Lab-grown food pipe offers hope for children with esophageal condition

Scientists at Great Ormond Street Hospital (GOSH) and University College London (UCL) have created the first laboratory-grown esophagus – the food pipe – that is able to safely replace an entire part of the organ and restore normal function, including swallowing, without the need for immunosuppression in a growing animal.

This is a major leap toward personalized regenerative treatments for children born with life-threatening esophageal conditions and may pave the way for translation to other disease areas. Other studies have shown parts of this technique before, but this is the first time the entire process has been accomplished with such success.

Published today in nature biotechnology The study shows for the first time that a pig donor esophagus can be decellularized, repopulated with the recipient pig’s own cells, and transplanted into a growing, large-animal model to restore function without the need for immunosuppression. Eight recipient animals recovered well, with complete integration of the engineered tissue within 3 months, developing swallowing muscles that function to squeeze food toward the stomach. Immunosuppression was not required because the transplant was developed using the recipient’s cells and the tissues were grown with the animals.

The esophagus, also known as the ‘food pipe’, is important for nutrition and development. Children born with long-gap esophageal atresia (LGOA) have an disrupted esophagus, with a large gap between the upper and lower segments. GOSH is a leading site treating disorders associated with oesophageal atresia (OA), approximately 180 babies are born with OA each year in the UK, of which 10% have LGOA.

Babies born with LGOA may not survive without surgery, but the difference is often too large to correct immediately after birth. Instead, babies with LGOA typically require a feeding tube placed directly into their stomach, providing them with adequate nutrition while their hospital teams develop a treatment plan. Current surgical options are complex and invasive. One approach involves realigning the stomach or intestine to bridge the gap, both major operations with significant short- and long-term complications, including breathing and gastrointestinal problems and unknown long-term cancer risks.

While many children achieve good outcomes, there is a strong need for better options with lower risk of complications for these infants. Thanks to vital funding from Great Ormond Street Hospital Charity (GOSH Charity), including the Oak Foundation, LifeArk and the Francis Crick Institute, this research has been taken forward to identify different and better options and bring hope to more families.

A personalized, regenerative solution

The first step in this new technique is to create a scaffold, which acts as a tube-shaped base for the new organ. Scientists use the esophagus of a donor pig, which is identical to that of a human. Through a process called decellularization, the donor tissue is carefully removed of all pig cells, while leaving the underlying support structure intact.

Next, the scaffold is repopulated with muscle cells taken from a small biopsy of the recipient pig. These cells are multiplied in the laboratory and then injected directly into the scaffold. The graft is then placed in a bioreactor, a special container that pumps vital growth fluids through the tissue for a week. During this time, the cells settle down and proliferate, and they adapt to their new ‘home’. Overall, the procedure takes two months to complete, which is compatible with the current standard treatment of LGOA.

Research with pigs has now shown very encouraging results, providing a blueprint for human treatments. All eight animals survived in critical condition for the first 30 days after transplantation. By 6 months, the lab-grown graft had developed functional muscles, nerves and blood vessels. This allowed the transplanted esophagus to contract and move food like the native esophagus. Transplanted animals can eat normally and grow at a healthy rate. While some developed strictures, these were successfully managed through endoscopy, mirroring routine human clinical practice.

For the first time, this research team was able to map genes in the structure of the transplanted tissue (using a technique called spatial transcriptomics), to show that the genes turned on in the new esophagus were consistent with those expected in ‘natural’ tissue. Progressive regeneration of normal esophageal structures also occurred, including the barrier layer, muscles, nerves, and blood vessels necessary for a functioning esophagus. The engineered esophagus was shown to contract, generating movement and pressure with sufficient strength and coordination to allow normal swallowing.

If this technology is adapted for use in humans, scaffolds of different sizes derived from donor pigs could be kept ready to be developed and personalized, whenever needed, for newborns or children of different sizes and ages. When the feeding tube is placed, biopsy cells can be taken from the baby and incorporated into the scaffold in exactly the same way as described in this research – creating a personalized graft that will grow with the baby and will not require immunosuppressants.

hope for families

Casey McIntyre from London is a bubbly 2-year-old who loves his dog Daisy. You will never be able to tell how many operations he needed in his short life.

