Extracellular matrix-derived scaffolds in constructing artificial ovaries for ovarian failure: a systematic methodological review
Authors: Wu Tong , Huang Ke-Cheng , Yan Jin-Feng , Zhang Jin-Jin , Wang Shi-Xuan 
Published: April 2023

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 20 October 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).