Bioprinted Artificial Ovaries Demonstrated to be Fully Functional in Mice

Researchers cannot yet produce large amounts of tissue using tissue engineering approaches such as bioprinting, as there is still no good solution for the creation of a suitable blood vessel network to support sizable tissue sections. However, that hasn't stopped the research community from forging ahead to develop the necessary recipes to produce functional tissue of various types, just in very small amounts. In many cases this artificial tissue isn't exactly the same in structure as the tissue it replaces, but it is nonetheless still capable of carrying out the desired functions. Some organs or crucial parts of organs are small enough to be produced in entirety, however, and hence researchers are now able to carry out demonstrations such the one here, in which artificial mouse ovaries are created, transplanted, and shown to be fully functional. The engineered ovaries produce the desired hormones and are capable of supporting the full process of mammalian reproduction. It is a good example of the quality of tissue being produced these days; once the blood vessel hurdle is overcome, the generation of entire organs will follow shortly thereafter.

Patients undergoing treatment regimens that eradicate their disease, such as cancer, may be left with diminished ovary function. Therefore, the oncofertility field is tasked to develop a whole organ replacement that restores long-term hormone function and fertility for all patients. In past work, we and others have sought to create an engineered ovary with biomaterials and isolated follicles. Ovarian follicles are spherical, multicellular aggregates that include a centralized oocyte (female gamete) and surrounding support cells, granulosa and theca, that produce hormones in response to stimulation from the pituitary. The spheroid shape of a follicle is critical to its survival in that the support cells must maintain contact with the oocyte until it has matured and is ready for ovulation. Consequently, a three-dimensional (3D) material environment is critical to maintaining these cell-cell interactions and follicle shape.

Thus far, there have been several reports of live births from biomaterial implants in mice, and all have used isolated follicles or whole ovarian tissue encapsulated in a plasma clot or similar fibrin hydrogel bead containing growth factor components or purified vascular endothelial growth factor. These results are very encouraging and have validated both the model procedure and the need for graft vascularization for complete restorative organ function of isolated follicles in a biomaterial. However, hydrogel encapsulation of follicles poses several challenges, especially with respect to the size of anticipated transplants. Specifically, when translating this work to a large animal or human, the implant must house a significantly larger population of follicles and therefore must be considerably larger than those used in mice. At these scales, diffusion limits may become a concern.

Future strategies must permit channels within the hydrogels (to facilitate host vasculature infiltration) or including pre-embedded vasculature to sustain follicle viability and circulate follicular hormones. Moreover, the ovary is a heterogeneous organ that compartmentalizes different follicle pools (quiescent and growing) into the cortex and medulla regions that have varying stiffness. It is believed that this compartmentalization will be critical to providing long-term (multiple decades) function with an implant. Therefore, a biomaterial strategy that can produce a mimetic construct of spatially varying material properties may be required for optimal implant function and longevity.

3D printing can be used to address all of these future implant requirements for creating a human bioprosthetic ovary, a bioengineered functional tissue replacement. As the first steps towards this goal, here, we investigated porous hydrogel scaffolds with murine follicles seeded throughout the full depth of the scaffold layers to create a murine bioprosthetic ovary. Microporous architectures were achieved through 3D printing partially crosslinked, thermally regulated gelatin. We found that specific scaffold architectures created a 3D feel by providing appropriate depth and multiple contact sites for the ovarian follicle, which resulted in optimal murine follicle survival and differentiation in vitro. The open micropores within the hydrogel scaffold provided sufficient space and nutrient diffusion for follicle survival and maturation in vitro and in vivo, as well as space for vasculature to infiltrate when implanted in vivo without the need for significant scaffold degradation as is required when using hydrogel encapsulation.

Follicle-seeded scaffolds become highly vascularized and ovarian function is fully restored when implanted in surgically sterilized mice. Moreover, pups are born through natural mating and thrive through maternal lactation. These findings present an in vivo functional ovarian implant designed with 3D printing, and indicate that scaffold pore architecture is a critical variable in additively manufactured scaffold design for functional tissue engineering.



I wonder how long it takes people to add 1 and 1 and realize between the calves growing in plastic bags from a couple of months back and this we are 80% to solving artificial wombs.

The day the conservative media gets the memo there will be a wonderful fallout. And I'll be laying back on my couch with a wide smirk on my face with a glass of wine enjoying their horror and outrage.

It's a great time to be alive.

Posted by: Anonymoose at May 17th, 2017 1:23 PM

Depends on which "conservatives" you're talking to, Anonymoose. There are more real, hardcore eugenicists than you might realize, and even the Christian groups aren't going to get in the way of something that might let older women have healthy babies.

