Delivery Systems for the BMPs   |    
Bone Induction by BMPs/OPs and Related Family Members in Primates The Critical Role of Delivery Systems
Ugo Ripamonti, MD, PhD; Lentsha Nathaniel Ramoshebi, PhD; Thato Matsaba, MSc; Jacqueline Tasker, MSc; Jean Crooks, MSc; June Teare, DMT
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Investigation performed at Bone Research Unit, South African Medical Research Council/University of the Witwatersrand, Medical School, Johannesburg, South Africa
Ugo Ripamonti, MD, PhD
Lentsha Nathaniel Ramoshebi, PhD
Thato Matsaba, MSc
Jacqueline Tasker, MSc
Jean Crooks, MSc
June Teare, DMT
Bone Research Unit, MRC/University of the Witwatersrand, 7 York Road, Parktown 2193, Johannesburg, South Africa. E-mail address for U. Ripamonti: 177ripa@chiron.wits.ac.za

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the South African Medical Research Council and University of the Witwatersrand. The authors choose not to provide The Journal and its readers with information concerning any commercial party and any material in this Work, which relationship may represent a conflict of interest.

J Bone Joint Surg Am, 2001 Apr 01;83(1 suppl 2):S116-S127
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Background: In a series of studies in the primate Papio ursinus, we have examined the capacity of bone morphogenetic proteins (BMPs/OPs) delivered in a variety of biomaterial carrier systems to elicit bone formation in heterotopic and orthotopic sites. In this review, we compare the osteoinductive effects of different biomaterial delivery systems that have or have not been pretreated with BMPs/OPs. In particular, we focus on the geometric induction of bone formation by sintered porous hydroxyapatite (SPHA) discs with concavities on their planar surfaces, which elicit bone formation without exogenously applied BMPs/OPs.

Methods: Heterotopic bone formation was examined by bilaterally implanting 100-mg pellets of a collagenous carrier containing BMPs/OPs in the rectus abdominis muscle of the adult baboon. Orthotopic bone formation was examined by implanting 1 g of a collagenous carrier containing BMPs/OPs into two full-thickness critical-sized 25-mm-diameter defects on each side of the calvaria of adult baboons. The BMPs/OPs whose effects were examined included recombinant human osteogenic protein-1 (rhOP-1), recombinant human transforming growth factor-ß1 (rhTGF-ß1), rhTGF-ß2, and porcine platelet derived transforming growth factor-ß1 (pTGF-ß1). Tissue from the rectus abdominis muscle was harvested 30 or 90 days after implantation. Tissue from the orthotopic calvarial model was examined at 1, 3, 6, 9, and 12 months after implantation. To demonstrate the effect of surface geometry on bone induction, hydroxyapatite powders were sintered to form solid discs with a series of concavities on the planar surfaces of the SPHA discs. The discs were either pretreated with exogenous rhOP-1 or not treated with exogenous OP-1. They were then implanted heterotopically or orthotopically into calvarial defects. Bone formation was evaluated histologically in undecalcified sections stained with Goldner’s trichrome stain or 0.1% toluidine blue.

Results: Naturally derived BMPs/OPs or rhOP-1 in a collagenous carrier elicit heterotopic bone formation and the complete healing of 25-mm-diameter critical-sized defects by day 90 following implantation. Binary applications of TGF-ß1 together with rhOP-1 in the collagen carrier induced massive endochondral ossicles in heterotopic sites and bone formation in calvarial defects. pTGF-ß1, rhTGF-ß1, and rhTGF-ß2 are powerful inducers of heterotopic endochondral bone formation but elicit limited bone formation in calvarial defects. SPHA discs pretreated with rhOP-1 elicited extensive bone formation in both heterotopic and orthotopic sites. However, SPHA without rhOP-1 also elicited bone formation in heterotopic and orthotopic sites and complete healing of the calvarial defects.

Conclusion: We have prepared SPHA discs with concavities on their planar surfaces that induce bone formation in heterotopic or orthotopic critical-sized calvarial defects without exogenously applied BMPs/OPs. This biomaterial induces bone formation by intrinsic osteoinductivity regulated by the geometry of the substratum. The incorporation of specific biological activities into biomaterials by manipulating the geometry of the substratum, defined as geometric induction of bone formation, may make it possible to engineer morphogenetic responses for therapeutic osteogenesis in clinical contexts.

Clinical Relevance: We have implemented a clinical trial using naturally derived BMPs/OPs extracted and purified from bovine bone matrices and implanted in craniofacial defects in humans. In addition, the discovery that specific geometric and surface characteristics of sintered hydroxyapatites can induce intrinsic osteoinductivity in primates paves the way for formulation and therapeutic application of porous substrata designed to obtain predictable intrinsic osteoinductivity in clinical contexts.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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