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Impaired skin regeneration in chronic wounds like diabetes corresponds to high oxidative stress, poor angiogenesis and insufficient collagen hyperplasia. Therefore, a multifaceted strategy for treatment is required to address critical...

Low strength and rapid biodegradability of Acellular Dermal Matrix (ADM) restrict 37 wider clinical application as rapid cell delivery platform in situ, for management of burn 38 wounds. Herein, extracted ADM was modified by dual cross-linking approach with ionic 39 crosslinking using chitosan (CTS) and covalent cross-linking using an iodine modified 2, 5-40 dihydro-2,5-dimethoxy-furan (DHF-I) cross-linker; termed as CsADM-Cl. In addition, 41 inherent growth factors and cytokines were found to be preserved in the CsADM-Cl, 42 irrespective of ionic/covalent crosslinking. CsADM-Cl demonstrated improvement in post 43 crosslinking stiffness with decreased biodegradation rate. This hybrid crosslinked hydrogel 44 supported adhesion, proliferation, and migration of human foreskin derived fibroblasts (HFCs) 45 and keratinocytes (HKC). Also, the angiogenic potential of CsADM-Cl was manifested by 46 chick chorioallantoic membrane (CAM) assay. CsADM-Cl showed excellent antibacterial 47 activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. 48 aureus). Moreover, CsADM-Cl treated full thickness (FT) burn wounds demonstrated rapid 49 healing marked with superior angiogenesis, well-defined dermal-epidermal junctions (DEJ), 50 mature basket weave collagen deposition, and development of more pronounced secondary 51 appendages. Altogether, the bioactive CsADM-Cl hydrogel established significant clinical 52 potential to support wound healing as an apt injectable antibacterial matrix to encounter unmet 53 challenges concerning critical burn wounds.

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