Chermahini, Zahra DelshadAbbasabadarabi, SoroushHeydari, ParisaMokhtari, NeginKhosravi, ArezooZarrabi, AliDelshad Chermahini, Zahra2025-11-152025-11-1520261773-22472588-894310.1016/j.jddst.2025.1076432-s2.0-105018878901https://doi.org/10.1016/j.jddst.2025.107643https://hdl.handle.net/20.500.14517/8507pH-responsive hydrogels that synchronize drug delivery with the inflammatory microenvironment can accelerate wound repair. We report a UV-crosslinked poly(beta-amino ester)/hyaluronic acid (P beta AE/HA) hydrogel that loads the proteolytic enzyme bromelain (Br) and couples its release to acidic conditions typical of injured tissue. The bio-hybrid network showed tunable mechanics (Young's modulus reduced from similar to 52 MPa in neat P beta AE to similar to 23-16 MPa after HA and Br incorporation), enhanced swelling at acidic pH (up to similar to 222 % at pH 5.6), and pH-dependent degradation (approximate to 70-80 % mass loss at pH 5.6 vs. approximate to 40-56 % at pH 7.4 over the test period). Br release was faster and diffusion-controlled in acid (Higuchi; approximate to 70 % by 48 h) but more regulated at neutral pH (zero-order-like; approximate to 50 % by 48 h), indicating microenvironment-sensitive delivery. L929 fibroblasts cultured on P beta AE/HA-Br exhibited high viability, improved adhesion, and elevated collagen-I expression, consistent with matrix remodeling support. In LPS-challenged RAW 264.7 macrophages, the hydrogels significantly reduced pro-inflammatory cytokines (TNF-alpha, IL-6) and enhanced reparative mediators (IL-10, TGF-beta), while immunofluorescence imaging confirmed a phenotypic switch from M1 to M2 macrophages, collectively demonstrating robust immunomodulatory activity. Human umbilical vein endothelial cells formed substantially longer and more branched tubes on P beta AE/HA-Br (approximate to 140 % of control), confirming pro-angiogenic activity. Together, these results demonstrate that P beta AE/HA-Br hydrogels integrate environmental sensing with enzyme delivery to dampen inflammation, promote vascularization, and support matrix regeneration highlighting their promise as smart wound-healing dressings and adaptable platforms for regenerative medicine.eninfo:eu-repo/semantics/closedAccessPoly(Beta-Amino Ester)Hyaluronic AcidBromelainpH-Responsive HydrogelWound HealingImmunomodulationAngiogenesisPoly(β-Amino Ester)Article