Aloe/poloxamer hydrogel as an injectable β-estradiol delivery scaffold with multi-therapeutic effects to promote endometrial regeneration for intrauterine adhesion treatment

Intrauterine adhesion (IUA) is characterized by endometrial stromal replaced with fibrous tissue during the trauma or operation induced injury. Current clinic IUA management mainly involves surgical removal of the connective tissues and physical separation and often results in reoccurrence. It is of clinic interest to directly address the issue via facilitating the endometrial repair and thereby inhibiting the formation of re-adhesion. To this end, we designed a nanocomposite aloe/poloxamer hydrogel for beta-estradiol (E2) intrauterine delivery to exert multi-therapeutic effects and promote endometrial regeneration for IUA treatment. Nanoparticulate decellularized uterus (uECMNPs) was prepared to encapsulate E2 (E2@uECMNPs), which improved the solubility and prolonged cargo release. Then, E2@uECMNPs were further embedded into the thermosensitive aloe-poloxamer hydrogel (E2@uECMNPs/AP). Multiple components from E2@uECMNPs/AP system could collectively promote proliferation and inhibit apoptosis of endometrial stromal cells. E2@uECMNPs/AP significantly increased morphological recovery and decreased uterine fibrosis rate compared with IUA rats in other groups in vivo. Additionally, the levels of Ki67, cytokeratin, and estrogen receptor beta were all up-regulated, along with the decreased expression of TGF-beta 1 and TNF-alpha in the uterus from rats receiving E2@uECMNPs/AP therapy. Taken together, in situ administration of E2@uECMNPs/AP hydrogel could effectively promote endometrial regeneration and prevent the re-adhesion.