Graft-mediated bone regeneration is the most frequently used approach for skeletal reconstruction. [2] Although autologous bone grafts have been considered as the "gold standard" for bone graft materials, they are usually limited by their availability and donorsite morbidity. [3] Demineralized bone matrix (DBM) graft, with low immunogenicity, represents a promising allogeneic alternative to autologous graft and has been increasingly used for bone reconstruction in orthopedics and oral maxillofacial surgery. DBM is a form of allograft through mineral acid extraction to remove major mineral components, which poses better exposure of osteoinductive factors especially like bone morphogenetic proteins (BMPs), key growth factors for induction of bone formation. [4] Unlike synthetic materials, DBM possesses the complex native extracellular matrix (ECM) composition and structure, allowing better cellular proliferation and differentiation within the tissue. In addition, DBM offers an optimal nature collagen matrix that gives bone its toughness and resilience and contributes to a preferable environment for cell attachment. [5] Given its good biocompatibility, mechanical property, and osteoconductivity, DBM has become more acceptable in bone tissue engineering. [6] However, the application of DBM 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+nogginsuppression 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 photopoly merizable 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 nogginsuppression 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.
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