Injectable Hybrid-Hydrogel Mediated Calcium-Sensing Receptor (CaSR) Activation for Enhanced Osteogenesis and Bone Remodeling

Abstract

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—essential for effective bone regeneration to affirm the osteoconductivity. Chitosan-alginate hydrogels are particularly promising due to their mechanical stability, biodegradability, and ability to deliver bioactive compounds sustainably. To enhance their osteoinductive properties, bioinorganic ions like strontium (Sr²⁺) based hybrid nanocomposites were explored. Strontium garnered attention for its ability to activate calcium-sensing receptor (CaSR)-mediated signaling pathways by regulating bone resorption and bone formation by various bone matrix proteins, promoting bone homeostasis and regeneration. Strontium's ionic similarity to calcium enables it to act as a robust activator of CaSR, triggering pathways for enhanced bone regeneration. Building on this, we developed an innovative hybrid material hydrogel by reinforcing 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 controls. This study underscores the transformative potential of Sr-Fe-TQ hydrogels as 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.