Harnessing 3D Bioprinted Hydrogels With Polydeoxyribonucleotide for Effective Recovery of Volumetric Muscle Loss

Polydeoxyribonucleotide (PDRN) has attached considerable attention in tissue regeneration due to its effects on cell proliferation, angiogenesis, and inflammatory regulation. Its capacity to activate signaling pathways through adenosine receptors renders PDRN a promising therapeutic candidate for muscle regeneration. However, the influence of PDRN strand configuration—single‐stranded (ssPDRN) versus double‐stranded (dsPDRN)—within biomaterial environments and its subsequent effects on muscle cells has not been investigated. In this study, ssPDRN and dsPDRN are integrated into gelatin methacrylate (GelMA)‐based bioinks to develop myogenesis‐promoting bioinks. The prepared bioinks exhibited structural integrity, suitable printability, and cytocompatibility with C2C12 myoblasts. RT‐PCR analysis revealed the differential effects between ssPDRN and dsPDRN groups on gene expression related to the Wnt/β‐catenin and JAK/STAT signaling pathways, showing that the structural configuration of PDRN influences its biological activity. Especially, ssPDRN promoted earlier regulation of inflammation‐related genes, suggesting a faster initiation of the regenerative process in the volumetric muscle loss (VML) model. Furthermore, in vivo experiments proved faster muscle remodeling and recovery in mice treated with GelMA/ssPDRN matrices following VML injury. Therefore, our results demonstrate that the structural form of PDRN is a decisive factor for the biological response in skeletal muscle tissue engineering and can be used to develop effective scaffolds.