Author: Javier del Río
“This could eventually help in developing new fertility preservation treatments”.
Currently, there are many research lines focused on the improvement of assisted reproduction technologies (ART) and the development of new ones that guarantee new reproductive options for patients. Among the most recent investigated topics there are some worth to mention, like 3D-printed ovaries, stem cells-derived gametes or the use of CRISPR-Cas9 technology for embryos. All these promising approaches have opened new paths of research in ART, too. Recently, a paper has been published reporting functional human eggs grown in the laboratory for the first time.
The study was carried out by McLaughlin and colleagues from University of Edinburgh (UK), whose research focuses on the mechanisms of follicle development. As part of the procedure, ovarian samples were collected from 10 women, aged between 25 and 39, who were undergoing elective caesarean section. Tissue pieces that showed no damage or abundant stromal tissue were dissected in the laboratory. A total of 87 fragments with follicles of a mean diameter of 40 μm were cultured for 8 days at 37°C in humidified air with 5% CO2 and renewing half the media every two days. Secondly, the growing follicles (presumably secondary follicles) were mechanically dissected and cultured individually for another 8 days in the same incubation conditions.
In the following step, those follicles with visible antral cavities were isolated, from which 48 oocyte-granulosa cell complexes were removed. These were then placed on a membrane with growth-supporting proteins for the next 4 days. A total of 32 complexes containing oocytes >100 μm in diameter showed significant oocyte growth and were selected for in vitro maturation. After 24 hours, only 9 emitted polar bodies and presented cumulus cell expansion. In their paper, the authors point out the larger size of these polar bodies compared to those from in vivo grown oocytes, suggesting the possibility that oocytes may have lost a valuable part of cytoplasm.
Finally, the team confirmed the proper organization of the polar bodies and the presence of a meiotic spindle in all 9 oocytes by confocal analysis, which supported the in vitro maturation process.
Although complete oocyte growth and maturation had been previously achieved in mice, this is the first time researchers have developed human oocytes all the way from their earliest stages up to the point at which they would be released from the ovaries in vivo. The authors point out that these oocytes were of low quality, which explains their low maturity and the low probabilities of resuming the meiotic division.
These results provide proof of concept in developing a complete in vitro growth system to support human oocyte maturation. However, there is a need to optimize each of the stages of development and to enhance our understanding of how culture systems affect the growth process, in particular the epigenetic status of any embryo derived from these eggs. Also, genetic analysis of the obtained oocytes is needed to confirm their healthy condition.
Despite these issues, researchers believe that this could represent a new approach for women whose oocytes fail to fully develop in their body or who need to undergo any sort of harmful treatment such as chemotherapy or radiotherapy, which can damage oocytes and cause infertility. It would also be an alternative for girls suffering from cancer who have not yet hit puberty. Because these patients cannot produce mature oocytes, cryopreservation and reintroduction of ovarian tissue may represent a valid option, but they imply a potential risk of reinserting cancer cells, too. In addition, it may be useful for women who experiment premature fertility loss and for low responders, whose follicles do not respond to external stimulation. Potential applications of this technique would aim to women who opt for in vitro fertilization treatments and whose oocytes are too immature to be used. Furthermore, it will help to understand the mechanisms involved in the development of human oocytes.
Definitely, there is a chance that the new technique could increase the total number of oocytes available for in vitro fertilization and a woman’s odds of conceiving. Much more work is needed though to make sure the technique is safe before it can be ascertained whether these oocytes remain normal during the process, and if they could actually lead to healthy live births once fertilized.
1. McLaughlin M, Albertini DF, Wallace WHB, Anderson R, Telfer E. Metaphase II oocytes from human unilaminar follicles grown in a multi-step culture system. Mol Hum Reprod. 2018;1-8.
Author: Javier Del Río Riego
One of the scientific advances made in recent years is 3D printing of human organs. The creation of an organ from a suitable material often allows medical doctors to decide on the best way to perform a surgical procedure. In addition, it opens up new possibilities for the use of 3D printing technologies in organ transplant programs. Now, researchers from Northwestern University Feinberg School of Medicine and McCormick School of Engineering have developed prosthetic ovaries made of gelatin, which allowed mice to conceive and give birth to healthy offspring.
