Three-dimensional structure micelles of heparinpoloxamer improve the therapeutic effect of 17β-estradiol on endometrial regeneration for intrauterine adhesions in a rat model

Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17 beta-estradiol (E-2) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat's endometrium to form an IUA model. 17 beta-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E-2-HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E-2-HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17 beta-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E-2-HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E2-HP hydrogel showed a prolonged release of E-2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E-2-HP hydrogel group. We also demonstrated that E2-HP hydrogel in the recovery of IUA was closely related to the suppression of ER stress signals via the activation of downstream signals, PI3K/Akt and ERK1/2. HP hydrogel might be an effective approach to deliver E-2 into the injured endometrium. Therapeutic strategies targeting ER stress using E-2-HP hydrogel might be a promising solution for the treatment of women with intrauterine adhesions.