Injectable Self-Healing Natural Polymer Hydrogel for Mesenchymal Stem Cell-Mediated Osteogenesis

Abstract

Osteoporosis is characterized by progressive bone loss and structural deterioration caused by an imbalance between bone resorption and formation. Although mesenchymal stem cells (MSCs) possess strong osteogenic potential, their therapeutic use is limited by poor retention, low survival, and insufficient maturation after direct injection. Here, we report an injectable, self-healing polysaccharide hydrogel designed to enhance MSC delivery and osteogenic differentiation for bone regeneration. The hydrogel forms through dynamic Schiff-base crosslinking between succinylated chitosan and aldehyde-modified hyaluronic acid, enabling rapid in situ gelation, uniform cell encapsulation, and structural recovery after mechanical disruption. The system exhibits tunable mechanical properties compatible with osteogenic mechanotransduction. Encapsulated MSCs maintained high viability, formed spheroid-like structures, and showed accelerated osteogenic maturation, evidenced by increased alkaline phosphatase activity, enhanced mineral deposition, and upregulation of osteoblast and osteocyte markers. Notably, the hydrogel microenvironment promoted osteogenic commitment even without differentiation supplements. These findings demonstrate that the hydrogel provides a mechanically instructive and biologically supportive environment for MSC-mediated bone regeneration and represents a promising minimally invasive strategy for osteoporotic bone repair.