Compositions and methods for treatment of bone defects

Abstract

The present invention relates to the field of treatment of bone defects. The invention provides a composition for treatment of bone defects as well as methods for treatment of such defects.

1 .- 55 . (canceled) 
     
     
         56 . A curable, bone reconstruction composition comprising a biocompatible carrier and one or more bioactive agents, wherein the one or more bioactive agents comprise (a) an antiresorptive agent comprising a bisphosphonate, and/or (b) fosfomycin. 
     
     
         57 . The bone reconstruction composition according to  claim 56 , wherein the biocompatible carrier comprises calcium sulphate, calcium phosphate and/or hydroxyapatite. 
     
     
         58 . A composition comprising
 a) a bone reconstruction composition according to  claim 56 ,
 wherein the biocompatible carrier comprises calcium salts, hydroxyapatite, natural polymers, and/or synthetic polymers; 
 wherein at least one of the bioactive agents accelerates curing of the composition and wherein at least one of the bioactive agents decelerates curing of the composition 
 wherein the bioactive agent that accelerates curing of the composition is fosfomycin 
 wherein the bioactive agent that decelerates curing of the composition is a bisphosphonate, and 
   b) a biocompatible matrix comprising solid particles of natural origin;
 wherein the particles of the biocompatible matrix comprise or consist of bone graft material and/or demineralised bone matrix (DBM). 
   
     
     
         59 . A kit-of-parts comprising:
 a) a bone reconstruction composition as defined in  claim 58 , and   b) a biocompatible matrix as defined in  claim 58 .   
     
     
         60 . A method for treatment of a bone defect in an individual in need thereof, which method comprises
 a) providing a curable bone reconstruction composition comprising a biocompatible carrier and at least one bioactive agent,   b) providing a biocompatible matrix comprising solids particles and/or scaffolds of natural or synthetic origin,   c) contacting the site of bone defect in said individual with alternating layers of said composition and said biocompatible matrix,   wherein said treatment comprises applying said bone reconstructing composition and said biocompatible matrix to the bone defect by injection and/or moulding,   wherein said bone reconstruction composition and said biocompatible matrix are impacted in at least 2 alternate layers, wherein at least one layer comprises said bone reconstruction composition and at least one layer comprises said biocompatible matrix,   thereby treating said bone defect.   
     
     
         61 . The method according to  claim 60 , comprising providing a biocompatible carrier and one or more bioactive agents, wherein at least one of the bioactive agents decelerates curing of the composition. 
     
     
         62 . The method according to  claim 60 , comprising providing a biocompatible carrier and one or more bioactive agents, wherein at least one of the bioactive agents accelerates curing of the composition. 
     
     
         63 . The method according to  claim 60 , comprising providing a biocompatible carrier and two or more bioactive agents, wherein at least one of the bioactive agents decelerates curing of the composition and one other bioactive agent accelerates curing of the composition. 
     
     
         64 . The composition according to  claim 58 , wherein said decelerating bioactive agent comprises a bisphosphonate selected from a group consisting of Zoledronic acid, Pamidronic acid, Neridronic acid, Olpadronic acid, Alendronic acid, Ibandronic acid, Risedronic acid, pharmaceutically acceptable salts of any of the aforementioned and combinations of any of the aforementioned. 
     
     
         65 . The composition according to  claim 58 , wherein said decelerating bioactive agent comprises a growth or differentiation factor selected from the group consisting of bone morphogenic proteins (BMPs) 1,2,3,4,5,6,7,8a,8b, 10, 15; members of the TGF-superfamily; platelet-derived growth factor (PDGF); fibroblast growth factors (FGFs); insulin-like growth factors (IGFs); metalloproteinases; vascular endothelial growth factor (VEGFs A, B, C or D); angioprotein 1 and 2; and combinations thereof. 
     
     
         66 . The composition according to  claim 58 , wherein said decelerating bioactive agent comprises a BMP antagonist inhibitor selected from the group consisting of members of the DAN family, members of the twisted gastrulation family, and noggin/chordin. 
     
     
         67 . The composition according to  claim 58 , wherein said decelerating bioactive agent comprises a signaling protein selected from the group consisting of Wnt proteins, lymphoid enhancer-binding factor 1 (Lef1), β-catenin, parathyroid hormone-related protein (PTHrP), colony stimulating factors, Indian hedgehog homolog (IHH), Hypoxia-inducible factor 1-alpha (HIF-α) and combinations thereof. 
     
     
         68 . The composition according to  claim 58 , wherein said decelerating bioactive agent comprises a human cell suspension comprising mesenchymal stem cells and/or lymphocytes and/or platelet rich plasma (PRP) and/or the stromal vascular fraction of lipoaspirate of autogenic or allogenic origin. 
     
     
         69 . The composition according to  claim 58 , wherein said decelerating bioactive agent comprises a radioactive material selected from the group consisting of Cesium-131, Cesium-137, Cobalt-60, Iridium-192, Iodine-125, Palladium-103, Ruthenium-106, Radium-226 and combinations thereof. 
     
     
         70 . The composition according to  claim 58 , wherein said decelerating bioactive agent comprises a cytokine selected from the group consisting of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), receptor activator of nuclear factor kappa-B ligand (RANKL), core-binding factor alpha 1 (cbfa1), osteogenin, or SMADs proteins 1-8, osteogenic growth peptide (OGP), and combinations thereof. 
     
     
         71 . The composition according to  claim 58 , wherein said decelerating bioactive agent comprises or consists of an antibiotic selected from the group consisting of meropenem, gentamicin, tetracycline, vancomycin, tobramycin, gentamycin, cephalosporin and a combination thereof. 
     
     
         72 . The composition according to  claim 58 , wherein the particles and/or scaffolds of the biocompatible matrix comprises synthetic metallic structural scaffolds, and/or particles or synthetic non-metallic scaffolds, and/or particles or cancellous bone, or combinations thereof. 
     
     
         73 . The composition according to  claim 58 , wherein the particles and/or scaffolds of the biocompatible matrix comprises synthetic metallic or non-metallic scaffolds and/or particles, and wherein said scaffold and/or particles are 3D-printed. 
     
     
         74 . The composition according to  claim 58 , wherein the biocompatible matrix comprises particles of cancellous bone and wherein the cancellous bone is allograft and/or autograft. 
     
     
         75 . The composition according to  claim 58 , wherein the biocompatible matrix comprises particles of cancellous bone and wherein said cancellous bone comprises demineralized bone matrix or fibers. 
     
     
         76 . The composition according to  claim 58 , wherein the particles and/or scaffolds of the biocompatible matrix have a particle size of no more than 20 mm. 
     
     
         77 . The composition according to  claim 58 , wherein the biocompatible matrix comprises particles of cancellous bone, wherein the cancellous bone is autograft and wherein said autograft is vascularized. 
     
     
         78 . The composition according to  claim 58 , wherein the biocompatible matrix comprises particles of cancellous bone and wherein said cancellous bone comprises no more than 10% water and no more than 5% lipids.