Tuesday, May 16, 2017

Oh Good, Another Way to Make More Babies

Scientists 3-D Print Mouse Ovaries That Actually Make Babies

Not all girls grow up to be mothers. Sometimes they choose not to be, and sometimes circumstances take those choices away. A superfluity of cancers and genetic diseases can destroy women’s ovaries. Or treatments like radiation—used to save a woman’s life—can render those egg-producing organs useless. Ovaries also mediate female hormones. Without them, young patients might never go through puberty; grown women could enter menopause early. 

Today, a team of bioengineers reported a possible fix: 3-D printed ovaries. Their proof of concept—published in Nature Communications—only works on mice so far, but they could end up replacing the uterus-flanking, chestnut-sized organs in humans, too. 

Ovaries are filled follicles—these are immature eggs surrounded by sacs of estrogen and other essential hormones. “The function of the ovary is to shepherd these follicles through maturity into full grown eggs every month,” says Teresa Woodruff, a reproductive scientist at Northwestern University’s Feinberg School of Medicine, and co-author of the study.

To recreate an ovary’s function, Woodruff and her fellow researchers had to start with the ovary’s form. “You tend to think of the skeleton as bones in a body that hold up our flesh,” she says. “But interestingly, every type of organ has an extracellular matrix made from stiffer substances that act like scaffolds.” Last year, they used chemicals to strip away all the follicles, blood vessels, and assorted tissue from a human ovary, leaving only this collagen superstructure. Under the microscope, the scaffold was patterned like an interweaving lattice.

“The next step was to use ovarian tissue as ink,” says Woodruff. Tissue … as ink … yeah, it’s as difficult as it sounds. Tissue, in this sense, is broken-down collagen called gelatin. It’s possible to squirt it out of a printer, but only if it’s at the right temperature. Too hot, and the structure sags; too cold, and it clumps. The Goldilocks zone for tissue ink turned out to be about about 30˚C.

Biomedical engineer Alexandra Rutz, who at the time was a grad student at Northwestern, and is now a post-doc at École Des Mines De Saint-Étienne in Gardanne, France, solved the temperature problem. Then she had to figure out the best pattern to deposit the gelatin so it formed a lattice structure similar to the collagen of a real ovary. Trial and error meant seeding various mesh patterns in vitro with follicles and seeing which would develop the blood vessels and tissue necessary to keep the immature eggs alive. Once they found the right match, the team was ready to put the organ inside a body.

A very tiny body. “Microsurgeries are something we do in the lab pretty frequently,” says Woodruff. Using magnifying glasses, dissecting scopes, and tiny scalpels, they surgically removed one working ovary each from nine female mice and replaced them with 3-D printed prosthetics. (Two of the nine were controls whose printed ovaries had no follicles, and thus no potential to form embryos.) Once the mice had recovered from surgery, the researchers had them mate with male mice—all of which had proven their fertility by fathering previous litters. Pass out the cigars: Three of the females with prosthetic lady parts had babies. 

All this happened pretty quickly—female mice ovulate every four days. Their pregnancies last about 20 days. And those cute little babies are old enough to make babies of their own within four months. Woodruff and her team let those babies make babies, then let those babies make more babies, just to make sure the printed ovaries produced no long term side effects. The process worked perfectly. Additionally, the mothers with 3-D printed organs could nurse normally, which indicated their hormones were just fine—a good sign for ovary-stricken humans.

They’ll have to wait a bit longer. Woodruff says first they have to prove their concept works with larger ovaries. They’ll implant these into mini pigs, which have bodies big enough to hold human organs, and similar menstrual cycles to human females. Woodruff hopes that step, along with clinical trials to establish the treatment is fully safe and effective, will take less than five years. “Gelatin is already FDA approved, so that makes some of the process pretty straightforward,” she says.

Ovaries are complicated organs—with hormonal connections to the brain and ovulation cycles that require new blood vessels to grow every month—but Woodruff says they could be good models for other groups working on printed organs. In the future, all the cool kids will be inked on the inside.

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