Spatiotemporally Programmed Nanofiber Scaffold for Coordinated Hierarchical Multi‐Tissue Regeneration in Pressure Ulcers

ABSTRACT

Stage IV pressure ulcers (PUs) represent the most severe form of chronic wounds, involving full‐thickness damage to skin, vasculature, nerves, and muscle, and remain difficult to treat due to the need for coordinated multi‐tissue regeneration. Here, we develop a nanofiber scaffold that orchestrates multimodal tissue repair through the integration of biophysical guidance and spatiotemporally controlled biochemical signaling. The scaffold features a sandwich‐structured architecture composed of poly(ε‐caprolactone) (PCL) nanofibrous layers with distinct functions. A radially aligned, wound‐facing layer is functionalized with a center‐increasing gradient of keratinocyte growth factor 2‐loaded collagen nanoparticles, enabling rapid diffusion‐driven delivery to accelerate early re‐epithelialization. The outer layer comprises randomly oriented PCL nanofibers, ensuring mechanical support and structural stability. Between these layers, phase‐change material microparticles co‐encapsulating basic fibroblast growth factor and indocyanine green enable near‐infrared‐triggered, on‐demand release, sustaining local bFGF availability to support vascular reconstruction and subsequent muscle regeneration. This temporally coordinated delivery strategy couples early‐stage epidermal repair with prolonged support for deeper tissue regeneration. In a rat stage IV PU model, the scaffold accelerates wound closure and promotes coordinated regeneration of multiple tissue components, outperforming clinically used wound dressings. Collectively, this work establishes a nanofiber‐based strategy for spatiotemporally orchestrated tissue regeneration in severe wounds.