneous hydrogel has a viscoelastic nature and has a modulus of elasticity between 1 and 200 kPa. ### Claim 2 (depends on 1) The hybrid heterogeneous hydrogel according to claim 1 wherein a fraction of pores in the through porous array having a diameter between 10 and 30 microns is more than 60%. ### Claim 3 (depends on 1) The hybrid heterogeneous hydrogel according to claim 1 wherein the microbeads comprise at least 90% by weight of polymerized acrylamide compound. ### Claim 4 (depends on 1) The hybrid heterogeneous hydrogel according to claim 1 wherein the aggregates contain between 10 and 30 microbeads. ### Claim 5 (depends on 1) The hybrid heterogeneous hydrogel according to claim 1 wherein the aggregates have a conformation resembling a bunch of grapes, each aggregate having an increasing cross-section from one end to the other end along a length of the aggregate with a cross-section that is substantially circular in a sectional plane that is perpendicular to the length of the aggregate. ### Claim 6 (depends on 1) The hybrid heterogeneous hydrogel according to claim 1 wherein the dendrimer monomer comprises one macromolecular dendritic branch of polyoxyethylene, the macromolecular dendritic branch of polyoxyethylene being functionalized by one or more bioactive copolymerizable materials chosen from the group consisting of a derivative of a complex sugar, a derivative of a tissue adhesion peptide and a derivative of a polymer conjugate coupled with antibodies against lipid derivatives, the one or more bioactive copolymerizable materials covering a wall of the three-dimensional percolating paths of the through porous array. ### Claim 7 (depends on 6) The hybrid heterogeneous hydrogel according to claim 6 wherein the wall of the three-dimensional percolating paths is functionalised by means of several different bioactive copolymerizable materials. ### Claim 8 (depends on 1) The hybrid heterogeneous hydrogel according to claim 1 wherein the dendrimer monomer comprises one macromolecular dendritic branch of polyoxyethylene, the macromolecular dendritic branch of polyoxyethylene being functionalized by one or more bioactive molecules, wherein the one or more bioactive molecules are chosen from the group consisting of a derivative of complex sugars, derivatives of a tissue adhesion peptide or of a peptide with an angiogenic activity, derivatives of a peptide stimulating nerve re-growth, derivatives of a peptide stimulating cell proliferation and differentiation, a derivative of a polymer conjugate coupled with antibodies against lipid derivatives, and chemokines of the Stromal-derived factor-1 (SDF-1) class. ### Claim 9 (depends on 1) The hybrid heterogeneous hydrogel according to claim 1 wherein the dendrimer monomer comprises a central core A, and said plurality of branches are polyoxyethylene branches and said unsaturated ethylene radical is an acrylate or methacrylate radical. ### Claim 10 (depends on 1) The hybrid heterogeneous hydrogel according to claim 1 wherein the acrylamide compound is N-(2-hydroxypropyl) methacrylamide (HPMA) and said plurality of branches are polyoxyethylene branches and said plurality of branches which do not correspond to the single branch functionalized with an unsaturated ethylene radical are functionalized at their periphery with bioactive agents conferring bioactive properties for tissue regeneration. ### Claim 11 (depends on 1) A method comprising applying the hybrid heterogeneous hydrogel according to claim 1 as a permanent filler implant. ### Claim 12 A method for fabricating a hybrid heterogeneous hydrogel comprising: forming microbeads by phase separation induced by copolymerization at a temperature between 45° C. and 55° C. from a reaction mixture comprising the following compounds: a dendrimer monomer having a plurality of branches and in which only a single branch is functionalized with an unsaturated ethylene radical, the other branches being devoid of ethylene radicals, an acrylamide compound chosen from an N-substituted methacrylamide and N-substituted acrylamide, and at least one bifunctional unsaturated ethylene cross-linking agent comprising two reactive vinyl bonds, and a free radical initiator, the microbeads defining closed non-communicating micropores having a size that is smaller than 20 nm, the microbeads having a diameter of more than 1.5 microns and less than 10 microns, the microbeads being assembled to one another to form aggregates between 5 and 50 microbeads, the aggregates being joined to one another by cross-linking points to define a hybrid heterogeneous hydrogel having a through porous array defining three-dimensional percolating paths and pores, a majority of said pores having a diameter between 10 and 30 microns and a fraction of pores having a diameter between 30 and 300 microns is more than 20% and wherein the hybrid heterogeneous hydrogel has a viscoelastic nature and has a modulus of elasticity between 1 and 200 kPa; wherein copolymerization is performed with a first temperature plateau followed by a second plateau or a temperature gradient to form the microbeads, the temperature of the first plateau being between 45° C. and 55° C. and the second plateau or the temperature gradient having temperatures at least 5° C. higher than the temperature of the first plateau and wherein the reaction mixture is injected into cylindrical-shaped, heat-conducting molds. ### Claim 13 (depends on 12) The method for fabricating a hybrid heterogeneous hydrogel according to claim 12 wherein the molar ratio between the dendrimer monomer and the at least one bifunctional unsaturated ethylene cross-linking agent is between 0.1 and 0.8. ### Claim 14 (depends on 13) The method for fabricating a hybrid heterogeneous hydrogel according to the claim 13 wherein the dendrimer monomer has a molecular mass between 6,220 g/mol and 23,280 g/mol. ### Claim 15 (depends on 12) The method for fabricating a hybrid heterogeneous hydrogel according to claim 12 wherein a bioactive copolymerizable material is present in the reaction mixture forming the microbeads, the bioactive copolymerizable material being chosen from the group consisting of a derivative of a complex sugar, a derivative of a tissue adhesion peptide and a derivative of a polymer conjugate coupled with antibodies against lipid derivatives. ### Claim 16 (depends on 12) The method for fabricating a hybrid heterogeneous hydrogel according to claim 12 wherein the reaction mixture is injected into molds having inner walls covered by polytetrafluoroethylene. ### Claim 17 (depends on 12) The method for fabricating a hybrid heterogeneous hydrogel according to claim 12 comprising copolymerizing the reaction mixture at a first temperature for at least 80 minutes to form the microbeads followed by a temperature increase of the molds and of the reaction mixture by at least 5° C. ### Claim 18 (depends on 12) A method for fabricating a filler implant comprising fabricating a hybrid heterogenous hydrogel according to the method of claim 12 and further comprising assembling of the aggregates to one another by a three-dimensional printing method to form a filler implant.