Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin 2228-5881 16 2 2026 06 15 Fish Skin-Derived Acellular Matrix with pH-Modulating Nanogels for Wound Healing 387 402 10.34172/apb.46166 EN Hanieh Mahdiani https://orcid.org/0009-0001-9053-430X Faegheh Yazdani Haleh Bakhshandeh Hossein Aminianfar Nazanin Samiei Sholeh Maslehat Amir Amanzadeh Mahsa Khoramipour Shahram Azari Mohammad Ali Shokrgozar https://orcid.org/0000-0002-9198-4070 Rassoul Dinarvand https://orcid.org/0000-0003-0694-7556 Journal Article 10.34172/apb.46166 2025 08 09 2026 03 23 Introduction: Fish skin–derived acellular dermal matrices (FS-ADMs) are promising wound dressings due to their low zoonotic risk and minimal chemical processing. This study investigated the combined effects of pH modulation as a chemical intervention and FS-ADM as a physical scaffold on wound healing. Carp skin was selected for its favorable lipid composition and high exudate absorption capacity. Methods: Hyaluronic acid (HA)–based nanogels composed of HA and L-lysine, with or without tannic acid (TA), were synthesized and characterized using FTIR spectroscopy and light scattering. Full-thickness excisional wounds were created in 30 Wistar rats and evaluated over 21 days for re-epithelialization, collagen organization, neovascularization, inflammation, and appendage regeneration. Animals were divided into five groups: negative control, FS-ADM alone (SC), FS-ADM with HA nanogel (SC+NC), and FS-ADM with two TA-loaded HA nanogel formulations (SC+NP1 and SC+NP2). Data were analyzed using GraphPad Prism 9.0. Results: The nanogels exhibited sustained acidifying behavior, reducing pH by approximately 1.5 units over seven days in vitro. Degradation studies showed scaffold breakdown of 37% within three days and 60% by day 21, indicating suitable biodegradation kinetics. Medicated FS-ADMs demonstrated excellent biocompatibility, maintaining 96% L929 fibroblast viability. The SC+NC group exhibited the most effective healing (9.67±0.58), achieving complete epithelialization, organized collagen deposition, and sebaceous gland regeneration by day 21. The SC+NP2 group also showed substantial healing, including hair follicle regeneration. HA nanogel without TA outperformed TA-loaded systems, suggesting a dominant role of HA in enhancing tissue repair. Conclusion: Combining FS-ADM with pH-modulating nanogels significantly accelerates wound healing through sustained acidification and represents a promising strategy for chronic wounds such as diabetic ulcers.