Doping bioactive elements into a collagen scaffold based on synchronous self-assembly/mineralization for bone tissue engineering

Pure collagen is biocompatible but lacks inherent osteoinductive, osteoimmunomodulatory and antibacterial activities. To obtain collagen with these characteristics, we developed a novel methodology of doping bioactive elements into collagen through the synchronous self-assembly/mineralization (SSM) of collagen. In the SSM model, amorphous mineral nanoparticles (AMN) (amorphous SrCO(3), amorphous Ag(3)PO(4), etc.) stabilized by the polyampholyte, carboxymethyl chitosan (CMC), and collagen molecules were the primary components under acidic conditions. As the pH gradually increased, intrafibrillar mineralization occurred via the self-adaptive interaction between the AMNs and the collagen microfibrils, which were self-assembling; the AMNs wrapped around the microfibrils became situated in the gap zones of collagen and finally transformed into crystals. Sr-doped collagen scaffolds (Sr-CS) promoted in vitro cell proliferation and osteogenic differentiation of rat bone marrow mesenchymal stromal cells (rBMSCs) and synergistically improved osteogenesis of rBMSCs by altering the macrophage response. Ag-doped collagen scaffolds (Ag-CS) exhibited in vitro antibacterial effects on S. aureus, as well as cell/tissue compatibility. Moreover, Sr-CS implanted into the calvarial defect of a rat resulted in improved bone regeneration. Therefore, the SSM model is a de novo synthetic strategy for doping bioactive elements into collagen, and can be used to fabricate multifunctional collagen scaffolds to meet the clinical challenges of encouraging osteogenesis, boosting the immune response and fighting severe infection in bone defects.