Engineered Dermis Loaded with Confining Forces Promotes Full-thickness Wound Healing by Enhancing Vascularisation and Epithelialisation

Tissue-engineered skin is ideal for clinical wound repair. Restoration of skin tissue defects using tissue-engineered skin remains a challenge owing to insufficient vascularisation. In our previous study, we developed a 3D bioprinted model with confined force loading and demonstrated that the confined force can affect vascular branching, which is regulated by the YAP signalling pathway. The mechanical properties of the model must be optimised to suture the wound edges. In this study, we explored the ability of a GelMA-HAMA-fibrin scaffold to support the confined forces created by 3D bioprinting and promote vascularisation and wound healing. The shape of the GelMA-HAMA-fibrin scaffold containing 3% GelMA was affected by the confined forces produced by the embedded cells. The GelMA-HAMA-fibrin scaffold was easy to print, had optimal mechanical properties, and was biocompatible. The constructs were successfully sutured together after 14 d of culture. Scaffolds seeded with cells were transplanted into skin tissue defects in nude mice, demonstrating that the cell-seeded GelMA-HAMA-fibrin scaffold, under confined force loading, promoted neovascularisation and wound restoration by enhancing blood vessel connections, creating a patterned surface, growth factors, and collagen deposition. These results provide further insights into the production of hydrogel composite materials as tissue-engineered scaffolds under an internal mechanical load that can enhance vascularisation and offer new treatment methods for wound healing. STATEMENT OF SIGNIFICANCE: Tissue-engineered skin is ideal for use in clinical wound repair. However, treatment of tissue defects using synthetic scaffolds remains challenging, mainly due to slow and insufficient vascularization. Our previous study developed a 3D bioprinted model with confined force loading, and demonstrated that confined force can affect vascular branching regulated by the YAP signal pathway. The mechanical properties of the construct need to be optimized for suturing to the edges of wounds. Here, we investigated the ability of a GelMA-HAMA-fibrin scaffold to support the confined forces created by 3D bioprinting and promote vascularization in vitro and wound healing in vivo. Our findings provide new insight into the development of degradable macroporous composite materials with mechanical stimulation as tissue-engineered scaffolds with enhanced vascularization, and also provide new treatment options for wound healing.