Scientists from Great Ormond Street Hospital (GOSH) and University College London (UCL) have created the first lab‑grown oesophagus - 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 towards personalised regenerative treatments for children born with life threatening oesophageal 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 today in Nature Biotechnology the study shows for the first time that a pig donor oesophagus can be decellularised, 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 3 months. Immunosuppression was not needed as the implant was developed using the recipient's cells and the tissue grew with the animals. [1]
The oesophagus, also known as the 'food-pipe', is crucial for nutrition and growth. Children born with long-gap oesophageal atresia (LGOA) have an interrupted oesophagus, with a wide gap between the upper and lower segments. GOSH is a leading site to treat malformations linked to oesophageal 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. Thanks to significant funding from Great Ormond Street Hospital Charity (GOSH Charity), including the Oak Foundation, LifeArc and the Francis Crick Institute, this research has been driven forward to identify different and better options, and bring hope to more families.
A personalised, 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 oesophagus, which is very similar to a human's. Through a process called decellularisation, 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 6-month mark, the lab-grown grafts had developed functional muscle, nerves, and blood vessels. This allowed the transplanted oesophagus 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. [2]
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 oesophagus were in line with what would be expected in 'natural' tissue. There was also a progressive regeneration of normal oesophageal structures, with a barrier layer, muscle, nerves and blood vessels needed for a functioning oesophagus. The engineered oesophagus 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 personalised 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 personalised graft that would grow with the child and not require immunosuppressants.
Hope for families
Casey Mcintyre from London is a bubbly 2 year-old, who loves his dog, Daisy. You would never be able to tell that he needed so many operations in his short life.
Mum, Silviya (38) said: "We had several scans before Casey was born so we knew he had issues with his food pipe but it was still very worrying to find out he was born with 11cm of it missing. He's had major operation after major operation as we simply couldn't get the gap to close using his own tissue. After being referred to GOSH we had the best option at the time – pulling up his stomach to close the 'gap' but it's been a long road and he still has a feeding tube while he develops his swallowing.
"The repeated surgeries have left him with some damage to his vocal cords so he's developing his speech and noise-making to catch up. Once he's eating enough through his mouth, we'll be able to take his tube out."
Dad, Sean (35) said: "People can never tell Casey has spent half of his life in hospital, and hopefully he won't remember, but the memories will never leave us.
"We've had to learn things as new parents that we never considered would be part of our family life, from feeding him through a stomach tube to what to do if the hospital call with an urgent update in the middle of the night.
"To look at him, he's just amazing and we are very proud of him. Whatever the team did for him was really a miracle but the idea that there could be one operation early in your child's life, that could transplant a working piece of oesophagus, and then we could move on would be life changing."
Professor Paolo De Coppi, NIHR and Nuffield Professor of Paediatric Surgery at UCL Great Ormond Street Institute of Child Health (UCL GOS ICH) and Consultant Paediatric Surgeon at GOSH led the research team. He said: "The oesophagus 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 oesophagus 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 5 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 oesophagus, 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 recognised 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, paediatric 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." Dr Durkin's work was supported by GOSH Charity via a Lewis Spitz surgical scientist PhD studentship.
Professor De Coppi is Co-Theme Lead of Tissues and Regenerative Medicine at the NIHR GOSH Biomedical Research Centre 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 humanised 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 Programmes, 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. At GOSH Charity, we want every child treated at GOSH to have the best chance, and best childhood possible, and providing funding for key projects like this one, demonstrates the impact innovative research can have on those that need it most."
Next steps
The team is now refining the process to generate longer grafts, standardise manufacture and reduce manual steps, and carry out further safety testing. Further studies will focus on tracking the cells on the tissue, optimising 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 5 years.
All research at GOSH is supported by the NIHR GOSH Biomedical Research Centre but the NIHR did not directly fund the animal research.
