Mechanically Adaptive Hydrogels Reprogram Apoptotic Cell Clearance to Prevent Tissue Fibrosis.

Abstract

Abnormal mechanical stimulation drives fibrotic scar formation in active wounds by sustaining mechanotransduction, promoting apoptotic cell accumulation and pro-fibrotic amplification that constrain functional regeneration. To address this challenge, we developed a mechanically adaptive hydrogel patch (Gel/VP) through the integration of an interpenetrating polymer network and CNC@PDA@ZIF8 dynamic nanofillers, in which the interpenetrating network provides structural load-bearing and adaptive deformation, while the nanofillers form a force-induced, reconfigurable dissipative network via hydrogen bonding and π-π interactions, collectively dissipating tensile energy upon pre-stretched application, establishing a reverse mechanical buffer at the wound interface, suppressing sustained Piezo1-YAP activation, restoring macrophage efferocytosis-mediated apoptotic cell clearance, and ultimately limiting fibrotic scar formation. The interpenetrating architecture endows the patch with a tunable elastic window matched to the mechanical environment of skin (elastic modulus of 7-15 kPa with twofold extensibility). Under reverse mechanical buffering, the macrophage phagocytic rate increases from 22.50% to 64.50%, significantly enhancing apoptotic cell clearance. In vivo, the patch achieves near-complete wound closure (>95%) within two weeks, markedly reduces α-SMA+ myofibroblast accumulation, promotes ordered collagen remodeling, and substantially decreases scar formation. Overall, by leveraging material-mediated reverse stress buffering to restore macrophage efferocytosis, this study targets apoptotic cell clearance at an early stage of fibrosis and provides a robust antifibrotic material strategy for the functional regeneration of active wounds. STATEMENT OF SIGNIFICANCE: Abnormal mechanical stretching during wound healing is a key yet underrecognized driver of fibrotic scar formation, and current therapies rarely address this physical cue. Here, we develop a stress-adapted hydrogel patch that forms a "reverse mechanical buffer" under pre-stretch, actively redistributing tensile forces at the wound interface. This buffering suppresses mechanotransduction (Piezo1-YAP signaling) while restoring macrophage-mediated clearance of apoptotic cells. By integrating an interpenetrating polymer network with dynamic nanofillers, the material achieves adaptive energy dissipation and mechanical compatibility with skin. This work establishes a mechanically guided, immunomodulatory approach to limit fibrosis, offering a promising biomaterials strategy for scarless healing and functional tissue regeneration.