Developing an Artificial Ovary Using the “Tissue Engineering” Approach

Maintaining women’s fertility, mainly of those beginning chemotherapy, is one of the main challenges facing physicians and researchers in the fertility field over the past two decades. Current leading treatments are embryo freezing and egg freezing, treatments that are partially effective but do not provide a solution to young women, mainly girls, who have not started to ovulate. A promising approach entered the clinic in the past decade - ovary tissue is frozen (the ovary is the female reproductive organ that produces the female productive cells – eggs) and returned to the patient when she is cured from cancer and wants children. However, this method has limited success rates and includes the risk of returning cancerous cells to the patient’s body (if the ovary was cancerous prior to treatment). To address these limitations, and parallel to clinical approaches developed in the past decade, an innovative approach developed in the world of “tissue engineering” - in vitro maturation of young ovarian follicles (the follicles are found in the ovary and contain the egg within them). These follicles, that are in their early maturation stages, are called “primordial follicles” and comprise most of the follicle population in the ovary. Therefore, the potential in the ability to grow these follicles is tremendous.

To date, the main research strategy focused on growing ovarian tissue in a culture or on growing a group of isolated follicles in various hydrogels. In research conducted by Dr. Michal Shachar Goldenberg from the Chemical Engineering department at the Ashdod campus in collaboration with Prof. Smadar Cohen from the Biotechnology Engineering department at Ben Gurion University, conducted with the doctoral student Shani Felder a system was developed for in vitro growth of ovarian follicles which is unique in that it simulates/imitates the natural ovary. This research was recently published in the prestigious journal, Biomaterials. The study hypothesis was that a shared culture of primordial follicles with ovarian scaffolds, along with biochemical stimuli that exist in a healthy ovary, will stimulate the maturation of the primordial follicles. And indeed, as part of the research a three-dimensional growth system was developed (like a scaffold), comprised of a polysaccharide called an alginate loaded with growth factors (unique proteins that foster maturation of the follicle), with follicles and scaffolds implanted from pig tissue (for the research model). The study initially focused on testing the system in vitro, while the three-dimensional system with all its components was grown in a laboratory incubator for several weeks. Over time the positive effect of the addition of various growth factors and the effect of their concentrations and the type of growth factor on the follicle maturation process was observed. The potential of the three-dimensional system to serve as an artificial ovary was then examined. To do so the alginate scaffolds were implanted (containing growth factors that stimulate follicle maturation, but also with additional growth factors that stimulate the formation of blood vessels following the implantation) in female mice with a depressed immune system whose ovaries were removed (so they could not ovulate). The study findings showed that the “artificial ovary” returned ovulation to the female mice.

Overall, this study lays the foundations for restoration of the ovarian environment for the benefit for follicle maturation, both in vitro and in vivo, employing a simple approach inspired by body functions. In the future it will be possible to continue research in the aim of developing the challenging procedure of growing human primordial follicles, on the path to reaching the overarching goal – a functioning artificial ovary.