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

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.