Antifibrotic hydrogel strategies for scarless tissue regeneration: mechanisms, design, and application

Abstract

Tissue repair is a highly coordinated process, yet dysregulated fibrosis often diverts healing toward scar formation, resulting in permanent structural and functional impairment. Achieving scarless regeneration requires precise modulation of the wound microenvironment to support functional tissue reconstruction. Hydrogels, owing to their biocompatibility, tunable mechanics, and controllable delivery capabilities, have emerged as promising platforms for regenerative therapy. Recent multifunctional hydrogels can regulate tissue repair through microstructural engineering, mechanical modulation, immune regulation, pro-angiogenic stimulation, and dynamic extracellular matrix remodeling, thereby suppressing fibrotic progression. However, current reviews mainly focus on accelerating wound closure and lack systematic discussion of antifibrotic hydrogel design across different tissues. In this review, we summarize the key mechanisms underlying scar formation and propose design principles for hydrogel-mediated scarless regeneration. We further highlight recent advances in multiple tissues, including skin, tendon, cornea, urethra, nerve, endometrium, liver, myocardium, emphasizing both shared principles and tissue-specific requirements. Finally, we discuss translational challenges and future opportunities, particularly AI-driven hydrogel design for functional regeneration.