Human Endometrium‐Derived Adventitial Cell Spheroid‐Loaded Antimicrobial Microneedles for Uterine Regeneration

Abstract Asherman's syndrome (AS) occurs as a consequence of severe damage to the endometrial basalis, usually leading to menstrual abnormalities, infertility, and recurrent miscarriage in women. Currently, human endometrium‐derived adventitial cells (En‐ADVs) are considered ideal seed cells with high pluripotency for regenerative medicine. However, critical issues such as noninvasive repair of tissues, targeting of native stem cells, and continuous action in the injured sites are not well resolved. Herein, En‐ADV spheroid‐loaded hierarchical microneedles (MN/En‐ADV) for in situ intrauterine repair are developed. The flexible microneedles are fabricated with gelatin methacryloyl and lactoferrin, imparting the characteristics of rapid degradation and antimicrobial activity. Benefiting from an array of microwells on microneedles, En‐ADVs can rapidly form 3D cell spheroids, which display higher potential for cell proliferation, differentiation, and migration than dissociated cells. With the application of MN/En‐ADV, the repaired uteri show well‐defined myometrial regeneration, angiogenesis, and an increase of endometrial receptivity in a rat AS model. Notably, embryos are able to implant in the reconstructed sites and remain viable, indicating that this system promotes the restoration of both normal morphology and reproductive function in the injured uterus. It is anticipated that multifunctional MN/En‐ADV can be an ideal candidate for versatile in situ tissue regeneration.