The artificial ovary is a “house” for egg-producing follicles, just like the original ovary, Christiani Amorim, who studies animal reproduction at Université catholique de Louvain in Belgium, tells The Scientist by email. “We aim to recreate the right conditions the follicles need to survive.”
Several groups are competing and collaborating to develop the perfect artificial ovary, and so far studies show it is possible to use the synthetic organ to restore ovarian function in mice. Perfecting the structure, stiffness, and capabilities of the human artificial ovary is now the focus, with teams nearing the point where they could start testing them out in women. If shown to work, this structure could have other uses too, in everything from toxicology studies to postponing childbearing to possibly helping transgender individuals with hormone delivery.
Cancer patients are the first focus, Marie-Madeleine Dolmans, Amorim’s colleague at Université catholique de Louvain, tells The Scientist by phone. To help these women, researchers have tried shielding the ovaries during treatment, by moving them outside of the area that will be radiated or by removing, preserving, and transplanting ovarian tissue back into patients after cancer treatment. This last technique, which relies on an individual’s natural ovaries, has restored ovarian function and led to the birth of more than 100 babies worldwide, according to a recent paper written by Dolmans and colleagues.
Research in rhesus monkeys has shown that ovary transplantation to the arm can lead to normal hormone function, and an oocyte from transplanted tissue led to a healthy baby monkey.
But, Dolmans explains, cryopreservation and transplantation aren’t an option for everyone. Women with cancers that metastasize currently have no options for fertility after treatment. That’s because the risk of extracting malignant cancer cells and reinserting them back into the body after chemotherapy or radiation is quite high. Girls who have not yet hit puberty are also unable to participate in cryopreservation and later transplantation.
“It’s these women we’re trying to help,” says materials scientist Ariella Shikanov of the University of Michigan. To do this, researchers would extract follicles from women before treatment, remove any that appear to be cancerous, then freeze the tissue. Once a patient is cancer-free and at an age to start menstruation or have a child, the follicles would be unfrozen, injected into an artificial ovary, and transplanted back into the body.
A matrix of fibrin, typically found in the scaffolding of blood clots, with the right balance of the proteins fibrinogen and thrombin, appears to build the best home for artificial ovaries, Amorim and colleagues reported December 13 in the Journal of Assisted Reproduction and Genetics. This mix creates a structure that most closely resembles a real ovary, the team writes.
Other teams are working to optimize artificial ovary production and the development of the follicles embedded within them. Shikanov and colleagues, for instance, are working on identifying the correct signals and transcription factor activity at work in the early stages of follicle development. Knowing which signals spur development could help researchers to create—chemically or genetically—the right environment to coax the follicles to grow.
Meanwhile, Mary Zelinski of Oregon Health & Science University and colleagues are tackling another challenge: figuring out exactly where to implant artificial ovaries to ensure hormone function and fertility and also to collect data on the health of offspring born via transplantation. So far, her research in rhesus monkeys has shown that transplantation of natural ovarian tissue to the arm can lead to normal hormone function. Additionally, she bred a baby monkey from oocytes developed in transplanted tissue. That monkey went on to have normal pregnancies and did not show signs of premature cellular aging, the team reported in September in the Journal of Assisted Reproduction and Genetics.
The biggest challenge right now, says obstetrics and gynecology expert Teresa Woodruff of Northwestern University Feinberg School of Medicine, is trying to make an ovary that is structurally sound and durable, able to last up to 10 years or more in the body. To do this, she and her colleagues have been using ovary ink to print a three-dimensional superstructure capable of supporting follicles inside mice. These animals have even gone on to have babies. Unlike the matrix made by Dolmans and Amorim, the 3D-printed ovary can be composed primarily from collagen, elastins, growth factors, and other bioactive agents.
“3D printing is very trendy at the moment, but since we showed in our last publication that our fibrin matrix has a comparable fiber structure and rigidity to human ovaries, I wonder if 3D printing is really a strategy for the creation of an artificial ovary for human application,” Amorim writes.
Woodruff disagrees. She says the biological ink used in 3-D printing an ovary allows researchers to have more control in developing an organ that is closer in structure to an actual ovary, which could help with getting it connected to the vasculature it needs.
Amorim and Dolmans argue that by using materials that are already developed by the body without 3-D printing, approval to start testing their artificial ovary in women may come easier. In fact, testing could begin in the next few years.
The utility of artificial ovaries goes beyond giving cancer patients more options for becoming a mother, though. Most immediately, a lab-grown ovary could help in toxicology studies. Because the tissue would allow follicles to survive and grow similar to the conditions in the original organ, researchers could test the effects of drugs or compounds in the environment that act as endocrine disruptors. Clinically, artificial ovaries could help older women continue to produce hormones to combat osteoporosis, heart disease, and other side effects of menopause. They could also give transgender individuals a more natural hormone delivery system.
“I see a great potential for the artificial ovary,” Amorim says.
Correction (January 2): The article had the incorrect byline. The Scientist regrets the error.
Correction (January 5): The pull quote incorrectly stated that the implanted ovaries were artificial. They were in fact natural tissues taken from and then transplanted back into the monkey. Paragraph nine has been updated to clarify. The Scientist regrets the error.