Engineered tissue offers hope for children born with ‘missing’ esophagus

Scientists from Great Ormond Street Hospital (GOSH) and University College London (UCL) have created the first lab‑grown esophagus—the food pipe—shown to safely replace a full section of the organ and restore normal function, including swallowing, in a growing animal without the need for immunosuppression.

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

Published in Nature Biotechnology, the study shows for the first time that a pig donor esophagus can be decellularized, repopulated with the recipient’s pig’s own cells, and implanted in a growing, large-animal model to restore function without the need for immunosuppression.

The eight recipient animals recovered well, developed working swallowing muscles to squeeze food down towards the stomach, with full integration of the engineered tissue within three months. Immunosuppression was not needed as the implant was developed using the recipient’s cells and the tissue grew with the animals.

The esophagus is crucial for nutrition and growth. Children born with long-gap esophageal atresia (LGOA) have an interrupted esophagus, with a wide gap between the upper and lower segments. GOSH is a leading site to treat malformations linked to esophageal atresia (OA), with around 180 babies born with OA in the UK each year, 10% of which have LGOA.

Children born with LGOA cannot survive without surgery, but the gap is often too large to close immediately after birth. Instead, babies with LGOA typically require a feeding tube placed directly into their stomach, enabling adequate nutrition while their hospital teams develop a treatment plan.

The current surgical options are complex and invasive. One approach involves repositioning the stomach or the intestine to bridge the gap, both major operations with significant short- and long-term complications including breathing and gastrointestinal problems, and an unknown long-term cancer risk.

While many children achieve good outcomes, better options with reduced risk of complications are sorely needed for these babies. This research has been driven forward to identify different and better options, and bring hope to more families.

A personalized, regenerative solution

The first step in this new technology is to create a scaffold, which acts as a tube-shaped base for the new organ. Scientists use a donor pig’s esophagus, which is very similar to a human’s. Through a process called decellularization, the donor tissue is carefully stripped of all the pig cells, while keeping the underlying support structure intact.

Next, the scaffold is repopulated with a recipient pig’s muscle cells, taken from a small biopsy. These cells are multiplied in a lab 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 one week.

During this time, the cells settle and spread, and they adapt to their new “home.” In all, this process takes two months to complete, a timeline compatible with current standard treatment of LGOA.

Research with pigs has now shown very encouraging results, providing a blueprint for human treatment. All eight animals survived the critical first 30 days after transplant. By the six-month mark, the lab-grown grafts had developed functional muscle, nerves, and blood vessels. This allowed the transplanted esophagus to contract and move food like a native food pipe.

The transplanted animals could eat normally and grow at a healthy rate. While some developed narrowing (strictures), these were successfully managed through endoscopy, mirroring routine human clinical practice.

For the first time ever, this research team were able to map the genes in the structure of the implanted tissue (using a technique called spatial transcriptomics), to show that the genes turned on in the new esophagus were in line with what would be expected in “natural” tissue.

There was also a progressive regeneration of normal esophageal structures, with a barrier layer, muscle, nerves and blood vessels needed for a functioning esophagus. The engineered esophagus was shown to contract, producing movement and pressure with sufficient strength and co-ordination to allow normal swallowing.

If this technology is adapted for use in humans, different sizes of scaffold, derived from donor pigs, could be stored ready to be developed and personalized for newborns or children of varying sizes and age, whenever needed.

Biopsy cells could be taken from the child when the feeding tube is placed and incorporated into the scaffold in exactly the same way as described in this research—creating a personalized graft that would grow with the child and not require immunosuppressants.

Professor Paolo de Coppi, NIHR and Nuffield Professor of Pediatric Surgery at UCL Great Ormond Street Institute of Child Health (UCL GOS ICH) and Consultant Pediatric Surgeon at GOSH led the research team.

He said, “The esophagus is a really complex organ, without a blood supply from its own vessels, so it cannot be ‘transplanted’ in the way you might expect. To develop alternatives, it is essential 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 can be successfully offering an engineered tissue alternative to children who desperately need it within five years.”

Dr. Marco Pellegrini, Senior Researcher at UCL GOS ICH co-leading the study, said, “Our technology could allow us to build a child a new esophagus, using their own cells, collected in a surgery they are having anyway, combined with a ready-prepared scaffold from pig tissue. Because the graft contains the child’s own muscle progenitor cells, it would be recognized as their own tissue.

“This means it could grow with them over time, without the risk of rejection and without the need for long-term immunosuppression.”

Dr. Natalie Durkin, pediatric surgical registrar and lead author of the study from GOSH and UCL GOS ICH, said, “After successful implantation, our grafts grew, matured and began to function like native tissue. Each one of these steps represents a key milestone in being able to deliver this as a viable treatment option for children in the near future.”

Professor de Coppi is Co-Theme Lead of Tissues and Regenerative Medicine at the NIHR GOSH Biomedical Research Center and went on to say, “For more than 50 years, pig heart valves have been used to extend and save the lives of patients with heart disease, and this technology is now commonplace in cardiac surgery.

“More recently, xenotransplantation has been explored in humans as a potential solution to organ shortages. In our work, we demonstrate that pig tissue, once stripped of all cellular material, can serve as a scaffold to engineer humanized tissue that is fully biocompatible. I believe we are now standing at a similar new frontier in regenerative medicine.”

Aoife Regan, GOSH Charity’s Director of Impact and Charitable Programs, said, “We are thrilled to see the success of this research, which is offering more hope to children with a highly complex and rare condition, which can significantly affect their quality of life and childhood.”

Next steps

The team is now refining the process to generate longer grafts, standardize manufacture and reduce manual steps, and carry out further safety testing. Further studies will focus on tracking the cells on the tissue, optimizing blood flow and preparing the therapy for first-in-human trials. The team hope to be able to offer this as a research trial in the next five years.