For some of the hundreds of thousands of women who are diagnosed with cancer each year, chemotherapy may be a particularly bitter pill to swallow: the same treatments that could save their lives might also compromise their ability to have children.
While recent advances in cancer therapies have vastly increased rates of survival, these aggressive treatments often come with severe complications including ovarian failure. Now, scientists report at the 34th Annual Meeting of European Society of Human Reproduction and Embryology in Barcelona that an artificial ovary capable of supporting human eggs may someday help preserve the ability of female cancer survivors to conceive children.
The artificial ovary was designed and executed by a team of researchers led by Susanne Pors, a biologist at Copenhagen University Hospital Rigshospitalet. By extracting a woman’s ovarian tissue prior to cancer therapy and stripping it of malignant cells, Pors was able to preserve enough functionality to support the growth and maintenance of human follicles, which carry immature eggs.
Cancer remains a leading cause of death worldwide, with over 6 million new cases diagnosed in women in each year. Up to 10 percent of them are in women under the age of 45. The most effective treatments typically consist of chemotherapy or radiation therapy, which cull fast-growing cancerous cells from the body. These treatments come with immense collateral damage, however, and many of the more fragile tissues, including ovarian follicles, may be wiped out alongside the tumors. While it is possible to conceive naturally after chemotherapy, infertility is not uncommon, and many women seek preemptive measures to preserve the ability to bear biological children.
Men about to undergo fertility-compromising treatments have been utilizing the easy, fast and cost-effective option of sperm banking since the 1970s. In contrast, the options for fertility preservation in women are, by comparison, logistically challenging and often prohibitively expensive, costing up to 10 times what men pay to store their semen. For instance, women who do not currently have a partner or source of sperm typically cannot utilize embryo freezing. And while unfertilized eggs can be cryopreserved, the process of harvesting is not trivial: the body must first be cued to release mature eggs after an intensive period of hormonal treatment, which may itself aggravate some cancers. Depending on the timing and severity of the diagnosis, delaying chemotherapy for the sake of egg collection may be inadvisable. What’s more, both these techniques can only be performed on women after they reach reproductive age.
Another alternative is to extract ovarian tissue prior to chemotherapy for later reimplantation. But while this preservation technique can be done on female patients of any age, it is still considered experimental, has a lower overall success rate in achieving pregnancy, and, unlike the aforementioned techniques, runs the risk of reintroducing cancerous cells into the body. While all of a woman’s eggs are produced prior to birth and not at risk of developing cancer, tissues like the ovaries are vulnerable, especially in blood cancers like leukemia or lymphoma or ovarian cancer itself.
This new technology takes the first steps towards circumventing the issue of cancer reintroduction. Using ovarian tissue from human donors, Pors and her colleagues dislodged the components of the samples that were susceptible to cancerous growth, including all living cells and DNA, using a soapy detergent that extracted these elements from the surrounding matrix. This created a “decellularized scaffold”—an ovarian shell entirely free of potential residual cancer. Pors then seeded this scaffold with immature human or mouse follicles and grafted the complex into female mice.
Pors knew that the first few days after the transplant were the most critical. When the artificial ovary enters its mouse surrogate, it must quickly establish connections with the mouse’s circulatory system and settle into place; if the housewarming process takes too long, the follicles within may perish from lack of oxygen and nutrients. Three weeks later, Pors was thrilled to discover that about 25 percent of both the human and mouse follicles had survived the transplant and could be reliably recovered.
While mouse follicles have previously survived seeding onto similar decellularized scaffolds, human follicles are, by comparison, extremely finicky: even in ideal laboratory conditions, it’s a challenge to keep them alive past two weeks, according to Pors. These findings mark the first time human follicles have survived on a decellularized scaffold.
“It’s the next step towards a big discovery, where we can actually get fertilizable human oocytes [eggs],” says Ariella Shikanov, a biomedical engineer at the University of Michigan who was not involved in the study. However, Shikanov advises that the findings must also be approached with caution: even if eggs continue to be supported by the decellularized matrix, there is no guarantee that viability will be restored once the entire system is transplanted back into the body.
“Natural materials are difficult to control,” Shikanov explains. For instance, harvesting ovarian tissue from individual women inevitably raises the issue of person-to-person variation: not all ovaries are built the same. For women who are able to reintroduce their own tissue into their bodies after chemotherapy, this is not an issue—but for anyone reliant on donor tissue, problems ranging from follicle-ovary incompatibility to outright graft rejection may occur.
Shikanov and several researchers in the field are currently crafting artificial ovaries with synthetic polymers and hydrogels, which may afford more precise control over the mechanical properties of the scaffold. But while synthetic technology is increasingly good at mimicking the human body, decellularized scaffolds like Pors’ could be a more straightforward way to restore an ovary, as they come pre-loaded with functional biological architecture.
“In the future, we can combine the advantages of both fields—the natural scaffold and the mechanics of synthetics,” says Shikanov.
Pors cautions that it will be at least five to 10 years before this technology is ready for clinical trials in women. Next, she and her colleagues plan to push the limits of follicle development in their artificial ovary. Now that the preliminary hurdles have been overcome, Pors hopes that their scaffolds will eventually be able to sustain follicles until eggs mature, a process that takes at least six months. Pors theorizes that this will require a more faithful reconstitution of an ovary, which requires the addition of support cells that help nourish and stabilize the follicles as they mature within the matrix. She’s optimistic.
“With methods like these, we can tell women that a cancer diagnosis is not where everything stops,” Pors says. “You can get out the other side and have a normal life.”