Abstract (as presented by the authors of the scientific work):
"Emerging additive manufacturing techniques enable investigation of the effects of pore geometry on cell behavior and function. Here, we 3D print microporous hydrogel scaffolds to test how varying pore geometry, accomplished by manipulating the advancing angle between printed layers, affects the survival of ovarian follicles. 30° and 60° scaffolds provide corners that surround follicles on multiple sides while 90° scaffolds have an open porosity that limits follicle-scaffold interaction. As the amount of scaffold interaction increases, follicle spreading is limited and survival increases. 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."
Covered topics (the letter size corresponds to the frequency of mentioning in the text):
Discussion (as presented by the authors of the scientific work):
"In this work, we investigated how scaffold pore geometry affected the growth and maturation of ovarian murine follicles as well as developed a bioprosthetic ovary that restored ovarian function in vivo in mice. 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 encapsulation22,23. The techniques developed here are the necessary first steps to validate the significant undertaking of exploring such an approach for creating a human bioprosthetic ovary.
Importantly, we accomplish on-platform ovulation through a biomaterial that did not require mechanical manipulation or digestion of the material to release an egg. Mechanical manipulation or enzymatic digestion of the biomaterial may impact the health of the generated egg and therefore reducing intervention by using our scaffolds may be more desirable for future in vitro fertility applications such as in vitro fertilization. Furthermore, live birth was achieved with the implant alone; angiogenic growth factors, hormone stimulation and embryo transfer were not required18,19,51,57,58. Since exogenous hormones were not given to the animals, ovulation was triggered endogenously which depends on estradiol and inhibin production from the follicles seeded within the implanted bioprosthesis59. Subsequent events also signified that the bioprosthetic ovary was an active participant in the reproductive axis in vivo, including ovulation of a healthy egg through the scaffold, and progesterone production from the remaining CL to produce a receptive uterine wall and stimulate lactation. The resulting pups from the bioprosthetic ovary developed normally with their own reproductive competency, as they were all able to sire or deliver healthy litters. These results highlight the high functionality of our bioprosthetic ovary using a scalable and adaptable method.
In future years, the 3D printed bioprosthetic scaffold can be repopulated with ovarian tissues (either native or iPS derived)60. The advantage of 3D printing is the opportunity to scale the size of the tissue to the size needed for the transplant recipient (e.g., for a child who is transitioning through puberty or for an adult). Furthermore, the construct could be printed with embedded vasculature to help alleviate nutrient demands in large (multi-cm) tissues. With these first steps presented here, the use of 3D printing will allow for new investigations in reproductive biology. For example, varying stiffness with multi-material printing as well as varying pore size can be used to create a construct that separates quiescent and growing follicle pools, which is necessary for transplant longevity and continued hormone cyclicity61,62. Future studies will require optimizing the number of cells transferred to the scaffold and the assessment of durable function; these studies are ongoing. While additional experimentation is required to establish that human folliculogenesis will be supported in a similar manner as the mouse follicles shown here, and that the isolated follicles are free of cancerous cells, this bioprosthetic ovary may become a promising solution for restoring hormone and fertility function in oncofertility patients. Outside of reproductive biology, our findings will likely impact others developing tissue units and other spheroid cultures63, and underscore the importance of independently investigating the impact of architectural variables when designing scaffolds for other soft tissue and organ targets."
Full-text access of the referenced scientific work:
Laronda MM, Rutz AL, Xiao S, Whelan KA, Duncan FE, Roth EW, Woodruff TK, Shah
RN. A bioprosthetic ovary created using 3D printed microporous scaffolds restores
ovarian function in sterilized mice. Nat Commun. 2017 May 16;8:15261. doi:
10.1038/ncomms15261. PubMed PMID: 28509899.
https://www.nature.com/articles/ncomms15261
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