Therapeutic Effect of a Composite Acellular Matrix/Hyaluronic Acid Thermosensitive Hydrogel for the Interstitial Cystitis/Bladder Pain Syndrome in a Rat Model

ABSTRACT This study investigated the therapeutic effects of a composite small intestinal submucosa decellularized extracellular matrix/hyaluronic acid (HA)‐incorporated thermosensitive hydrogel (HA‐Gel) on interstitial cystitis (IC) in rats. The HA‐Gel was fabricated using rabbit small intestinal submucosa‐derived extracellular matrix as a thermosensitive scaffold combined with HA, and an IC rat model was established using the UPK3A65–84 peptide. Rats were divided into five groups: IC group, IC + HA group, IC + Gel group, IC + HA‐Gel group, and a non‐modeled control group. After 14 days of treatment, urodynamic analysis revealed that the HA, IC + Gel, and IC + HA‐Gel groups exhibited significantly increased interval voiding times and maximum bladder capacities compared to the IC group, with the most pronounced improvement observed in the IC + HA‐Gel group ( p < 0.01). Histopathological evaluation revealed reduced mucosal edema, inflammatory cell infiltration, and mucosal denudation in all treatment groups, particularly in the IC + HA‐Gel group ( p < 0.01). Mast cell infiltration was also markedly suppressed by HA‐Gel ( p < 0.01). Immunofluorescence and molecular analyses further indicated that HA, Gel, and HA‐Gel effectively downregulated the expression levels of CD3, ICAM‐1, TNF‐α, IFN‐γ, IL‐1β, IL‐6, and TRPM8 in bladder tissues, with the most significant reductions observed in the IC + HA‐Gel group ( p < 0.01). Notably, both Gel and HA‐Gel remained detectable in bladder tissues for over 14 days post‐administration. In conclusion, HA‐Gel not only improves voiding function and bladder capacity in IC rats but also suppresses inflammatory responses, demonstrating promising therapeutic potential and providing new insights for the clinical management of IC/bladder pain syndrome (BPS).