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 β-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 ([email protected]), which improved the solubility and prolonged cargo release. Then, [email protected] were further embedded into the thermosensitive aloe-poloxamer hydrogel ([email protected]/AP). Multiple components from [email protected]/AP system could collectively promote proliferation and inhibit apoptosis of endometrial stromal cells. [email protected]/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 β were all up-regulated, along with the decreased expression of TGF-β1 and TNF-α in the uterus from rats receiving [email protected]/AP therapy. Taken together, in situ administration of [email protected]/AP hydrogel could effectively promote endometrial regeneration and prevent the re-adhesion.