Construction of an artificial ovary based on human preantral follicules

Menshikova N.K., Kirillova A.O., Mishieva N.G., Semenova M.L.

1) Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow, Russia; 2) M.V. Lomonosov Moscow State University, Moscow, Russia
The artificial ovary is a temporary construct suitable for transplantation in women, which consists of isolated follicles and possibly other cells encapsulated in a natural or artificial scaffold (Chiti, Dolmans, Donnez, & Amorim, 2017).
This technology can help patients diagnosed with cancers to preserve and restore fertility when any other options (controlled ovarian hyperstimulation, followed by embryo or oocyte vitrification or ovarian tissue cryopreservation) are inaccessible to them. Currently, there are no routine fertility preservation methods in patients having malignant ovarian tumors and a risk of ovarian metastases. Cancer treatment-related infertility negatively affects quality of life in patients. The development of new fertility preservation methods in this group of patients is an extremely urgent and important task.
This paper considers the concept of an artificial ovary and the history of this technology and its possible applications to preserve the reproductive potential of women. Particular attention is paid to necessary conditions for the functioning of a biofabricated ovarian construct, such as the cellular composition and source of follicles, and the characteristics of a scaffold. This paper is concerned with the latest world achievements in creating an artificial ovary. Animal models have been used to provide evidence for the artificial ovary concept and to obtain viable offspring. In vitro culture of human follicles, followed by xenotransplantation, has shown their ability to grow in ovarian constructs.
Conclusion: Despite its complexity, the artificial human ovary technology is developing successfully today. Owing to this new technology, in the future there may be successful therapeutic human transplantation of artificial ovaries created in vitro. The artificial human ovary technology can also have other important applications, for example, in the study of folliculogenesis and in the toxicological studies of the effect of different drugs on human reproductive function.


