Controlled release of BMP-2 using a heparin-conjugated carrier system reduces in vivo adipose tissue formation

There is growing concern about unwanted effects associated with the clinical use of recombinant human bone morphogenetic protein-2 (rhBMP-2) at high concentrations, including cyst-like bone formation and excessive fatty marrow formation. We, therefore, evaluated the induction of mineralized/adipose tissue formation and the bone-healing pattern associated with the controlled release of E. coli-derived rhBMP-2 (ErhBMP-2) by a heparin-conjugated fibrin (HCF) system using ectopic and orthotopic in vivo models, respectively. In the ectopic transplantation model, mineralized tissue formed at the most superficial layer of the transplanted area and on the surfaces of grafted materials, and most of the interstitial space within the transplanted area was filled with excessive adipose tissue specifically at sites that received ErhBMP-2. However, sites that received ErhBMP-2 and HCF showed significantly increased mineralized tissue formation and decreased adipose tissue formation compared to the normal fibrin system with ErhBMP-2. In the orthotopic (calvarial defect) model, controlled release of ErhBMP-2 induced by HCF significantly reduced adipose tissue formation within the defect area compared to the clinically approved absorbable collagen sponge. From these results, it can be concluded that the use of a HCF system loaded with ErhBMP-2 may reduce adipose tissue formation and enhance mineralized tissue formation.