Double-Network DNA Macroporous Hydrogel Enables Aptamer-Directed Cell Recruitment to Accelerate Bone Healing

Abstract

Recruiting endogenous bone marrow mesenchymal stem cells (BMSCs) in vivo to bone defect sites shows great promise in cell therapies for bone tissue engineering, which tackles the shortcomings of delivering exogenous stem cells, including limited sources, low retention, stemness loss, and immunogenicity. However, it remains challenging to efficiently recruit stem cells while simultaneously directing cell differentiation in the dynamic microenvironment and promoting neo-regenerated tissue ingrowth to achieve augmented bone regeneration. Herein, a synthetic macroporous double-network hydrogel presenting nucleic acid aptamer and nano-inducer enhances BMSCs recruitment, and osteogenic differentiation is demonstrated. An air-in-water template enables the rapid construction of highly interconnective macroporous structures, and the physical self-assembly of DNA strands and chemical cross-linking of gelatin chains synergistically generate a resilient double network. The aptamer Apt19S and black phosphorus nanosheets-specific macroporous hydrogel demonstrate highly efficient endogenous BMSCs recruitment, cell differentiation, and extracellular matrix mineralization. Notably, the enhanced calvarial bone healing with promising matrix mineralization and new bone formation is accompanied by adapting this engineered hydrogel to the bone defects. The findings suggest an appealing material approach overcoming the traditional limitations of cell-delivery therapy that can inspire the future design of next-generation hydrogel for enhanced bone tissue regeneration.