Bone Morphogenetic Proteins and the Induction of Bone Formation: From Laboratory to Patients Ugo Ripamonti, MD, PhD a,b, * , Manolis Heliotis, MBChB, BDS, MSc, FDSRCS, FRCS c , Carlo Ferretti, DDS, MDent, FCD(SA)MFOS d a Bone Research Unit, Medical Research Council/University of the Witwatersrand, Medical School, 2193 Parktown, Johannesburg, South Africa b School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Medical School, 2193 Parktown, Johannesburg, South Africa c North West London Regional Maxillofacial Unit, Northwick Park Hospital, London, UK d Division of Maxillofacial and Oral Surgery, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa The osteogenic soluble molecular signals of the transforming growth factor-b (TGF-b) superfam- ilydthe bone morphogenetic/osteogenic proteins (BMPs/OPs)dinduce endochondral bone forma- tion as a recapitulation of embryonic development and uniquely in primates the TGF-b isoforms per se [1–3]. Together with the soluble molecular signals, regenerative medicine in craniomandibu- lofacial surgery starts by erecting scaffolds of biomimetic biomaterial matrices that mimic the supramolecular assembly of the extracellular matrix of bone [3,4]. Naturally derived BMPs/ OPs and gamma-irradiated human recombinant osteogenic protein-1 (hOP-1) delivered by alloge- neic and xenogeneic insoluble collagenous bone matrices initiate the induction of bone formation in heterotopic extraskeletal and orthotopic skele- tal sites of the nonhuman primate Papio ursinus. This process culminates in complete calvarial regeneration by day 90 and maintains the regener- ated constructs by day 365 [3–6]. The induction of bone by hOP-1 in Papio ursinus develops as a mosaic structure with distinct spatial and tempo- ral patterns of gene expression of members of the TGF-b superfamily that singly, synergistically, and synchronously initiate and maintain tissue induction and morphogenesis [3,7]. Highly purified, naturally derived BMPs/OPs and hOP-1 delivered by collagenous bone matri- ces and porous hydroxyapatite, respectively, in- duce bone formation in mandibular defects of human patients. Clinical trials have used doses that are many times higher than the doses suggested by the results in animal models, in- cluding nonhuman primates. Supraphysiologic doses of single recombinant gene proteins suggest a flaw in the single morphogen approach to human osteoinduction. The induction of bone by available single recombinant human BMPs/OPs (ie, BMP-2 and OP-1) is too costly because of the high doses required to induce an often compara- tively mediocre regenerated osseous construct in clinical contexts. In humans, the induction of bone is on a different scale compared with animal models, including nonhuman primate species. The induction of bone formation can be en- hanced significantly by the synergistic induction of bone formation, however, in which relatively low doses of TGF-b isoforms synergize with hOP-1 to initiate rapid and substantial bone formation in heterotopic and orthotopic sites of the nonhuman Supported by the South African Medical Research Council, the University of the Witwatersrand, Johannesburg and the National Research Foundation. * Corresponding author. Bone Research Unit, Med- ical Research Council/University of the Witwatersrand, Medical School, 2193 Parktown, Johannesburg, South Africa. E-mail address: ugo.ripamonti@wits.ac.za (U. Ripamonti). 1042-3699/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.coms.2007.07.006 oralmaxsurgery.theclinics.com Oral Maxillofacial Surg Clin N Am 19 (2007) 575–589