Bioengineered Tissues For Uterine Reconstruction

Summary Uterine-factor infertility affects up to 8.0% of infertile women, 13.3% of those with a history of miscarriage, 24.5% of those with miscarriage and infertility and 1:500 or 1.5 million women worldwide. The use of human allogeneic uterine tissues is a good option for uterine reconstruction, but its clinical use can be compromised by donor shortage, and immunologic complications. Alternatives are needed. Recently, we reported, in Nature Biotechnology, the application of autologous cell seeded-bioengineered uterine constructs for subtotal organ replacement in a rabbit model. The engineered constructs maintained luminal patency, developed native uterine tissue-like cellular and acellular structure and biomechanical properties; and supported embryo attachment, placentation, pregnancy, and full-term delivery of viable offspring following natural mating. While rabbits provide proof-of principle for this approach, they do not have a simplex uterus or monthly menstrual cyclicity. The most appropriate preclinical model that parallels the uterine structure and function of women are old-world monkeys who have a relatively thick simplex uterus, a monthly menstrual cycle including cycles of growth, differentiation, degeneration (menses), and regeneration during their reproductive life. Recently, we completed a series of tests using bioengineered implants that accommodate the thicker simplex uterus of NHPs and assessed structural maturation; but did not assess the contribution of seeded vs. peripheral cells and matrix production in structural regeneration, or their relationship to native uterine/endometrial biology and function. To this end, the goal of this study is to measure the ability of autologous cell-seeded polymer scaffolds to reproduce primate-like uterine tissue-like structure and function with significant surgically created uterine defects. The approach is to identify the cellular and acellular origin of structural and functional regeneration; thus exploring the biology of the regeneration process in these bioengineered implants. The clinical potential for successful treatment of uterine factor infertility includes repair of adenomyosis/adenomyomas and uterine fibroid resection; restoration of endometrial function in Asherman’s Syndrome; and reconstruction of normal uterine anatomy and function in women with congenital abnormalities. Aim 1 will assess the structural development of the seeded bioengineered implants and test the hypotheses that these implants develop native uterine tissue-like structure and size; consist of both labeled seeded myometrial/endometrial and peripheral cells that contribute cellular and acellular development similar to native tissue. Aim 2 will assess the functional development of bioengineered uterine constructs and will test the hypotheses that they develop biomechanical and contractile properties similar to that of native uteri; and functional endometrial markers consistent with normal uterine receptivity, implantation and pregnancy. These studies will translate the work done in rabbits to a primate model that is highly relevant in structure and physiology to that of women, and help us better understand the underlying biology of a bioengineering approach for treating uterine factor infertility.