Injectable hybrid hydrogel-mediated calcium-sensing receptor (CaSR) activation for enhanced osteogenesis and bone remodeling†

Injectable hydrogels have transfigured bone tissue engineering by offering minimally invasive solutions for treating irregularly shaped critical-size bone defects. Unlike traditional fixed-shaped bone grafts that require invasive surgeries and precise defect matching, injectable hydrogels adapt to defect geometries and accelerate healing. The hydrogels mimic the extracellular matrix with their porous, interconnected 3D architecture, promoting cell adhesion, proliferation, differentiation, vascularization, and nutrient flow, which are essential for effective bone regeneration and affirm the osteoconductivity. Chitosan–alginate hydrogels are particularly promising due to their mechanical stability, biodegradability, and ability to deliver bioactive compounds sustainably. To enhance its osteoinductive properties, bioinorganic ions such as strontium (Sr²⁺)-based hybrid nanocomposites have been explored. Strontium has garnered attention for its ability to activate the calcium-sensing receptor (CaSR)-mediated signaling pathways by regulating bone resorption and bone formation by various bone matrix proteins, thereby promoting bone homeostasis and regeneration. Strontium's ionic similarity to calcium enables it to act as a robust activator of CaSR, triggering pathways that enhance bone regeneration. Building on this, we developed an innovative hybrid material hydrogel by reinforcing the chitosan–alginate hydrogels with a Sr–Fe–TQ (strontium–iron–thymoquinone) nanocomposite. This bioengineered hydrogel system demonstrated excellent hemocompatibility (in human RBCs), cytocompatibility, biocompatibility, and enhanced efficiency in vitro in MG-63 osteoblast-like cells. In vivo studies using a rabbit critical-size defect model showed accelerated bone remodeling, achieving better defect closure and superior bone volume restoration (∼99%) compared to the controls. This study underscores the transformative potential of the Sr–Fe–TQ hydrogel as an injectable, osteoconductive, and osteoinductive scaffolds for critical-size defect repair. By combining minimally invasive delivery, sustained bioactive release, and superior regenerative outcomes, this hydrogel system addresses key challenges in bone tissue engineering, paving the way for next-generation biomaterials in regenerative medicine.