Work

An ibuprofen-eluting electrospun membrane prevents ureteral fibrosis by dampening macrophage-associated fibroblast activation

Year: 2026

Type: article

Abstract: Background Ureteral stricture is driven by unresolved inflammation and progressive matrix deposition, yet mechanism-guided local therapies remain limited. Methods We integrated spatial transcriptomics of human normal and stricture ureters with an in-house scRNA-seq reference generated from three stricture specimens and independently evaluated annotation using the normal ureter dataset GSE194129. Urothelial injury-conditioned medium (UICM), primary ureteral fibroblasts, and THP-1-derived macrophages were used to model epithelial-immune-stromal signaling. An ibuprofen-functionalized PCL/gelatin electrospun membrane (P/G-PLL-IBU) was characterized and tested in a rabbit ureteral thermal-injury model. Results Spatial analysis identified a fibro-inflammatory niche with co-enrichment of fibroblast and macrophage programs in stenotic regions. Low normal-reference feature spots displayed cytoskeletal remodeling-associated signatures. UICM contained increased IL-6 and HMGB1 and elevated LDH release, induced an inflammatory fibroblast-like state, and produced a macrophage activation state dominated by pro-inflammatory features. Conditioned medium from UICM-activated macrophages enhanced FN1, COL1A1, α-SMA, and Smad2/3 phosphorylation in UICM-primed fibroblasts. Soluble ibuprofen suppressed macrophage NF-κB/COX-2-associated activation, and conditioned medium from treated cultures elicited lower profibrotic responses in fibroblasts. PGE 2 add-back partially restored these responses. P/G-PLL-IBU preserved nanofibrous architecture, released ibuprofen for 56 days, and showed favorable hemocompatibility and cytocompatibility. In rabbits, P/G-PLL-IBU reduced early and long-term collagen deposition and upper urinary tract dilation for up to 90 days. Delayed membrane placement produced no detectable reversal of established fibrosis within the 30-day post-treatment observation window. Conclusion Together, human spatial mapping and stepwise in vitro analyses link macrophage activation to fibroblast Smad2/3-associated remodeling in ureteral stricture, and local ibuprofen delivery via electrospun membrane can blunt this trajectory after ureteral injury.

Source: Materials Today Bio

DOI: 10.1016/j.mtbio.2026.103771