artificial ovary


  1. Tomao F., Peccatori F., Del Pup L., Franchi D., Zanagnolo V., Panici P.B., Colombo N. Special issues in fertility preservation for gynecologic malignancies. Crit. Rev. Oncol. Hematol. 2016; 97: 206-19.
  2. Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M. et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015; 136(5): E359-86.
  3. Mahajan N. Fertility preservation in female cancer patients: An overview. J. Hum. Reprod. Sci. 2015; 8(1): 3-12.
  4. Spears N., Lopes F., Stefansdottir A., Rossi V., De Felici M., Anderson R.A., Klinger F.G. Ovarian damage from chemotherapy and current approaches to its protection. Hum. Reprod. Update. 2019; 25(6): 673-93.
  5. Wo J.Y., Viswanathan A.N. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int. J. Radiat. Oncol. Biol. Physics. 2009; 73(5): 1304-12.
  6. Hao X., Anastácio A., Liu K., Rodriguez-Wallberg K.A. Ovarian follicle depletion induced by chemotherapy and the investigational stages of potential fertility-protective treatments – A review. Int. J. Mol. Sci. 2019; 20(19): 4720.
  7. Donnez J., Dolmans M.M. Fertility preservation in women. Nat. Rev. Endocrinol. 2013; 9(12): 735-49.
  8. Levine J.M., Kelvin J.F., Quinn G.P., Gracia C.R. Infertility in reproductive-age female cancer survivors. Cancer. 2015; 121(10): 1532-9.
  9. Назаренко Т.А., Ашрафян Л.А., Бирюкова А.М., Кириллова А.О., Мартиросян Я.О., Джанашвили Л.Г., Буняева Е.С. Характеристика и тактика ведения онкологических больных, нуждающихся в сохранении репродуктивного материала. Акушерство и гинекология. 2020; 11: 93-9. [Nazarenko T.A., Ashrafyan L.A., Biryukova A.M., Kirillova A.O., Martirosyan Ya.O., Dzhanashvili L.G., Bunyaeva E.S. Characteristics and management of cancer patients who wish to preserve their reproductive capacity. Obstetrics and Gynecology. 2020; 11: 93-9. (in Russian)].
  10. Буняева Е.С., Кириллова А.О., Хабас Г.Н., Абубакиров А.Н., Мишиева Н.Г. Современные методы сохранения фертильности у пациенток с онкологическими заболеваниями органов репродуктивной системы. Акушерство и гинекология. 2021; 7: 45-52. [Bunyaeva E.S., Kirillova A.O., Khabas G.N., Abubakirov A.N., Mishieva N.G. Modern methods of fertility preservation in female patients with reproductive system cancers. Obstetrics and Gynecology. 2021; 7: 45-52. (in Russian)].
  11. Gellert S.E., Pors S.E., Kristensen S.G., Bay-Bjørn A.M., Ernst E., Andersen C.Y. Transplantation of frozen-thawed ovarian tissue: an update on worldwide activity published in peer-reviewed papers and on the Danish cohort. J. Assist. Reprod. Genet. 2018; 35(4): 561-70.
  12. Donnez J., Dolmans M.M., Diaz C., Pellicer A. Ovarian cortex transplantation: Time to move on from experimental studies to open clinical application. Fertil. Steril. 2015; 104(5): 1097-98.
  13. Ковальская Е.В., Кириллова А.О., Буняева Е.С., Хабас Г.Н., Камалетдинов Н.С., Назаренко Т.А., Абубакиров А.Н. Эффективность дозревания ооцитов, полученных в ходе овариэктомии у онкологических пациенток. Акушерство и гинекология. 2019; 9: 87-91. [Kovalskaya E.V., Kirillova A.O., Bunyaeva E.S., Khabas G.N., Kamaletdinov N.S., Nazarenko T.A., Abubakirov A.N. Efficiency of maturation of oocytes obtained from cancer patients during ovariectomy. Obstetrics and Gynecology. 2019; 9: 87-91. (in Russian)].
  14. Roussou P., Tsagarakis N.J., Kountouras D., Livadas S., Diamanti-Kandarakis E. Beta-thalassemia major and female fertility: The role of iron and iron-induced oxidative stress. Anemia. 2013; 2013. 617204.
  15. Bedoschi G., Navarro P.A., Oktay K. Chemotherapy-induced damage to ovary: Mechanisms and clinical impact. Future Oncol. 2016; 12(19): 2333-44.
  16. Amorim C.A., Shikanov A. The artificial ovary: current status and future perspectives. Future Oncol. 2016; 12(19): 2323-32.
  17. Oktay K. Ovarian tissue cryopreservation and transplantation: preliminary findings and implications for cancer patients. Hum. Reprod. Update. 2001; 7(6): 526-34.
  18. Dolmans M.M., Luyckx V., Donnez J., Andersen C.Y., Greve T. Risk of transferring malignant cells with transplanted frozen-thawed ovarian tissue. Fertil. Steril. 2013; 99(6): 1514-22.
  19. Kim J., Perez A.S., Claflin J., David A., Zhou H., Shikanov A. Synthetic hydrogel supports the function and regeneration of artificial ovarian tissue in mice. NPJ Regen. Med. 2016; 1: 16010.
  20. Kniazeva E., Hardy A.N., Boukaidi S.A., Woodruff T.K., Jeruss J.S., Shea L.D. Primordial follicle transplantation within designer biomaterial grafts produce live births in a mouse infertility model. Sci. Rep. 2015; 5: 17709.
  21. McLaughlin M., Albertini D.F., Wallace W.H.B., Anderson R.A., Telfer E.E. Metaphase II oocytes from human unilaminar follicles grown in a multistep culture system. Mol. Hum. Reprod. 2018; 24(3): 135-42.
  22. Rodgers R.J., Irving-Rodgers H.F., Russell D.L. Extracellular matrix of the developing ovarian follicle. Reproduction. 2003; 126(4): 415-24.
  23. Chiti M.C., Dolmans M.M., Hobeika M., Cernogoraz A., Donnez J., Amorim C.A. A modified and tailored human follicle isolation procedure improves follicle recovery and survival. J. Ovarian Res. 2017; 10(1): 1-9.
