A strong wet-adhesive hydrogel with reactive oxygen species-scavenging and sustained estradiol release for intrauterine adhesion prevention.

Abstract

Intrauterine adhesions (IUA) are a major cause of female infertility and are mainly associated with aberrant endometrial repair and fibrotic remodeling after intrauterine procedures. However, current therapeutic strategies remain insufficient for effective endometrial repair and IUA prevention. Here, we developed a catheter-deliverable, 17β-estradiol (E2)-loaded bioactive wet-adhesive hydrogel (TNGF-E2) integrating mechanical reinforcement and postoperative microenvironment regulation for IUA prevention and functional endometrial repair. In this system, E2-loaded hybrid poloxamer micelles (MC-F127-E2) served as crosslinking nodes, with their surface aldehyde groups linking gallic acid-grafted gelatin (Gel-GA), while vinyl groups copolymerized with N-[tris(hydroxymethyl)methyl]acrylamide (THMA) and acrylic acid-N-hydroxysuccinimide ester (AA-NHS) under 365 nm UV irradiation to form a dense crosslinked network. The hydrogel achieved rapid adhesion by absorbing wound fluid and forming hydrogen bonds between THMA/Gel-GA and tissue surfaces, followed by stable wet adhesion via covalent reactions between AA-NHS esters and tissue amino groups. Its mechanical support and self-healing properties enabled stable intrauterine retention for up to 14 days. GA incorporated in the hydrogel scavenged reactive oxygen species (ROS), promoted M2 macrophage polarization, and reduced inflammatory cytokine levels. Meanwhile, sustained E2 release promoted cell proliferation, migration, and angiogenesis. In an IUA rat model, TNGF-E2 restored endometrial thickness and gland number and increased embryos implantation numbers. Overall, TNGF-E2 exhibited strong potential for IUA prevention and treatment through the combined effects of barrier protection and regulation of the pathological microenvironment. STATEMENT OF SIGNIFICANCE: Intrauterine adhesions (IUA) remain a challenging postoperative complication because current treatments cannot sufficiently suppress fibrotic remodeling or restore functional endometrium. Here, we developed a catheter-deliverable, estradiol (E2)-loaded bioactive wet-adhesive hydrogel (TNGF-E2) integrating mechanical reinforcement and postoperative microenvironment regulation for IUA prevention and functional endometrial repair. TNGF-E2 also integrates reactive oxygen species (ROS) scavenging and sustained estradiol release. By reducing oxidative stress, inflammation, and fibrosis while promoting endometrial regeneration and angiogenesis, TNGF-E2 effectively prevented IUA and improved fertility, offering a promising strategy for postoperative endometrial repair.