Bone regeneration using cell-mediated responsive degradable PEG-based scaffolds incorporating with rhBMP-2

Abstract

The treatment of large osseous defects remains a challenging clinical problem in orthopedic surgery. Particularly, strategies to control the appropriate degradation rate adapting to the tissue reconstruction are of essential for tissue regeneration. Here we report on a strategy to achieve adaptive degradation rate using cell-secreted protease as a switch. Disulfide-containing PEG-based scaffolds have been synthesized, and demonstrated to be responsive to the cell-secreted redox microenvironment. Thus, the cell-triggered degradation and liberation of growth factor are achieved. The osteoinductive growth factor, recombinant human bone morphogenetic protein-2 (rhBMP-2), is incorporated into the scaffold for bioactivity promotion. Degradations under the stimuli of reduced glutathione (GSH) at intracellular and extracellular concentrations was studied with the results of duration time ranging from 0.5 h to 22 days regulated by both concentrations of redox medium and polymer precursors. The rhBMP-2 loaded scaffolds evidently induced the ectopic bone formation in the mouse thigh muscles. In addition, we further investigated the in vivo effects of rhBMP-2-loaded scaffolds in a rabbit radius critical defect by radiography, three dimensional micro-computed tomographic (μCT) and synchrotron radiation-based micro-computed tomography (SRμCT) imaging, histological analysis, and biomechanical measurement. Scaffolds underwent gradual resorption and replacement by new bone and induced reunion of bone marrow cavity at 12 weeks, much better than the effect of self-repairing group. The results indicated that both osteoinduction and appropriate degradation played a crucial role in accelerating and promoting bone augmentation, as well as effective proangiogenesis. Such a strategy appears promising as 3D temporal scaffolds for potential orthopedic applications.