Microenvironment‐Protected Exosome‐Hydrogel for Facilitating Endometrial Regeneration, Fertility Restoration, and Live Birth of Offspring

Abstract

Thin endometrium is a primary cause of failed embryo transfer, resulting in long‐term infertility and negative family outcomes. While hormonal treatments have greatly improved fertility results for some women, these responses remain unsatisfactory due to damage and infection of the complex endometrial microenvironment. In this study, a multifunctional microenvironment‐protected exosome‐hydrogel is designed for facilitating endometrial regeneration and fertility restoration via in situ microinjection and endometrial regeneration. This exosome hydrogel is formulated via Ag+‐S dynamic coordination and fusion with adipose stem cell‐derived exosomes (ADSC‐exo), yielding an injectable preparation that is sufficient to mitigate infection risk while also possessing the antigenic contents and paracrine signaling activity of the ADSC source cells, enabling regeneration of the endometrial microenvironment. In vitro, this exosome‐hydrogel exerts an outstanding neovascularization‐promoting effect, increased human umbilical vein endothelial cell proliferation and tube formation for 1.87 and 2.2 folds. In vivo, microenvironment‐protected exosome‐hydrogel also reveals to promote neovascularization and tissue regeneration while suppressing local tissue fibrosis. Importantly, regenerated endometrial tissue is more receptive to give embryos and birth to a healthy newborn. This microenvironment‐protected exosome‐hydrogel system offers a convenient, safe, and noninvasive approach for repairing thin endometrium and fertility restoration.

In situ delivery of apoptotic bodies derived from mesenchymal stem cells via a hyaluronic acid hydrogel: A therapy for intrauterine adhesions

“…Given that angiogenesis is important for the fine restoration of endometrial structure because it is required for oxygen and nutrient delivery [ 50 ], we assessed neovascularization using CD31 immunostaining. Increased CD31 staining was observed in the ABs and HA/ABs groups at 3 and 7 d post-surgery relative to the NR and HA groups ( Fig.…”

The Complicated Effects of Extracellular Vesicles and Their Cargos on Embryo Implantation

“…EVs derived from serum and uterine fluid may be used, as a noninvasive and accurate marker of endometrial station, to identify women with implantation defects, demonstrate the optimal timing for embryo transfer, and replace the traditional endometrial biopsy (83,126,127). EVs-based preparation may be a promising approach to endometrial regeneration and improving pregnancy outcomes (128).…”

Application of Bioactive Hydrogels for Functional Treatment of Intrauterine Adhesion

“…The advantages of hydrogel treatment include the potential for sustained exosome release, resulting in the maintenance of higher local concentrations of pharmacologically important compounds for extended periods, and reducing the need for repeated dosing in a clinical setting, thus making them a promising candidate for use in exosome-based endometrial repair applications ( Pan et al, 2020 ). Lin et al ( Lin et al, 2021 ) developed a microenvironment-protected exosome-hydrogel for endometrial regeneration ( Figures 7A–C ). This PEG hydrogel was injectable, antibacterial, and facilitated controlled ADSC-exo release in order to promote endometrial regeneration.…”

“…(C) Performance of ADSC-exosome-hydrogel in endometrial receptivity. Reproduced with permission ( Lin et al, 2021 ). Copyright 2021 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.…”