Pre-Vascularized 3-Dimensional Skin Substitutes Promote Angiogenesis and Tissue Repair in a Murine Model of Refractory Skin Ulcers

Restoring blood flow is crucial for treating refractory ulcers. Despite advancements in various biomaterials, none incorporating pre-formed blood vessels have been commercialized. To address this, we developed a pre-vascularized three-dimensional (3D) skin substitute (PV-3D skin) designed to enhance healing when treating refractory ulcers. This study aimed to evaluate the therapeutic role of PV-3D skin transplantation in refractory ulcer models, induced by applying mitomycin C to wounds in severe immunodeficient mice. The wounds were then treated with PV-3D skin, non-vascularized 3D skin, skin grafts, or wound dressings. The PV-3D skin group demonstrated healing dynamics comparable to those of the skin graft group, with similar tissue morphology and wound temperature changes. Furthermore, at day 7 post-transplantation, the PV-3D skin group demonstrated significantly higher hypoxia-inducible factor 1-alpha expression levels compared to the 3D skin group. By day 14, the PV-3D skin group exhibited a significantly larger vascular area compared to the 3D skin group. Notably, PV-3D skin treatment stimulated host-derived angiogenesis, thereby enhancing wound healing and reducing the recurrence of refractory ulcers. These results suggest that PV-3D skin transplantation offers a promising therapeutic approach for refractory ulcers, especially in terms of angiogenesis.