Enhanced Osteoinductivity of Demineralized Bone Matrix with Noggin Suppression in Polymer Matrix

Demineralized bone matrix (DBM), a potential alternative to autologous bone grafts, has been increasingly used for clinical bone repair; however, its application in larger defects has not been successful partly due to the rapid dispersion of DBM particles and relatively lower osteoinductivity. Here, a novel strategy is created to complement the osteoinductivity of DBM by incorporating DBM in a biopolymer hydrogel combined with the abrogation of BMP antagonism. Combined treatment of DBM+noggin-suppression displays increased osteogenic potency of human bone marrow mesenchymal stem cells (hBMSCs) in vitro. An injectable chitosan (MeGC)-based hydrogel with heparinization (Hep-MeGC) is further developed to localize and stabilize DBM. Noggin-suppression reveals a significant increase in osteogenesis of hBMSCs in the photopolymerizable Hep-MeGC hydrogels with the encapsulation of DBM. Moreover, the combination of DBM+noggin-suppression in the injectable Hep-MeGC hydrogel displays robust bone healing in mouse critical-sized calvarial defects in vivo. The mechanistic analysis demonstrates that noggin-suppression increases DBM osteoinductivity by stimulating endogenous BMP/Smad signals. These results have shown promise in DBM's ability as a prominent bone grafting material while being coupled with gene editing mechanism and a localizing 3D scaffold. Together, this approach poses a significant increase in the efficiency of DBM-mediated craniofacial bone repair and dental osteointegration.