Injectable Thermosensitive Hydrogel Incorporating Platelet-Derived Factors for Endometrial Repair.

Abstract

Intrauterine adhesion (IUA) is characterized by endometrial fibrosis, impaired vascularization, and loss of endometrial receptivity, resulting in infertility and adverse reproductive outcomes. Current clinical treatments remain limited because of inadequate tissue regeneration and high rates of adhesion recurrence. While hydrogel-based therapeutics show promise, their clinical translation is frequently hindered by potential cytotoxicity from chemical crosslinkers and the absence of multifaceted bio-inductive niches. Herein, we present a highly translatable, cell-free strategy utilizing a physically crosslinked, injectable thermosensitive hydrogel composed of Poloxamer 407 (P407) and natural Hyaluronic Acid (HA) to deliver platelet-derived factors (PDFs) for comprehensive endometrial repair. By eschewing chemical modifications, this pristine formulation ensures superior biosafety, rapid in situ gelation tailored to complex uterine morphologies, and optimized sustained-release kinetics. In a rat model of IUA, PDFs@Gel treatment significantly improved endometrial morphology, including increased endometrial thickness and gland number, while reducing fibrosis compared with untreated IUA animals. Immunofluorescence and western blot analyses further demonstrated enhanced expression of CK18, Vimentin, VEGF-A, and VEGF-R2 after treatment, indicating improved epithelial and stromal regeneration together with enhanced angiogenesis-associated activity. Meanwhile, reduced TGF-β expression and a decreased pSmad2/3-to-Smad2/3 ratio supported suppression of TGF-β/Smad-mediated fibrotic signaling. Reproductive evaluation further showed improved embryo implantation and live birth outcomes following PDFs@Gel administration. Collectively, these findings suggest that PDFs@Gel represents a promising biomaterial strategy for endometrial repair and functional recovery in IUA. STATEMENT OF SIGNIFICANCE: Rather than serving solely as a drug carrier or anti-adhesion barrier, the proposed hydrogel functions as a multifunctional regenerative platform that combines structural protection with sustained delivery of platelet-derived regenerative cues. The physically crosslinked hyaluronic acid/Poloxamer 407 network offers a simple and potentially translatable design without chemical modification or additional crosslinkers. By simultaneously addressing fibrosis, tissue regeneration, and fertility restoration, this study demonstrates a practical biomaterial design strategy for intrauterine applications and provides a translational platform for regenerative therapies requiring simultaneous anti-adhesion and tissue-repair functions.