by Mahaa Ahmed
figures by Jovana Andrejevic

Each of the organs in our body has an important role to play. So, what happens when one of them is damaged? For many years, one of the only solutions to an irreparably damaged organ was an organ transplant; however, the need for organs far exceeds the number of donors. Approximately 17 people die each day waiting for an organ transplant. But organ transplants, in addition to helping save lives, are sometimes also critical in helping bring about new life. For as many as 5% of reproductive-age individuals around the world, pregnancy is not an option to achieving parenthood because of an absent or damaged uterine tract, a condition called uterine factor infertility (UFI). UFI is a broad term that encompasses those that do not have a uterus or have impaired uterine function and therefore cannot conceive. Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, referring to congenital UFI, affects 1 out of every 4,500 women worldwide. Acquired UFI, on the other hand, refers to individuals who underwent hysterectomies or surgical removal of their uterus. While news articles and interviews have popped up over recent years describing successful childbirths following the lengthy process of a uterine transplant, such operations are still rare. Although uterine transplants from living or deceased donors have been the main focus over the past twenty years, tissue-engineered uteruses may provide another pathway to parenthood for those seeking alternatives to surrogacy, adoption, or foster parenting. 

Current treatment for UFI

While recent advances in medicine have allowed uterine transplants to begin to emerge as a viable option for treating those with UFI, as of late 2020, only approximately 100 uterine transplants have been done around the world. These transplants are comprised of three major surgeries in order to reach the ultimate goal of childbirth (Figure 1). As such, there are risks to all parties involved, including the organ recipient, the organ donor (if living), and the fetus. 

Figure 1. After an in-depth screening process, a series of medical evaluations, and identification of an organ donor, an individual can begin to prepare for a uterine transplant. Transplant surgery typically takes 5-8 hours. After successful transplantation, an embryo retrieved via in vitro fertilization is implanted into the uterus with hopes of pregnancy. After pregnancy is achieved, the baby is delivered via C-section. After 1-2 childbirths, the patient undergoes a hysterectomy. The entire process can take upwards of 3 years. 

The lengthy process of a uterine transplant begins with a series of medical evaluations and screenings. Once an individual is approved as a candidate for a uterine transplant, they undergo in vitro fertilization (IVF). During this process, ova (eggs) are retrieved from the patient, as those with UFI still have normally functioning ovaries that produce eggs; these eggs are then fertilized outside of the human body with sperm. Then, after a living or deceased donor is identified, their uterus is transplanted into the patient. Similar to patients who have had other organ transplant procedures, the organ recipient must then take immunosuppressive medications to make sure their body does not reject the organ. Depending on the health status and stability of the patient post-transplant, approximately six months later or once the uterus is fully healed, an embryo is implanted into the transplanted uterus with hopes of pregnancy. If pregnancy is achieved, then the patient is treated by a team of doctors specializing in high-risk pregnancies, as the patient continues to take immunosuppressive medications and must be monitored in case of organ rejection. Additionally, babies born from uterus transplant recipients have occasionally been born prematurely and therefore need to be closely monitored at neonatal units. 

Once the patient is ready to give birth, the baby is delivered via Cesarean section (C-section), a surgical procedure where an incision is made in the mother’s abdomen and uterus, because those with UFI cannot deliver vaginally. Current uterine transplant trials tend to allow participants to have up to two children in succession—given that the patient must remain on immunosuppressive medications throughout this lengthy process, support beyond two childbirths is not offered so that the patient can discontinue immunosuppressive drugs and reduce their long-term exposure to them as well. After having one to two children, therefore, the uterus is removed via hysterectomy. Although uterine transplants provide an opportunity for those with UFI to achieve parenthood, the process is lengthy, costly, and similar to those waiting for other vital organ transplants, tending to have a discrepancy between low supply and high demand. As such, there is a lot of interest in bioengineering uteruses to eliminate these limiting factors.

