Skin grafting and regeneration: Bridging biological barriers towards functional regeneration

Despite being the clinical gold standard of care for severe skin defects, autologous grafting is constrained by limited donor resources, associated morbidity, and incomplete functional recovery. These challenges have catalyzed a transition toward regenerative approaches that seek holistic restoration of cutaneous structure, physiological function, and psychosocial well-being. Significant hurdles persist, notably an imbalanced regenerative microenvironment leading to scarring, immune rejection limiting graft survival, and inadequate vascularization and innervation hampering functional integration. Translational challenges further include limited model validity, complex scalable manufacturing, difficulties in long-term efficacy verification, and cost-related accessibility issues. To overcome these obstacles, next-generation strategies are converging on three key approaches. The first is seed cell reprogramming, such as the use of induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs). The second involves smart biomaterials combined with advanced fabrication techniques like 3D bioprinting to generate pre-vascularized grafts. The third is the spatiotemporally controlled delivery of bioactive factors. The future points toward intelligent, personalized systems where electronic skin (E-skin) enables real-time monitoring and artificial intelligence (AI) supports risk prediction and implant design via multi-omics data. Realizing this vision will require deep integration across disciplines, alongside adaptive regulatory and reimbursement frameworks. This narrative review aims to summarize current advances in skin grafting and regenerative strategies, with a particular focus on the biological barriers that limit functional skin regeneration and the emerging approaches developed to overcome them.