The bioprosthetic ovaries are constructed of 3D-printed scaffolds that house immature eggs, and have been successful in boosting hormone production and restoring fertility in mice. The material used for building up these ovaries is a biological hydrogel made from decomposed collagen naturally found in animal ovaries. This material is degradable to allow cellular remodelling, contains cell adhesion sites and shows soft durable mechanical properties. Scientists built the ovaries by printing various patterns of overlapping gelatin filaments on glass slides. Modulating the distance between these filaments, as well as the advanced angle between layers, allowed for the generation of different pore sizes and geometries.
The ovaries are referred to as "bioprosthetic" organs because they contain both living material (ovarian cells) and nonliving material (gelatin). They release hormones in the same way a normal ovary would, allowing the animal to go through its natural cycle, including ovulation. Also, this scaffolding needed to be made of organic materials, stiff enough to be handled during surgery and sufficiently porous to interact naturally with the tissues of the mouse body. In the study, after having placed the biosynthetic ovaries in the mouse, 40-50 follicles were carefully implanted into each scaffold.
Vascularization in the ovary is critical because it provides oxygen and nutrients to the follicles, and because it allows follicle-produced hormones to circulate in the blood stream. Since gelatin is a natural material, the body can recognize the implant as a regular body part and allows blood vessels to grow into it.
Although mice had been sterilized by the removal of both ovaries, the reproductive tract (including the oviduct), had been left intact to assess fertility through natural mating after the surgical introduction of the 3D-printed organs. The study culminated in the pairing of a dozen female mice, two mice with sham controls (bioprosthetic ovary without follicles) and seven mice with bioprosthetic ovaries were mated with males who had previously sired pups. Three bioprosthetic ovary recipients had litters of one or two pups each, while none of the sham controls had pups. In all cases, the mothers produced milk to feed them.
FUTURE APPLICATIONS IN HUMANS
Researchers hope in particular to help cancer survivors whose treatments had damaged their ovaries. The 3-D printed bioprosthetic scaffold can be repopulated using patient's previously extracted own follicles or donated samples from ovarian tissues. Another possible use would be helping women with impaired ovaries, so that symptoms of menopause could be alleviated. Rather than using synthetic hormones, which often entail unpleasant side effects, women could have an all-natural source of hormones implanted directly into her body.
The team is now preparing a similar trial on pigs, which are closer to humans in size and biology. They believe that it might be a challenge to scale up the 3D-printed structure to the size needed for human use.
Original publication: Laronda MM, Rutz AL, Xiao S, Whelan KA, Duncan FE, Roth EW et al. A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nat Commun. 2017; 8:15261.
(1) Available from: http://www.npr.org/sections/health-shots/2017/05/20/528646323/scientists-one-step-closer-to-3-d-printed-ovaries-to-treat-infertility. [Cited 22 May 2017].
Authors: Shuyana Deba Rementeria, Javier Del Río Riego and Sara Sanz Juste
Since 2015, the fertility-related company OvaScience from Canada has recently launched a new technique called AUGMENT, which has resulted in high controversy around the world.
WHAT IS AUGMENT?
It is a new IVF technique designed to improve women’s oocyte quality.
How does it work? Through this technique, doctors have to biopsy tissue from the lining ovaries of a woman normally under general anaesthesia, the entire procedure being performed via laparoscopic surgery. Then, samples are transported to the OvaScience laboratory, where the mitochondria from egg precursor cells are isolated and subsequently transferred through ICSI into a mature egg, as well as the sperm.
Serving patients in a total of six countries: Canada, Spain, Japan, Panama, Turkey and United Arab Emirates.
What do you think about it? Do you think it is a useful technique? Would you offer this approach at your fertility clinic?
You can read more about OvaScience and their treatments in the following links. If you cannot find any paper, let us know and we will send it to you.
In the scientific area:
Fakih M. The AUGMENTSM Treatment: Physician Reported Outcomes of the Initial Global Patient Experience. Journal of Fertilization: In Vitro - IVF-Worldwide, Reproductive Medicine, Genetics & Stem Cell Biology. 2015;03(03).
Couzin-Frankel J. Eggs unlimited. Science. 2015;350(6261):620-624.
Imudia A, Wang N, Tanaka Y, White Y, Woods D, Tilly J. Comparative gene expression profiling of adult mouse ovary-derived oogonial stem cells supports a distinct cellular identity. Fertility and Sterility. 2013;100(5):1451-1458.e2.
Woods D, Tilly J. Isolation, characterization and propagation of mitotically active germ cells from adult mouse and human ovaries. Nature Protocols. 2013;8(5):966-988.
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