Prathik Somayaji

Article of Discussion: “A tissue-engineered uterus supports live births in rabbits“, Nature biotechnology, 2020, Renata S. Magalhaes, J. Koudy Williams, Kyung W. Yoo, James J. Yoo & Anthony Atala 

Why do we need Uterine Tissue Engineering?

The uterus is an essential organ involved in mammalian reproduction, it supports embryo implantation, houses the fetus and provides an interface for host-fetus interaction thereby aiding in fetal development. But what happens when the uterus is subjected to congenital anomalies or acquired diseases? These adversely affect the uterine integrity and significantly compromise its functionality. Did you know that approximately 6% of women having trouble conceiving are affected by uterine dysfunction? This often impairs the uterus’s ability to support implantation and pregnancy. It’s a real challenge, but there’s a promising bold idea of allogenic uterine transplantation. This involves transplanting a uterus from a donor. Faced with eminent challenges, like donor suitability, need for lifelong anti-rejection medications – successive damage to kidneys and may require a transplant if damage sustained – surgical complications, risk of infection, development of vaginal strictures amongst others. 

This is where the field of uterine tissue engineering steps in—with a bold idea:

 What if we could build a uterus from scratch using the patient’s own cells? 

Scientists are actively developing innovative solutions and pioneering the creation of tissues and organ substitutes from the patient’s own cells, meticulously blended with compatible biomaterials. This approach significantly reduces the likelihood of the body rejecting the transplant and the subsequent transmission of diseases. This promising advancement holds great potential in the ongoing battle against infertility stemming from uterine dysfunction.

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How Do You Build a Uterus?

Creating an artificial uterus begins with a structure called a scaffold—a porous, 3D mold that mimics the natural shape and tissue architecture of the uterus. This scaffold acts like a framework that supports the growth of new cells and tissues.

Numerous studies have demonstrated and found success in using nanofibers composed of Polycaprolactone (PCL) for uterine muscle cells to grow and develop into smooth muscles. This is because they possess structural similarities and emulate the environment conducive to the growth and functioning of smooth muscles found within the uterus. Other biocompatible and biodegradable materials like collagen, cellulose, and PLGA-coated PGA are also commonly used.

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What Did the Research find?

In a study by Magalhaes et al., 2020, semicircular scaffolds of PLGA-coated PGA, were seeded with a woman’s own uterine cells in a bold attempt to engineer the uterus. These scaffolds developed tissue layers that closely resembled the endometrium and myometrium—the inner and middle layers of the uterus. The results? Rabbits implanted with these tissue-engineered uterine segments were able to carry pregnancies to term, even delivering live offspring—a major milestone in reproductive medicine [1]. 

A functional tissue-engineered construct must satisfy three essential criteria:

1. Structural mimicry – Does the construct replicate the native tissue architecture with relevant anatomical features?
2. Biological similarity – Does the construct reflect native tissue characteristics, including cellular heterogeneity and extracellular matrix (ECM) composition?
3. Physiological function – Does the construct perform the same functions as native tissue, particularly in supporting implantation, gestation, and tissue remodeling?

On this basis, the key findings were:

Structural mimicry: 

• The engineered scaffolds formed a dual-layered smooth muscle structure—an inner circular and outer longitudinal layer—closely resembling the native uterus.
• The constructs developed native-like epithelial crypts, endometrial glands, and vascular structures, mimicking the structural complexity of a functional uterus.
• The endometrial thickness in the engineered tissues was significantly increased, similar to that of native endometrium.
• One-month post-implantation, the scaffold material partially degraded while preserving the luminal cavity and maintaining overall uterine architecture.
• By six months, there were no discernible histological boundaries between the native uterus and the implanted scaffold, indicating excellent tissue integration.
• Scaffold dimensions were crucial—smaller, semicircular grafts maintained their shape and supported function, while larger grafts collapsed or twisted..

Biological Similarity:

• The inner epithelial layer displayed cuboidal and elongated cells expressing cytokeratin (AE1/AE3) and vimentin, markers indicative of epithelial identity and structural support.
• The outer muscular layer yielded spindle-shaped smooth muscle-like cells that expressed smooth muscle actin, myosin, and calponin—essential components of contractile smooth muscle tissue.
• The collagen content in the engineered tissues was more comparable to that of native uterus than in non-cell-seeded controls.
• The constructs supported blood vessel formation and glandular density, reflecting native tissue heterogeneity.
• Hormone receptor expression (estrogen and progesterone receptors) was present, indicating hormonal responsiveness similar to a healthy endometrium.

Functional Capability:

• Rabbits receiving the cell-seeded scaffolds successfully conceived, carried pregnancies to term, and delivered live offspring—a landmark achievement in functional uterine engineering.
• Non-cell-seeded scaffolds failed to support fetal development, confirming the necessity of cellular integration for function.
• The engineered uteri supported stretch-induced tissue expansion up to 10 times their original size and weight, essential for accommodating fetal and placental growth.
• While the number of fetuses per pregnancy was slightly lower than normal, overall reproductive function was restored.
• The presence of functional hormone receptors facilitated endometrial receptivity, crucial for implantation and pregnancy maintenance.

Fig: The scaffold was made out of nano fibers of PGA/PLGA and was able to host a fetus rabbit when implanted in-vivo at the uterine horn via 6-0 vicryl sutures which also serve as demarcation marker to separate host tissue from the bioengineered tissue.

What are the limitations and what is next?

While this research is incredibly promising, there are still hurdles ahead:

• Despite these advancements in bioengineering, uterine tissues have achieved a level of complete functional uterus is very rare.
• This study focuses on rabbit models, which exhibit an oestrous cycle, in contrast to humans, who undergo a menstrual cycle. Does this disparity in reproductive cycles influence pregnancy outcomes? Consequently, it is imperative to extrapolate the findings of this study to human trials.
• A comprehensive evaluation is required to assess the long-term reproductive outcomes and the multiple pregnancy cycles induced by the implanted conduits.
• If the aforementioned conduct were to be employed for women experiencing recurrent implantation failure, while simultaneously possessing a substantial ovarian reserve, maintaining normal hormonal levels, and exhibiting genetically insignificant findings, it is pertinent to ascertain whether the cells obtained from the same patients would yield comparable outcomes.
• Instead of the invasive procedure of endometrial biopsy, could non-invasive approaches such as theutilization of menstrual blood stem cells be employed for the same purpose?

A Glimpse Into the Future

This groundbreaking work shows for the first time that a bioengineered lab-grown uterus can facilitate natural conception, gestation, and birth in a large animal model. If these results can be translated to humans, uterine tissue engineering could offer a revolutionary alternative to surrogacy and transplantation—potentially restoring fertility to millions of women worldwide.

Read the complete paper here.

References

[1]      R. S. Magalhaes, J. K. Williams, K. W. Yoo, J. J. Yoo, and A. Atala, “A tissue-engineered uterus supports live births in rabbits,” Nat Biotechnol, vol. 38, no. 11, pp. 1280–1287, Nov. 2020, doi: 10.1038/s41587-020-0547-7. *Article of discussion*

[2]      C.-Y. Kuo, H. Baker, M. H. Fries, J. J. Yoo, P. C. W. Kim, and J. P. Fisher, “Bioengineering Strategies to Treat Female Infertility,” Tissue Eng Part B Rev, vol. 23, no. 3, pp. 294–306, Jun. 2017, doi: 10.1089/ten.teb.2016.0385. *Cover image *