Heparin‐Conjugated Decellularized Bone Particles Promote Enhanced Osteogenic Signaling of PDGF‐BB to Adipose‐Derived Stem Cells in Tissue Engineered Bone Grafts

Adipose‐derived stem cells (ASCs) are a promising cell source for regenerating critical‐sized craniofacial bone defects, but their clinical use is limited due to the supraphysiological levels of bone morphogenetic protein‐2 required to induce bone formation in large grafts. It has been recently reported that platelet‐derived growth factor‐BB (PDGF) directly enhances the osteogenesis of ASCs when applied at physiological concentrations. In this study, a biomimetic delivery system that tethers PDGF to decellularized bone matrix (DCB) is developed to enhance osteogenic signaling in bone grafts by colocalizing PDGF‐extracellular matrix cues. Heparin is conjugated to DCB particles (HC‐DCB) to promote sustained binding of PDGF via electrostatic interactions. HC‐DCB particles bind to PDGF with >99% efficiency and release significantly less PDGF over 21 days compared to nonconjugated DCB particles (1.1% vs 22.8%). HC‐DCB‐PDGF signaling in polycaprolactone (PCL)‐fibrin grafts promotes >40 µg Ca2+ µg−1 DNA deposition by ASCs during in vitro osteogenic culture compared to grafts without HC‐DCB or PDGF. Furthermore, more bone formation is observed in grafts with HC‐DCB‐PDGF at 12 weeks following implantation of grafts into murine critical‐sized calvarial defects. Collectively, these results demonstrate that HC‐DCB enhances the osteogenic signaling of PDGF to ASCs and may be applied to promote ASC‐mediated bone regeneration in critical‐sized defects. This work develops a biomimetic biomaterials platform to promote adipose‐derived stem cell (ASC)‐mediated bone formation for treatment of large craniofacial defects. Platelet‐derived growth factor‐BB (PDGF) is tethered to heparin‐conjugated, decellularized bone particles (HC‐DCB) to provide augmented osteogenic signaling to ASCs in bone grafts. HC‐DCB‐PDGF signaling enhances in vitro ASC mineral deposition and in vivo bone formation within grafts implanted into critical‐sized defects.