The Biological and Clinical Grand Challenges For Craniomandibulofacial Reconstruction: The Dream of Bone Tissue...

Heterotopic Intramuscular implantation of the osteogenic proteins of the transforming growth factor-β (TGF-β) superfamily, in contexts the hTGF-β 3 morphogen, the recombinant human osteogenic protein-1 (hOP-1, also known as hBMP-7), and hBMP-2 recapitulate embryonic development. The heterotopic intramuscular microenvironment is replete with multiple cell types with cell stemness and stem cell niches of perivascular pericytes, myoendothelial and myoblastic cell lines together with multiple capillaries providing endothelial cell-derived signals regulating homeostasis, tissue induction, and morphogenesis, an ideal microenvironment for the induction of bone. The induction of bone formation in heterotopic sites in a variety of animal models, including nonhuman primates by both hOP-1 and hBMP-2 recapitulates embryonic development with the induction of cartilage' anlages before differentiation of osteoblastic cells and the induction of bone formation. Cell and molecular biologists together with skeletal reconstructionists alike expected thus that the heterotopic induction of bone by hBMPs was the biological and molecular proof of concept that isolated and purified proteinaceous components of the bone matrix could be used in clinical contexts, providing the selected proteins would induce bone formation in heterotopic sites of animal models, predominantly rodents. Translation in clinical contexts using hBMP-2 and hOP-1 however failed, and the limited osteoinduction in orthotopic intraskeletal sites is because the recombinant proteins when implanted in orthotopic sites whilst may initiate however limited amounts of bone, the completion of the bone induction cascade fails lacking the recapitulation of embryonic development. The lack and/or limited osteoinduction is thus a biological problem that indicates that BMPs and/or TGF-βs proteins (the latter in primates only), are not Nature selection for the induction of bone formation in clinical contexts. In spite of the often remarkable generation of heterotopic ossicles by hOP-1 and particularly by doses of hTGF-β 3 , translation in clinical contexts to regenerate mandibular defects often fail with the induction of noninspiring amounts of bone, certainly not comparable to the rapid and substantial induction of bone when hOP-1, and particularly hTGF-β 3 , are implanted heterotopically in the rectus abdominis muscle of the nonhuman primate Papio ursinus . The uninspiring induction of bone in clinical contexts is thus a multifaceted biological problem since hBMPs and hTGF-β 3 , when implanted in orthotopic cranio-mandibulo-facial sites are biologically unable to initiate the induction of bone formation via recapitulation of embryonic development. Tissue and molecular biologists alike need now to go back to the laboratory benches to molecularly dissect osteogenesis by autogenous bone grafts to relearn and meditate why so successful is osteogenesis by autogenous bone grafts in clinical contexts.