Bone grafts and biomaterials substitutes for bone defect repair: A review Bone grafts have been widely used in orthopaedics to treat bone defects, delayed union, non-union, and spinal fusion. Despite the emergence of synthetic bone graft substitutes, the integration of allogeneic grafts and synthetic substitutes with host bone has been compromised in long-term studies. Enhancing osteointegration is crucial. Growth factors like bone morphogenetic proteins (BMPs), parathyroid hormone (PTH), and platelet-rich plasma (PRP) have been added to structural allografts and synthetic substitutes. Although these factors show good bone formation, their application is limited due to high cost and potential adverse effects. Bioinorganic ions like magnesium, strontium, and zinc are considered alternatives to osteogenic biological factors. This paper reviews available bone grafts and substitutes, as well as biological and bio-inorganic factors for bone defect treatment. Bone grafting is a common surgical method for bone regeneration. Over two million procedures are performed annually. Autologous bone is considered the gold standard due to its osteoconductive, osteoinductive, and osteogenic properties. However, limited supply and donor site complications remain. Bone allografts are the second most common option, available in various forms. They are primarily osteoconductive, while demineralized bone matrix (DBM) preparations retain some osteoinductivity. However, inferior healing and disease transmission risks are reported. Synthetic bone substitutes have emerged as alternatives, with the global market revenue exceeding two billion in 2013. Bone grafting is gradually shifting from natural grafts to synthetic substitutes and biological factors. Calcium phosphate (CaP)-based biomaterials and recombinant human bone morphogenetic proteins (rhBMPs) are most widely used. BMPs, especially BMP-2 and BMP-7, are members of the TGF-β superfamily with superior osteoinductive properties. They have been extensively studied for treating skeletal defects. BMP-2 induces osteoblastic differentiation from mesenchymal stem cells, while BMP-7 promotes angiogenesis. Clinical trials have shown BMP-2's effectiveness in treating tibial open fractures. However, BMPs have high costs, potential adverse effects, and a dose-dependent effect. They are often combined with osteoconductive carriers like collagen, allografts, or autologous bone grafts. Fibroblast growth factors (FGFs) are secreted by various cells and play a role in fracture healing. They are not well understood in their role in bone healing. Growth factors like FGFs, vascular endothelial growth factors (VEGF), PTH, and PRP have been extensively investigated for their therapeutic potential in bone healing. However, their clinical application is limited due to high cost and potential adverse effects. Bioinorganic ions like magnesium, strBone grafts and biomaterials substitutes for bone defect repair: A review Bone grafts have been widely used in orthopaedics to treat bone defects, delayed union, non-union, and spinal fusion. Despite the emergence of synthetic bone graft substitutes, the integration of allogeneic grafts and synthetic substitutes with host bone has been compromised in long-term studies. Enhancing osteointegration is crucial. Growth factors like bone morphogenetic proteins (BMPs), parathyroid hormone (PTH), and platelet-rich plasma (PRP) have been added to structural allografts and synthetic substitutes. Although these factors show good bone formation, their application is limited due to high cost and potential adverse effects. Bioinorganic ions like magnesium, strontium, and zinc are considered alternatives to osteogenic biological factors. This paper reviews available bone grafts and substitutes, as well as biological and bio-inorganic factors for bone defect treatment. Bone grafting is a common surgical method for bone regeneration. Over two million procedures are performed annually. Autologous bone is considered the gold standard due to its osteoconductive, osteoinductive, and osteogenic properties. However, limited supply and donor site complications remain. Bone allografts are the second most common option, available in various forms. They are primarily osteoconductive, while demineralized bone matrix (DBM) preparations retain some osteoinductivity. However, inferior healing and disease transmission risks are reported. Synthetic bone substitutes have emerged as alternatives, with the global market revenue exceeding two billion in 2013. Bone grafting is gradually shifting from natural grafts to synthetic substitutes and biological factors. Calcium phosphate (CaP)-based biomaterials and recombinant human bone morphogenetic proteins (rhBMPs) are most widely used. BMPs, especially BMP-2 and BMP-7, are members of the TGF-β superfamily with superior osteoinductive properties. They have been extensively studied for treating skeletal defects. BMP-2 induces osteoblastic differentiation from mesenchymal stem cells, while BMP-7 promotes angiogenesis. Clinical trials have shown BMP-2's effectiveness in treating tibial open fractures. However, BMPs have high costs, potential adverse effects, and a dose-dependent effect. They are often combined with osteoconductive carriers like collagen, allografts, or autologous bone grafts. Fibroblast growth factors (FGFs) are secreted by various cells and play a role in fracture healing. They are not well understood in their role in bone healing. Growth factors like FGFs, vascular endothelial growth factors (VEGF), PTH, and PRP have been extensively investigated for their therapeutic potential in bone healing. However, their clinical application is limited due to high cost and potential adverse effects. Bioinorganic ions like magnesium, str