Dynamic GelMA/DNA Dual‐Network Hydrogels Promote Woven Bone Organoid Formation and Enhance Bone Regeneration

Abstract

Bone organoids, in vitro models mimicking native bone structure and function, rely on 3D stem cell culture for self-organization, differentiation, ECM secretion, and biomineralization, ultimately forming mineralized collagen hierarchies. However, their development is often limited by the lack of suitable matrices with optimal mechanical properties for sustained cell growth and differentiation. To address this, a dynamic DNA/Gelatin methacryloyl (GelMA) hydrogel (CGDE) is developed to recapitulate key biochemical and mechanical features of the bone ECM, providing a supportive microenvironment for bone organoid formation. This dual-network hydrogel is engineered through hydrogen bonding between DNA and GelMA, combined with GelMA network crosslinking, resulting in appropriate mechanical strength and enhanced viscoelasticity. During a 21-day 3D culture, the CGDE hydrogel facilitates cellular migration and self-organization, promoting woven bone organoid (WBO) formation via intramembranous ossification. These WBOs exhibit spatiotemporal architectures supporting dynamic mineralization and tissue remodeling. In vivo studies demonstrate that CGDE-derived WBOs exhibit self-adaptive properties, enabling rapid osseointegration within 4 weeks. This work highlights the CGDE hydrogel as a robust and scalable platform for bone organoid development, offering new insights into bone biology and innovative strategies for bone tissue regeneration.