Mum, Sylvia (38) said: “We had a series of scans before Casey was born, so we knew there was a problem with his esophagus, but it was still very worrying to find out he was born with an 11cm gap. He had major operation after major operation because we couldn’t close the gap using his own tissue. After being referred to GOSH we had the best option at the time – to close the ‘gap’ Pulling his stomach up, but it was a long road and he still had a feeding tube when he developed swallowing.

“There’s been some damage to his vocal cords due to repeated surgeries, so he’s developing the ability to speak and make noises. Once he gets enough food through his mouth, we’ll be able to take his tube out.”

Father, Sean, 35, said: “People can never tell that Casey has spent half her life in hospital, and hopefully they won’t remember, but the memories will never leave us.

“As new parents we had to learn things we never thought would be part of our family life, from feeding him through a stomach tube to what to do if we got a call in the middle of the night from the hospital asking for an urgent update.

“To see him, he’s absolutely amazing and we’re so proud of him. What the team did for him was truly a miracle, but the idea that your child can have an operation so early in life, to transplant a functioning piece of the esophagus, and then we can move on, will be life-changing.”

Professor Paolo De Coppi, Nuffield Professor of Pediatric Surgery at the NIHR and UCL Great Ormond Street Institute of Child Health (UCL GOSH ICH) and consultant pediatric surgeon at GOSH, led the research team. He said: “The esophagus is actually a complex organ, with no blood supply from its own vessels, so it cannot be ‘transplanted’ in the way you might expect. To develop alternatives, it is necessary to work with animal models that closely reflect human anatomy and function. In this respect, the pig esophagus closely resembles the human one. With the success of this research, we hope that we will be able to develop alternative models for those children within 5 years.” can successfully offer an engineered tissue alternative to those who desperately need it.”

Dr Marco Pellegrini, senior researcher at UCL GOS ICH, who is co-leading the study, said: “Our technique could allow us to create a new esophagus for a child, using their own cells, collected at the surgery they are having, combined with a scaffold made from pig tissue. Because the graft contains the child’s own muscle progenitor cells, it will be recognized as their own tissue. This means That it can grow with them over time without the risk of rejection and the need for long-term immunosuppression.”

Dr Natalie Durkin, pediatric surgical registrar and lead author of the study from GOSH and UCL GOSH ICH, said: “After successful transplantation, our grafts grew, matured and began to function like the native tissue. Each of these steps represents a significant milestone in being able to provide this as a viable treatment option for children in the near future.” Dr Durkin’s work was supported by the GOSH Charity through the Lewis Spitz Surgical Scientist PhD Studentship.

Professor Di Coppi is co-theme lead of Tissue and Regenerative Medicine at the NIHR Gosh Biomedical Research Center and said: “For more than 50 years, pig heart valves have been used to extend and save the lives of patients with heart disease, and this technique has now become commonplace in cardiac surgery. More recently, xenotransplantation has been explored in humans as a potential solution to organ shortage. In our work, we use that pig “Having demonstrated that tissue, once stripped of all cellular content, can serve as a scaffold to engineer humanized tissue that is completely bio-compatible, I believe we now stand at a similar new frontier in regenerative medicine.”

Aoife Regan, Director of Impact and Charitable Programs at GOSH Charity, said: “We are thrilled to see the success of this research, which gives more hope to children with highly complex and rare conditions, which can significantly impact their quality of life and childhood. At GOSH Charity, we want every child treated at GOSH to have the best chance, and the best childhood possible, and funding is available for major projects like this. “It shows how much impact innovative research can have on those who need it most.”

next steps

The team is now refining the process to generate longer grafts, standardize manufacturing and reduce manual steps, and conduct further safety testing. Further studies will focus on tracking cells on tissue, optimizing blood flow, and preparing the therapy for first-in-human trials. The team hopes that it can be introduced as a research trial in the next 5 years.

All GOSH research is supported by the NIHR GOSH Biomedical Research Center but the NIHR does not directly fund animal research.