Regenerative frontiers in craniofacial reconstruction: grand challenges and opportunities for the mammalian transforming growth factor-β proteins

Abstract

Science's fascination with bone and its repair processes span for thousands of years since the ancient Greek Hippocrates, the father of Medicine, made the key discovery that bone heals without scarring. Through the centuries, several lucid investigators perceived that the extracellular matrix of bone must be a reservoir of differentiating and morphogenetic factors ultimately responsible for its pronounced healing potential (reviewed in Urist, 1968, 1994; Reddi, 2000; Ripamonti et al., 2006).

Keywords: bone morphogenetic proteins; osteogenic proteins; regenerative medicine; transforming growth factor-β proteins.

Figure 1

Angiogenesis, capillary sprouting, vascular invasion, cellular trafficking, cell differentiation and the induction of the primate cortico-cancellous osteonic bone. (A) Endothelial-like cell detachment and migration from the vascular compartment (magenta arrow) to the bone-forming osteogenetic compartment (top right of magenta arrow); (B–D) osteogenesis in angiogenesis in the non-human primate Papio ursinus. Capillary sprouting and invasion patterning the induction of mesenchymal cellular condensations around the “osteogenetic vessels” of Trueta's definition (Trueta, 1963); (B) Mesenchymal condensations (light blue arrow) patterned around the invading osteogenetic vessels with foci of mineralization (dark blue arrow) facing osteoid seems populated by differentiating osteoblast-like cells; (C,D) Tissue patterning and morphogenesis as induced by the osteogenetic vessels with newly forming mesenchymal condensations patterning around the central morphogenetic vessels (light blue arrow in C and D) with foci of mineralization of the newly formed bone (dark blue arrows).

Figure 2

Tissue induction and morphogenesis of large and corticalized ossicles (A,C) upon implantation of 125 μg hTGF-β₃ in the Rectus Abdominis muscles of adult baboons Papio ursinus harvested on day 90 after heterotopic implantation; (B,D) undecalcified low power view of the newly formed ossicles with mineralized bone (in blue) with peripheral corticalization (light blue arrows) enveloping mineralized bone covered by osteoid seams and scattered remnants of collagenous matrix as carrier.