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.

Microneedles for in situ tissue regeneration

“… [ 152 ] Arrowhead needles: GelMA; Base: bottom layer was N-acryloyl glycinamide (NAGA), top layer was PEGMA Arrays: Height: 760 ​μm Shape: Arrowhead Strength: 0.2 ​N/needle bFGF The arrowhead needles allowed MNs steadily adhering to the tissues and released growth factors; Backing layer prevented tissue adhesions [ 153 ] GelMA, Arrays: Height: 600 ​μm Shape: conical Strength: 0.2 ​N/needle Lactoferrin, human endometrium-derived adventitial cells Cells could rapidly form more biologically active three-dimensional cell spheres within the micropores surrounding the needles. Lactoferrin inhibited bacterial infections [ 154 ] …”

“…In another study, Ding et al. prepared a layered GelMA hydrogel MNs containing lactoferrin (LF) with anti-inflammatory activity and antibacterial properties and human endometrium-derived epithelial cells (En-ADVs) [ 154 ]. The study designed a series of micropores on MNs in which EnADVs could be cultured as three-dimensional (3D) cell spheres.…”

The progress of fabrication designs of polymeric microneedles and related biomedical applications

“…[38] Li et al fabricated two-segment MNs with gelatin methacryloyl and lactoferrin for treating Asherman's syndrome due to their rapid degradation and satisfactory antimicrobial activities, and the MNs promoted the restoration of both normal morphology and reproductive function in the injured uterus. [86] Other applications…”

Developing biomedical engineering technologies for reproductive medicine

“…Moreover, novel multifunctional MN patches were designed and prepared by Zhu and Li et al, which were found to enhance endometrial repair in rats (Figure 11). 93,110 In comparison to dissociated cells, MSC cell spheroids had significant advantages of cell proliferation, cell differentiation, and cell migration. This study exhibited the extensive application prospects of cells and biomaterials in tissue repair.…”

“…(C and D) Design of multifunctional microneedle patch loaded with MSC. Reproduced with permission 110. Copyright 2022, John Wiley and Sons.ZHU ET AL.…”