AccScience Publishing / IJB / Online First / DOI: 10.36922/ijb.4941
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RESEARCH ARTICLE

3D-printed scaffolds with controlled-releasing compounds for ectopic activation of dormant ovarian follicles

Yali Yang1 ,  Huashan Zhao1 ,  Mingming Wu2 ,  Li Ge1,3 ,  Meiyue Wang1 ,  Feifei Du1 ,  Zhonglin Xiao1,4 ,  Li Xue1,3 ,  Pinpin Wang2,3 ,  Jie Chen1 ,  Tianxia Xiao1 ,  Pei-Gen Ren1* ,  Changshun Ruan2* ,  Jian V. Zhang1,5,6*
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1 Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
2 Center for Human Tissues and Organ Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
3 University of Chinese Academy of Sciences, Beijing, China
4 Faculty of Data Science, City University of Macau, Macau, China
5 Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen, Guangdong, China
6 Sino-European Center of Biomedicine and Health, Shenzhen, Guangdong, China
IJB, 4941 https://doi.org/10.36922/ijb.4941
Submitted: 24 September 2024 | Accepted: 30 October 2024 | Published: 30 October 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Throughout a woman’s reproductive life, hundreds of functioning follicles are activated for development, while thousands of dormant follicles remain in the ovaries. In vitro dormant follicle activation is an effective clinical strategy for women with fertility needs facing ovarian dysfunction. However, in vivo dormant follicle activation remains a challenge due to difficulties such as delivering stimulators to local sites. Here, we developed a compound-preloaded microporous scaffold by combining three-dimensional (3D) printing techniques with pharmacological activators to support and stimulate the activation and development of primordial follicles. The gelatin/alginate composite scaffolds exhibited exceptional mechanical properties and biological compatibility, effectively supporting the survival of ovarian granulosa cells for more than 7 days, which is essential for oocyte development. Furthermore, the ovarian tissue scaffold complex successfully survived after transplantation under the mouse kidney capsule, demonstrating its excellent biocompatibility. After pre-mixing widely used clinical activators into the bioink, the scaffold could gradually release the mixture of compounds, effectively activating primordial follicles. By transplanting the ovary–scaffold complex containing activators into the mouse abdominal subcutaneous pocket, dormant follicles could be activated subcutaneously and developed into growing follicles. The number of growing follicles is approximately three times higher compared to the group without activators. In conclusion, by integrating biomaterials, activators, and 3D printing technology, we have developed 3D-printed biological scaffolds that can ectopically support primordial follicle activation and development in vivo. This novel approach could provide a promising strategy for treating ovarian insufficiency and endocrine disorders in the clinic, without the need for in situ ovarian tissue grafting.

Graphical abstract
Keywords
3D printing
Scaffold
Dormant ovarian follicles
Activation
Transplantation
Funding
This study was supported by the National Natural Science Foundation of China (82301907), Guangdong Basic and Applied Basic Research Foundation (2024A1515010059 and 2024A1515030279), Shenzhen Medical Research Fund (B2404004), Shenzhen Science and Technology Program (JCYJ20220818101218040, JCYJ20220818103608017, JCYJ20220818103607015, JCYJ20220818102811025, JSGGKQTD20210831174330015), Shenzhen Key Laboratory of Metabolic Health (Grant No. ZDSYS20210427152400001), Sino-European Center of Biomedicine and Health.
Conflict of interest
The authors declare there is no conflict of interest.
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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing
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