  24. Yoon D.M., Fisher J.P. Natural and synthetic polymeric scaffolds. In: Roger Narayan, ed.Biomedical materials. Springer Nature; 2021: 257-83.
  25. Choi J.K., Agarwal P., Huang H., Zhao S., He X. The crucial role of mechanical heterogeneity in regulating follicle development and ovulation with engineered ovarian microtissue. Biomaterials. 2014; 35(19): 5122-8.
  26. Streets A.M., Huang Y. Microfluidics for biological measurements with single-molecule resolution. Curr. Opin. Biotechnol. 2014; 25: 69-77.
  27. Филатов М.А., Храмова Ю.В., Семенова М.Л. Рост и созревание фолликулов яичника мыши в альгинатном гидрогеле in vitro: состояние проблемы. Acta Naturae. 2015; 7(2): 52-61. [Filatov M.A., Khramova Yu.V., Semenova M.L. Growth and maturation of mouse ovarian follicles in alginate hydrogel in vitro: condition of the problem. Acta Naturae. 2015; 7(2): 52-61. (in Russian)]. Accessed: May 05, [Online]. Available:
  28. Shikanov A., Xu M., Woodruff T.K., Shea L.D. A method for ovarian follicle encapsulation and culture in a proteolytically degradable 3 dimensional system. J. Vis. Exp. 2011; 49: 2.
  29. Jin S.Y., Lei L., Shikanov A., Shea L.D., Woodruff T.K. A novel two-step strategy for in vitro culture of early-stage ovarian follicles in the mouse. Fertil. Steril. 2010; 93(8): 2633-9.
  30. Rajabzadeh A.R., Eimani H., Koochesfahani H.M., Shahvardi A.H., Fathi R. Morphological study of isolated ovarian preantral follicles using fibrin gel plus platelet lysate after subcutaneous transplantation. Cell J. 2015; 17(1): 145-52.
  31. Paulini F., Vilela J.M., Chiti M.C., Donnez J., Jadoul P, Dolmans M.M., Amorim C.A. Survival and growth of human preantral follicles after cryopreservation of ovarian tissue, follicle isolation and short-term xenografting. Reprod. Biomed. Online. 2016; 33(3): 425-32.
  32. Pors S.E., Ramløse M., Nikiforov D., Lundsgaard K., Cheng J., Andersen C.Y., Kristensen S.G. Initial steps in reconstruction of the human ovary: survival of pre-antral stage follicles in a decellularized human ovarian scaffold. Hum. Reprod. 2019; 34(8): 1523-35.
  33. Telfer E., Torrance C., Gosden R.G. Morphological study of cultured preantral ovarian follicles of mice after transplantation under the kidney capsule. J. Reprod. Fertil. 1990; 89(2): 565-71.
  34. Gosden R.G. Restitution of fertility in sterilized mice by transferring primordial ovarian follicles. Hum. Reprod. 1990; 5(2): 117-22.
  35. Carroll J., Gosden R.G. Physiology: Transplantation of frozen-thawed mouse primordial follicles. Hum. Reprod. 1993; 8(8): 1163-7.
  36. Dolmans M.M., Yuan W.Y., Camboni A., Torre A., Van Langendonckt A., Martinez-Madrid B., Donnez J. Development of antral follicles after xenografting of isolated small human preantral follicles. Reprod. Biomed. Online. 2008; 16(5): 705-11. 10.1016/S1472-6483(10)60485-3.
  37. Xiao S., Zhang J., Romero M.M., Smith K.N., Shea L.D., Woodruff T.K. In vitro follicle growth supports human oocyte meiotic maturation. Sci. Rep. 2015; 5: 17323.
  38. Soares M., Sahrari K., Chiti M.C., Amorim C.A., Ambroise J., Donnez J., Dolmans M.M. The best source of isolated stromal cells for the artificial ovary: Medulla or cortex, cryopreserved or fresh? Hum. Reprod. 2015; 30(7): 1589-98.
  39. Amorim C.A. Artificial ovary. In: Donnez J., Kim S.S., eds. Principles and practice of fertility preservation. Cambridge, UK: Cambridge University Press; 2011: 448-58.
  40. Kim J., Perez A.S., Claflin J., David A., Zhou H., Shikanov A. Synthetic hydrogel supports the function and regeneration of artificial ovarian tissue in mice. NPJ Regen. Med. 2016; 1 :16010. 1
  41. Mendez U., Zhou H., Shikanov A. Synthetic PEG hydrogel for engineering the environment of ovarian follicles. Methods Mol. Biol. 2018; 1758: 115-28.
  42. Day J.R., David A., Cichon A.L., Kulkarni T., Cascalho M., Shikanov A. Immunoisolating poly(ethylene glycol) based capsules support ovarian tissue survival to restore endocrine function. J. Biomed. Mater. Res. A. 2018; 106(5): 1381-9.
  43. Dolmans M.M., Martinez-Madrid B., Gadisseux E., Guiot Y., Yuan W.Y., Torre A. et al. Short-term transplantation of isolated human ovarian follicles and cortical tissue into nude mice. Reproduction. 2007; 134(2): 253-62.
  44. Luyckx V., Dolmans M.M., Vanacker J., Legat C., Fortuño Moya C., Donnez J., Amorim C.A. A new step toward the artificial ovary: survival and proliferation of isolated murine follicles after autologous transplantation in a fibrin scaffold. Fertil. Steril. 2014; 10 (4): 1149-56.
  45. Vanacker J., Dolmans M.M., Luyckx V., Donnez J., Amorim C.A. First transplantation of isolated murine follicles in alginate. Regen. Med. 2014; 9(5): 609-19.
  46. Chiti M.C., Dolmans M.M., Mortiaux L., Zhuge F., Ouni E., Shahri P.A.K. et al. A novel fibrin-based artificial ovary prototype resembling human ovarian tissue in terms of architecture and rigidity. J. Assist. Reprod. Genet. 2018; 35(1):41-8. 10.
  47. Dolmans M.M., Amorim C.A. Fertility зreservation: сonstruction and use of artificial ovaries. Reproduction. 2019; 158(5): F15-F25.