Posted by: Slicer at May 17th, 2017 3:02 PM

Techno-conservatives. Neo-Ludites. They are on the left on the right in the green and everywhere in between.

Mostly greens really. Their ape outs over technology are always a sight to behold.

Posted by: Anonymoose at May 17th, 2017 3:09 PM

Not sure what you mean by that Anonymoose. I am a fairly far right conservative myself, and I think that an artificial uterus would be a wonderful breakthrough. It would truly end the horror of abortion without burdening women with a pregnancy they don't want. I can't imagine anything that would make us (conservatives) happier than ending the slaughter of babies by being able to just transfer the baby to an artificial uterus.

Posted by: Tmr3608 at May 17th, 2017 3:27 PM

@Tmr3608 Everyone has something to be mad about when it comes to artificial wombs. In the case of your ideological leaning - two men having a child.

I knew we were close when last year some Chinese scientists developed an embryo in vitro up to the internationally allowed limit - just to show it's possible as they said ... yeah right, the Chinese never do things with no utility in mind.

As I said, I can't wait. The meltdown is going to be aaaaaamazing~.
I should probably throw a party and rotate "insightful" comments from social media and the press on my TV so my friends can have a laugh as well. Truly a highlight of the 21st century this. Man, oh man.

Posted by: Anonymoose at May 17th, 2017 4:42 PM

Ok, I suppose some Christians might oppose that, and there is a fair amount of intersectionality between Christian and conservative, but they are not the same ideology or movement, despite the overlap. Personally, I'm not Christian, and I believe two men having a baby is a personal choice that ought to be left to the individuals involved, as it properly does not fall under the purview of government. I think most conservatives would agree with that, even most Christians, who might privately disagree with the choice.

Posted by: Tmr3608 at May 17th, 2017 5:19 PM

First, this is not an artificial womb, it's an artificial ovary. An artificial womb is waaaay more difficult (you need a circulatory system for the womb, you need to supply nutrients and oxygen to the fetus and also the correct biochemical cues for its development at each stage during 9 months).

Second, it's not an artificial ovary created "de novo" (from, say, skin cells) but created from ovarian follicles. Thus, if you don't have eggs, this is useless.

Posted by: Antonio at May 17th, 2017 6:24 PM

You should keep up with the news Antonio. You lack the context.

Eggs - made from skin cells implanted in mice. Produced pups. Last year.
Embryo - grown to the maximum allowed time in vitro. Last year.
Late stage cow embryos matured in artificial womb like apparatus. Earlier this year.
Now this.

This field is progressing in the matter of months. In 2 to 3 years all the ingredients will be sufficiently mature for an artificial womb to be tested in a lab the way I see things.

Posted by: Anonymoose at May 17th, 2017 7:22 PM

Yes, eggs could be made from skin in humans, but then you can simply use IVF, that is much much easier than this. The point of this technique is to help pre-puverty girls that will receive some cancer treatment to have children in the future. The doctor will extract her ovaries/folicles and reimplant some folicles when adult.

"Embryo - grown to the maximum allowed time in vitro. Last year."

"The maximum allowed time" is different from the full needed time. It was in the womb only a few days. Researchers don't know yet how to go from a fertilized egg to birth. Mice have a 20-days gestation period. Ten years ago researchers grew a mouse embryo for 10 days. Still they can't grow a full mouse.

"Late stage cow embryos matured in artificial womb like apparatus. Earlier this year."

Same here. Only a few days. There is much yet to know and invent to substitute a real womb.

Posted by: Antonio at May 18th, 2017 12:37 AM

It's interesting how you can't mobilize the same optimism for fields you're not interested in Antonio. If you were equally pessimistic when you talked about anti-aging or cryopreservation you would have already given up on both of those ideas a long time ago.

We've made no progress in extending life in mice in well over a decade. It seems we've hit a wall and extending the lifespan of that species beyond 25% - a scientist from Buck recently talked on length about that in an interview and it's implications for human longevity. Does that phase you? No. I imagine you'll do your typical SENS is better tirade in answer.
But you can easily dismiss real progress in other fields so easily out of hand.

Human psychology is truly an amazing thing.

Posted by: Anonymoose at May 18th, 2017 2:54 AM

"It's interesting how you can't mobilize the same optimism for fields you're not interested in Antonio."

Wow, how did you deduce that? Do you have ESP? It's quite annoying when people think they can read your mind.

If I ever have children, they will probably be born by IVF. My girlfried had ovarian cancer and was extirpated an ovary and part of the other to remove the tumors. We don't know if what remains is functional, but if it is, we will probably have to use IVF.

Posted by: Antonio at May 18th, 2017 5:53 AM

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