Ibuprofen-Releasing Nanofiber Membrane Curbs Scarring After Ureteral Injury in Rabbits

Ureteral strictures—narrowings of the tube that carries urine from kidney to bladder—remain one of the more stubborn problems in urologic surgery. Once scarring takes hold, urine drainage falters, the kidney’s collecting system swells, infections recur, and renal function can slip away. Current fixes such as balloon dilation, endoureterotomy, long-term stenting, and reconstructive surgery suffer from variable durability and frequent reintervention. A new study published in Materials Today Bio reports a mechanism-guided alternative: an electrospun membrane that releases ibuprofen locally, blunting the inflammatory cascade that drives fibrotic narrowing in an animal model.

The research team, led by investigators at Nanjing Medical University, began with human tissue rather than a cell line. Using single-cell RNA sequencing on stricture specimens from three patients and the 10x Genomics Visium spatial transcriptomics platform on one stricture and one normal ureter, they mapped where immune and stromal programs converge within the diseased tissue. The analysis revealed a spatially organized fibro-inflammatory niche: fibroblast-associated genes such as COL1A1 and POSTN and macrophage-associated genes such as C1QA and MRC1 showed overlapping distributions in stenotic regions, accompanied by elevated fibroblast-myeloid network scores and expression of TGF-beta pathway components. Immunofluorescence staining independently confirmed accumulations of CD68-positive macrophages nestled close to COL1A1-positive fibroblast-rich zones. Normal ureter tissue showed far weaker and less convergent signals.

The authors note this is, to their knowledge, the first spatial transcriptomic analysis in ureteral stricture. The finding matters because conventional histology and bulk assays cannot resolve whether macrophages and activated fibroblasts actually occupy the same lesion microenvironment—a prerequisite for the paracrine crosstalk the team suspected was sustaining scarring even after mechanical recanalization. The spatial co-enrichment offers a tissue-level explanation for why endoscopic treatments, effective in selected early cases, yield inconsistent long-term durability across retrospective series and meta-analyses.

To dissect the mechanism, the researchers built a stepwise laboratory model. They generated urothelial injury-conditioned medium (UICM) by mechanically scraping SV-HUC-1 urothelial cells, a manipulation that produced measurable IL-6, HMGB1, and lactate dehydrogenase release—hallmarks of inflammatory and damage-associated signaling. When primary ureteral fibroblasts isolated from three human donors were exposed to UICM, they upregulated inflammatory genes including IL1B, IL6, and CCL2 and secreted IL-6, TNF-alpha, and IL-1 beta, but their classical fibrotic markers ACTA2, COL1A1, and FN1 remained unchanged. The team designated this state the inflammatory fibroblast-like cell, or iFib. UICM also activated THP-1-derived macrophages, raising NOS2/iNOS, TNF, IL1B, and CD86 expression alongside cytokine secretion, in a predominantly pro-inflammatory mixed activation pattern with only modest M2-associated features.

The pivotal step came next. Conditioned medium harvested from UICM-activated macrophages, when applied to fibroblasts and especially to the primed iFib, significantly increased FN1, COL1A1, and alpha-SMA expression and boosted Smad2 and Smad3 phosphorylation—the canonical downstream arm of TGF-beta signaling. Immunofluorescence confirmed elevated COL1A1 and alpha-SMA protein. In other words, injury-primed fibroblasts became highly responsive to macrophage-derived cues, transitioning toward a myofibroblast-like, matrix-producing phenotype. This two-step model—inflammatory priming followed by macrophage-driven fibrotic differentiation—suggests why early inflammation can set the stage for later scarring even after the original insult resolves.

Ibuprofen entered the picture as a locally deliverable nonsteroidal anti-inflammatory drug chosen for its well-characterized inhibition of cyclooxygenase-dependent prostanoid production and its chemical compatibility with poly-L-lysine conjugation, not for any assumed selectivity against NF-kappaB or TGF-beta/Smad pathways. In the cell model, ibuprofen at 10, 100, and 300 micromolar concentration-dependently reduced iNOS and CD86, lowered phosphorylated p65 and COX-2, and broadly dampened the mixed macrophage activation program—including Arg-1—rather than pushing cells toward an M2-like state. Conditioned medium from ibuprofen-treated macrophages elicited less FN1, COL1A1, alpha-SMA, and Smad2/3 phosphorylation in iFib. A prostaglandin E2 add-back experiment partially restored both macrophage activation markers and downstream fibroblast fibrotic responses in a concentration-dependent manner, identifying a PGE2-responsive component in the system, though the restoration remained incomplete relative to untreated controls.

