A sequential physical and chemical dual crosslinked multifunctional hydrogel with enhanced mechanical and osteogenic effects for vascularized bone tissue regeneration

Hydrogels have been recognized for their versatile in regenerative medicine; however, their inadequate mechanical and osteogenic properties have limited their applicability in bone tissue engineering (BTE). Hence, we present a novel approach to address this issue by developing sulfated methacrylate hyaluronic acid hydrogels (SMeHA@CM) doped with alendronate (ALN), calcium ions (Ca2+), and magnesium ions (Mg2+). This hydrogel system incorporates sequential physical and chemical crosslinking to facilitate the treatment of bone defects. Physical crosslinks form between the SO32−, ALN, and Ca2+/Mg2+ ions, resulting in nanocluster crosslinking and complete filling of irregular bone defects. Subsequently, the methacrylate groups within the polymer chain undergo polymerization under ultraviolet light irradiation, forming the second stage of chemical crosslinking in the SMeHA@CM hydrogel. These chemical crosslinks contribute strong chemical bonds, enhancing biomechanical strength, and stable support for bone regeneration. The SMeHA@CM hydrogel exhibits remarkable osteogenic capacity, primarily attributed to the cooperative action of SO32− and Mg2+ ions, which promote the recruitment of bone marrow stem cells and angiogenesis. Furthermore, the sustained release of SO32−-ALN-Ca2+/Mg2+ nanoclusters from the hydrogel system offers additional benefits for bone regeneration. Moreover, both in-vitro and in-vivo assessments confirm the significant potential of the newly developed SMeHA@CM hydrogel for applications in BTE.