Bone graft substitutes to repair critical-sized bone fractures have experienced significant development over the last few decades. Among them, whitlockite (WH)-based bone grafts have proven to be effective in mediating bone healing. In the current study, a next generation, nature-inspired scaffold was developed with strontium-functionalized whitlockite nanoparticles (nSrWH) to enhance the intrinsic properties of WH. A series of nSrWH (with 2.5, 5, 7.5% Sr atomic substitution) were fabricated using a rapid-mixing wet precipitation route. Subsequently, the functionalized whitlockite was integrated into a gelatin-chondroitin sulfate scaffold and subjected to both in vitro and in vivo studies to investigate its osteogenic potential. Results indicated that nSrWH-containing scaffolds promoted osteogenic differentiation while inhibiting osteoclast activity. The positive impact of nSrWH was found to be dose-dependent, with the 7.5% Sr atomic substitution exhibiting the most significant results. Furthermore, the scaffold induced superior de novo bone regeneration compared to its undoped counterpart in the mouse calvarial critical-sized defect model. Collectively, these findings suggest that nSrWH nanoparticles inherit the beneficial properties of whitlockite, coupled by the therapeutic effects of Sr2+, operating in concert for an overall enhanced bone regeneration. As such, they constitute promising candidates to meet the biomedical requirements for bioactive bone graft substitutes.
Keywords: bone regeneration; calcium phosphate bioceramics; cationic substitution; cryogel; strontium; whitlockite.