Small hops towards tissue-engineered uteruses

Although uterine transplants have resulted in at least sixteen live births around the world—six at Baylor University Medical Center, two at the Cleveland Clinic, and one at the University of Pennsylvania, tissue-engineered uteruses are another compelling option for individuals with UFI. The allure of bioengineered organs stems from the possibilities of providing greater accessibility, lower likelihood of transplant recipients experiencing organ rejection, and a potential decrease in waiting lists for organ transplants. By bioengineering an organ substitute from a patient’s own cells, the threat of organ rejection and susceptibility to infection can be reduced. Recent research aimed to demonstrate the feasibility of bioengineered uteruses in a model organism famous for reproduction: rabbits.

A group of researchers from the Wake Forest Institute for Regenerative Medicine recently reported successfully developing tissue-engineered uteruses for rabbits. Similar to how our own bodies are built on our skeletons, the size and shape of an organ is built upon a mesh-like scaffold. Therefore, to ensure proper shape and structure, the uterine tissue was developed using biodegradable scaffolds, which provide structural support for tissue development. The researchers could then adhere cells derived from an individual donor onto the scaffolds, tailoring the engineered uterus to the individual and reducing the likelihood of rejection.  

So, how exactly did the researchers implant these scaffolds into rabbits? To start, all rabbits had one of their uterine horns, the points where the uterus and fallopian tubes meet, removed. Unlike humans, female rabbits have bicornuate duplex uteruses or two separate uterine horns that each have their own cervices that open into one vagina—basically, each of these have the ability to carry pregnancy. As such, one of these horns was removed in order to develop a rabbit model that mimics the human female reproductive tract (depicted in the top panel of Figure 2). 

Figure 2. The top panel illustrates how rabbits of Experimental Groups #1-3 had one of their uterine horns fully excised and had the other horn partially excised, to create an area where the engineered scaffolds could be implanted. The Control Group was comprised of rabbits that were subject to a sham surgery in which their remaining uterine horn was not partially excised. Rabbits in Experimental Group #1 received scaffolds that were seeded with autologous cells, or cells from their own uterine tissue. Likewise, rabbits in Experimental Group #2 received scaffolds as well; however, these scaffolds were not seeded with their own cells. Finally, rabbits of Experimental Group #3 did not receive any scaffolds. They simply had their uterine edges stitched back together. 

Figure 2 illustrates the four different groups of rabbits tested in this study. Each of the rabbits from the three experimental groups underwent a partial excision of the other remaining uterine horn in order to create space for the bioengineered scaffolds to be implanted. These excisions were done to see if the implanted engineered uterine tissue could result in reconstruction and support live births. Unlike the experimental groups, rabbits in the control group underwent a sham surgery in which they did not actually have their remaining uterine horn partially excised. In Experimental Group #1, rabbits received a tissue-engineered scaffold made from their own cells, otherwise known as  autologous cells. Similarly, rabbits in Experimental Group #2 received a tissue-engineered scaffold; however, these scaffolds did not have any of the rabbits’ own cells. Rabbits part of Experimental Group #3 were not recipients of any bioengineered uterine tissue and simply had the edges of their partially excised horn sutured back together in order to simulate repairing the defect inflicted by the earlier partial excision surgery. 

Six months after rabbits underwent the various procedures and received their different scaffolds, only the rabbits of the control group and Experimental Group #1, in which rabbits received scaffolds with autologous cells, were able to support fertilization, fetal development, and live births. These findings, according to lead researcher Dr. Anthony Atala, have been 18 years in the making and provide a ray of hope for individuals with UFI. 

Looking towards the future

Although further research is needed before expanding bioengineered uteruses to human patients, tissue-engineered uteruses might soon become a clinical possibility. The potential for producing uterine tissue using patient-derived cells and biomaterials can circumvent many of the challenges associated with uterine transplants. In the meantime, however, more hospitals across the United States are looking to start uterine transplant programs and some, such as Baylor University, are even now providing them outside of research settings. Both options would allow individuals with UFI to pursue pregnancy and childbirth, something not thought to be possible until recently. 

Mahaa M. Ahmed is an Environmental Health MS student at the Harvard T.H. Chan School of Public Health

Jovana Andrejevic is a fifth-year Applied Physics Ph.D. student in the School of Engineering and Applied Sciences at Harvard University

Cover Image: “Uterus Anatomy Embroidery Hoop Art Wall Decor in Orange” by Hey Paul Studios is licensed under CC BY 2.0

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