Received 04.10.2021

Accepted 07.12.2021

About the Authors

Natalya K. Menshikova, Specialist of the 1st Gynecology Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia,, 117997, Russia, Mosсow, Ak. Oparina str., 4.
Anastasia O. Kirillova, PhD, Senior Researcher of the 1st Gynecology Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics,
Gynecology and Perinatology, Ministry of Health of Russia,, 117997, Russia, Mosсow, Ak. Oparina str., 4.
Nona G. Mishieva, Dr. Med. Sci., Leading Researcher of the 1st Gynecology Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia,, 117997, Russia, Mosсow, Ak. Oparina str., 4.
Maria L. Semyonova, Dr. Bio. Sci., Professor of the Department of Embryology, Faculty of Biology, M.V. Lomonosov Moscow State University,, 119991, Russia, Moscow, GSP-1, Leninskie gory, 1, build. 12.

Authors’ contributions: Kirillova A.O., Menshikova N.K., Semenova M.L. – development of the design of the investigation; Menshikova N.K. – writing the text; Kirillova A.O., Mishieva N.G. – editing.
Conflicts of interest: The authors declare that there are no possible conflicts of interest.
Funding: The investigation has been conducted within State Assignment No. 121040600436-7.
For citation: Menshikova N.K., Kirillova A.O., Mishieva N.G., Semenova M.L. Construction of an artificial ovary on the basis of human preantral follicles.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 12: 31-36 (in Russian)

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.