Extracellular matrix-derived scaffolds in constructing artificial ovaries for ovarian failure: a systematic methodological review

Abstract

STUDY QUESTION What is the current state-of-the-art methodology assessing decellularized extracellular matrix (dECM)-based artificial ovaries for treating ovarian failure? SUMMARY ANSWER Preclinical studies have demonstrated that decellularized scaffolds support the growth of ovarian somatic cells and follicles both in vitro and in vivo. WHAT IS KNOWN ALREADY Artificial ovaries are a promising approach for rescuing ovarian function. Decellularization has been applied in bioengineering female reproductive tract tissues. However, decellularization targeting the ovary lacks a comprehensive and in-depth understanding. STUDY DESIGN, SIZE, DURATION PubMed, Embase, Web of Science and the Cochrane Central Register of Controlled Trials were searched from inception until October 20, 2022 to systematically review all studies in which artificial ovaries were constructed using decellularized extracellular matrix scaffolds. The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. PARTICIPANTS/MATERIALS, SETTING, METHODS Two authors selected studies independently based on the eligibility criteria. Studies were included if decellularized scaffolds, regardless of their species origin, were seeded with ovarian cells or follicles. Review articles and meeting papers were removed from the search results, as were articles without decellularized scaffolds or recellularization or decellularization protocols, or control groups or ovarian cells. MAIN RESULTS AND THE ROLE OF CHANCE The search returned a total of 754 publications, and 12 papers were eligible for final analysis. The papers were published between 2015 and 2022, and were most frequently reported as coming from Iran. Detailed information on the decellularization procedure, evaluation method and preclinical study design was extracted. In particular, we concentrated on the type and duration of detergent reagent, DNA and extracellular matrix detection methods, and the main findings on ovarian function. Decellularized tissues derived from humans and experimental animals were reported. Scaffolds loaded with ovarian cells have produced estrogen and progesterone, though with high variability, and have supported the growth of various follicles. Serious complications have not been reported. LIMITATIONS, REASONS FOR CAUTION A meta-analysis could not be performed. Therefore, only data pooling was conducted. Additionally, the quality of some studies was limited mainly due to incomplete description of methods, which impeded specific data extraction and quality analysis. Several studies that used dECM scaffolds were performed or authored by the same research group with a few modifications, which might have biased our evaluation. WIDER IMPLICATIONS OF THE FINDINGS Overall, the decellularization-based artificial ovary is a promising but experimental choice for substituting insufficient ovaries. A generic and comparable standard should be established for the decellularization protocols, quality implementation, and cytotoxicity controls. Currently, decellularized materials are far from being clinically applicable to artificial ovaries. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the National Natural Science Foundation of China (Nos. 82001498 and 81701438). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER This systematic review is registered with the International Prospective Register of Systematic Reviews (PROSPERO, ID CRD42022338449).

Innovative Strategies for Fertility Preservation in Female Cancer Survivors: New Hope from Artificial Ovary Construction and Stem Cell-Derived Neo-Folliculogenesis

“…The main problem of decellularized OT matrix is the variable size of preantral follicles (30-150 µm), making them hardly adaptable to the pores of the matrix. One alternative is to transform this matrix into a thermosensitive hydrogel, an approach that allows perfect encapsulation of isolated follicles, while retaining the composition of the matrix: in vitro experiments using this procedure demonstrated that isolated mouse preantral follicles could successfully survive in decellularized OT [76,77]. Some studies demonstrated increased estradiol (E2) or progesterone (P4) compared to fresh ovaries in vitro [78,79] whereas others observed that follicular development and ovarian function of decellularized-based artificial ovaries contributed to higher E2 or P4 or inhibin A compared with those in ovariectomized mice, also in vivo [72,74,80].…”