Three-dimensional printing has been used to create mouse ovaries made of gelatin, able to ovulate and produce eggs that can be fertilised and carried to full term.
The achievement is described in the journal Nature Communications. It represents a big step towards what Teresa Woodruff of the Women’s Health Research Institute at Northwestern University, Illinois, described as the “holy grail” of regenerative medicine: creating prosthetic ovaries for women whose own have been damaged by cancer treatment.
The finding opens the possibility that one day women who preserve their ovaries by freezing them prior to cancer therapy might have their egg follicles isolated and implanted into a “prosthetic” ovary to mature. This is preferable to replacing the entire frozen ovary since it may still contain cancer cells, explains Woodruff.
Woodruff and colleagues used 3-D printing to create a “scaffold” of gelatin filaments that supports ovarian follicles. Not only do they contain the immature egg follicle but also the surrounding granulosa cells, which receive signals from the pituitary gland to produce the estrogen and estrogen necessary for ovulation and to sustain an ensuing pregnancy.
The decision to use a gelatin known as a hydrogel – derived from collagen and used in other forms as a gelling agent in foods, pharmaceuticals and cosmetics – was the key agent of success, the scientists report.
“Most hydrogels are very weak, since they’re made up of mostly water, and will often collapse on themselves,” says materials science team member Ramille Shah. “But we found a gelatin temperature that allows it to be self-supporting, not collapse, and lead to building multiple layers.”
The resulting filaments are flexible and interact well with mouse body tissues, but also retain enough rigidity to be handled during surgery.
The shape of the printed ovarian scaffold was modelled closely on the external supporting structure of a real mouse ovary. The frame and the size of the pores between the filaments were crucial to the survival of the follicles.
“This is the first study that demonstrates that scaffold architecture makes a difference in follicle survival,” Shah says. “We wouldn’t be able to do that if we didn’t use a 3-D printer platform.”
The printed ovarian scaffolds were implanted into mice whose own ovaries had been removed earlier.
The open nature of the structure influenced how follicles and immature eggs behaved, the scientists observed. It also allowed for the formation of blood vessels, which permitted the circulation of hormones during pregnancy, and triggered lactation after birth.
Having demonstrated the technique in live mice, Woodruff’s team is now working on scaling up the procedure to enable the creation of fully functional prosthetic ovaries for women.
Women who have frozen ovaries could use the prosthetic as a replacement for their isolated follicles, so that they could ovulate and sustain pregnancies.
On the other hand, pregnancy is not the only function of the ovary. The hormones produced by follicles are needed to trigger puberty. In female children, cancer treatment that damages the ovaries can often delay or prevent its onset. Existing treatments include hormone-replacement therapies and the implant of donor ovaries derived from cadavers. These prosthetic ovaries might also be used to accept donor follicles.