The delivery platform itself is an electrospun polycaprolactone/gelatin membrane functionalized with an ibuprofen-poly-L-lysine conjugate using EDC/NHS carbodiimide chemistry. Scanning electron microscopy showed the nanofibrous architecture survived modification, with mean fiber diameter rising modestly from about 348 nanometers for the blank membrane to roughly 452 nanometers after ibuprofen loading. Mechanical testing found comparable stiffness and tensile strength, with improved extensibility after functionalization. The membrane released ibuprofen continuously over 56 days in vitro, showed no significant changes in clotting times, and kept hemolysis ratios low. One caveat the authors flag prominently: the estimated areal drug loading of approximately 19.2 micrograms per square centimeter was calculated indirectly from feed ratios and gravimetric yield, and the initial total ibuprofen content of the finished membrane was never directly quantified.

The in vivo test used a rabbit model in which heated forceps clamp the mid-to-upper left ureter for five seconds, producing a reproducible thermal injury. With five rabbits per group per time point and blinded histological quantification, membranes were applied immediately over the injured segment. At days 7, 14, 30, and 90, the ibuprofen-eluting membrane consistently reduced Masson-positive collagen area, preserved ureteral architecture, and lowered renal pelvic dilation indices compared with burn-only and blank-membrane controls. Serum biochemical markers including AST, ALT, creatinine, and blood urea nitrogen also generally improved. Tissue collected at days 14 and 30 showed reduced expression of inflammatory genes such as CD86, CD68, PTGS2, NOS2, and IL1B, along with reduced TGF-beta1, FN1, COL1A1, and ACTA2. Major organs examined at day 90 showed no obvious treatment-associated histological abnormalities, though these readouts measure systemic safety signals in rabbits, not human clinical benefit.

A delayed-treatment arm delivered the study’s most sobering result. When membrane placement was postponed until day 14 after injury, with evaluation at day 44, the ibuprofen membrane produced only limited improvement: it did not significantly reduce Masson-positive area or renal pelvic dilation indices relative to controls, and serum abnormalities persisted. The authors conclude that delayed placement showed no detectable reversal of established fibrosis within the 30-day post-treatment observation window, while noting that a slower or longer-term effect cannot be excluded. The contrast with immediate coverage suggests the therapeutic window favors intervening before matrix deposition becomes entrenched—clinically pointing toward intraoperative or early postoperative deployment where ureteral injury is anticipated.

The study carries substantial limitations that the authors themselves enumerate. The human spatial atlas rests on three stricture specimens, and cross-dataset reference bias cannot be fully excluded. The conditioned-medium experiments could not distinguish macrophage-mediated signaling from direct carryover effects of residual ibuprofen or PGE2 on fibroblasts, since supernatants were collected without a treatment-free conditioning period. No head-to-head comparison with other NSAIDs was performed, so the findings support feasibility of ibuprofen-based local delivery without establishing superiority or unique pathway selectivity. The rabbit thermal injury model, while reproducible, differs from the iatrogenic, ischemic, and stone-impaction causes of human strictures. What the work does deliver is a spatially grounded cellular framework for the disease and proof of concept that a locally deployable anti-inflammatory biomaterial can attenuate the injury-inflammation-fibrosis continuum when applied early—an approach the authors position as an adjunct to, rather than a replacement for, existing surgical management.

Subject of Research: An ibuprofen-eluting electrospun membrane that suppresses macrophage-driven fibroblast activation to prevent ureteral fibrosis

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

Article References: Zhang, X., Zhong, D., Xu, Z., Li, Y., Zheng, J., Tian, Y., Qin, C., Pei, R., Wu, J., Wang, Y., & Song, N. (2026). An ibuprofen-eluting electrospun membrane prevents ureteral fibrosis by dampening macrophage-associated fibroblast activation. Materials Today Bio, 41, Article 103771. https://doi.org/10.1016/j.mtbio.2026.103771

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103771

Keywords: ureteral stricture, ibuprofen, electrospun membrane, spatial transcriptomics, macrophages, fibrosis, drug delivery, rabbit model, TGF-beta, PCL/gelatin, biomaterials, ibuprofen-eluting