Ultrasound-activated piezoelectric hydrogel scaffold for synergistic immunomodulation and angiogenesis in accelerated wound healing

Current wound therapies struggle to dynamically regulate immune responses and angiogenesis, often resulting in impaired healing, scarring, and poor tissue regeneration. The development of smart hydrogel scaffolds offers an opportunity to precisely modulate the wound healing process. Here, we present a pioneering wireless immunomodulatory strategy by integrating amino-modified barium titanate (BTN) nanoparticles with a natural collagen matrix, using oxidized gellan gum (OG) as a crosslinker, to fabricate a tilapia collagen (Col)-based biomimetic piezoelectric hydrogel scaffold (Col/OG/BTN). The hydrogel scaffold exhibits skin-like mechanical properties, controlled biodegradability, and ultrasound (US)-activated piezoelectricity, while providing a three-dimensional porous microenvironment for cell migration and signaling. Under US, the hydrogel scaffold reprograms pro-inflammatory M1 macrophages toward pro-healing M2 macrophages by modulating the phosphoinositide 3-kinase (PI3K) /protein kinase B (Akt) and tumor necrosis factor (TNF) signaling pathways, as revealed by transcriptomics. This immunoregulation synergizes with endothelial cell crosstalk to amplify pro-angiogenic factor secretion. Importantly, in vivo application of the Col/OG/BTN hydrogel scaffold significantly reduces inflammation, enhances angiogenesis, promotes collagen deposition, and stimulates hair follicle regeneration, ultimately achieving high-quality wound healing with functional restoration. In conclusion, this study demonstrates a spatiotemporally controllable approach to modulate the immune microenvironment of inflammatory wounds while promoting vascular regeneration, offering a clinically translatable strategy for regenerative medicine. STATEMENT OF SIGNIFICANCE: Current wound therapies face challenges in dynamically regulating immune responses and angiogenesis. We developed a tilapia collagen-based piezoelectric hydrogel scaffold integrated with oxidized gellan gum and amino-modified barium titanate nanoparticles (Col/OG/BTN hydrogel scaffold). This ultrasound-activated system uniquely reprograms pro-inflammatory macrophages to pro-healing phenotypes via PI3K/Akt and TNF pathways, synergistically enhancing angiogenesis and hair follicle regeneration. The scaffold eliminates implanted electrodes, offering wireless immunomodulation and vascular restoration, enabling high-quality wound healing with functional skin appendage recovery. This work provides a clinically translatable strategy for inflammatory wound repair through bioelectrical signaling.