M.D. Ramírez-Alba et al. Thiol-yne crosslinked alginate click-hydrogel for the electrical stimulation of skin wound healing. International Journal of Biological Macromolecules

M.D. Ramírez-Alba, L. Resina, J. García-Torres, R. Macovez, C. Alemán, M.M. Pérez-Madrigal. Thiol-yne crosslinked alginate click-hydrogel for the electrical stimulation of skin wound healing. International Journal of Biological Macromolecules 322 (2025) 146880. OPEN ACCESS

doi: doi.org/10.1016/j.ijbiomac.2025.146880

Abstract

Thanks to their biocompatibility and ability to support cell growth, alginate hydrogels are promising scaffolds for skin tissue regeneration. If conductive, they can further improve the wound healing process by electrical stimulation (ES). Herein, we explore the preparation and application of robust hydrogels synthesized via the thiol-yne click reaction, a highly efficient and rapid process. Hydrogels were obtained by functionalizing alginate with thiol groups and crosslinking them with a modified 3-arm polyethylene glycol (PEG) precursor (click-Alg). As a final step, the in situ chemical oxidative polymerization of poly(hydroxymethyl-3,4-ethylenedioxythiophene) (semi-interpenetrated PHMeEDOT) rendered them electro-responsive (click-Alg/PHMeEDOT). The gelation of the click-Alg hydrogels proceeded quickly (within 3 min), enabling rapid network formation for injectable application and resulting in high gel fraction, which ensured structural stability. After incorporating PHMeEDOT, a decrease in the pore size happened, while porosity remained predominantly open, with PHMeEDOT completely covering the pores surface. This coating enhanced the electrochemical response of click-Alg/PHMeEDOT hydrogels, whereas their mechanical similarity (with values of Young's modulus = 116 ± 10.7 kPa) to skin tissue is expected to reduce mismatch risks, improve integration, and minimize stress-related healing issues. Optimized in vitro assays with Vero and HFF-1 cells subjected to 0.6 V for 20 min showed significant wound closure after 2 h, implying that increased electrochemical activity played a key role in promoting wound closure under ES. Overall, we highlight the synergy between both matrices and the effectiveness and potential of click-Alg/PHMeEDOT hydrogels as electrode-like wound dressings for electrically-driven skin tissue repair.