The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing

Abstract

Purpose The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW. Methods Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/-mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.Results Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of Mladenka Jurin contributed equally to this paper. S. Vukicevic (*) : J. Curak : J. Brkljacic : M. Pauk : I. Erjavec : I. Dumic-Cule : R. Novak : V. Kufner : T. Bordukalo Niksic :

The rational use of animal models in the evaluation of novel bone regenerative therapies

“…In our opinion, literature based data represent only a small fraction of the total number of animals used. Despite this, after years of use in clinics both BMP devices have been confronted with major side-effects and their clinical use has been recently scrutinized [17,[82][83][84].…”

“…Osteogenic factors primarily belong to the TGF-β superfamily, and the most studied factors are bone morphogenetic protein BMP2, BMP4, BMP6 and BMP7 [16,17]. Because vascularization is essential for bone regeneration, angiogenic factors VEGF, PDGF, FGF and IGF are also being extensively tested for their usefulness in bone repair [18][19][20][21][22][23][24].…”

“…Ectopic models are relatively simple, less costly and less invasive. For example, ectopic bone formation models were recently used to elucidate whether the maturation status of implanted cells determines the origin of tissue-engineered bone [105] and to demonstrate new bone formation after the implantation of the OSTEOGROW device (rhBMP6 in autologous blood coagulum) without any signs of inflammation or fibrosis [17]. Although successfully used as a preliminary model for screening various formulations of osteogenic cells, scaffolds and growth factors, the ectopic model displays serious limitations including the eventual reabsorption of newly formed bone and the lack of effective mechanical stimulus required for bone remodelling [106].…”

Fetal vs adult mesenchymal stem cells achieve greater gene expression, but less osteoinduction

“…These findings may be related to the shorter expression of the transgene in fMSCs. Alternatively, initial high BMP2 expression and release from fMSCs could have caused a transient increase in number of osteoclasts derived from hematopoietic stem cells [24] but there was no evidence of bone remodeling in our histology to suggest this mechanism was at work. Based on our in vitro findings with fMSC, and recent work from our laboratory demonstrating superior outcomes of neocartilage growth with a mosaic of 90% naïve and 10% Ad-BMP2-transduced juvenile chondrocytes [25] , it was anticipated that the dilution of BMP2 expressing cells in the rapidly proliferating fMSC population may be an advantage in vivo.…”

Marshall R. Urist and the discovery of bone morphogenetic proteins

“…Vukicevic and Dr. Pecina explored the mechanisms and function of BMPs in patients with non-unions [3,7,20,21,26,[31][32][33]37], and Dr. Grgurevic made important contributions to understanding the role of circulating BMPs that led to the use of BMP6 locally in patients with bone defects [1,26,[32][33][34]. With numerous collaborators they published important discoveries and organized international BMP conferences (Figs.…”