Around 240 babies born in the UK each year are missing part or all of their oesophagus, a condition called long-gap oesophageal atresia that leaves them unable to feed by mouth. Current surgical repairs often fail, condemning children to repeated operations, hospital stays, and lifelong feeding tubes. The NHS and families bear immense costs, both financial and emotional. No long-term cure exists. This project aims to change that by growing a functional replacement oesophagus in the lab. The team has already succeeded in transplanting lab-grown tracheas into children. Now they plan to apply the same approach to the oesophagus: take a donor or synthetic scaffold, seed it with the baby’s own muscle, nerve, and lining cells, and nurture the construct in a bioreactor until it is ready for surgical implantation. If the technique works, it would offer a one-time, life-saving repair for these infants. The same method could later treat children and adults who lose their oesophagus to caustic burns or cancer. It could also be adapted to rebuild other parts of the gut, such as the small bowel, opening a new branch of regenerative surgery for the digestive tract.
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Background As an academic paediatric surgeon, I often deal with the devastating effects of congenital malformations. Long-gap oesophageal atresia is a congenital medical condition caused by abnormal embryological development of the oesophagus, affecting approximately 240 babies born in the UK annually; a number that is increasing [1]. Infants are unable to feed by mouth resulting in ongoing health implications such as recurrent endoscopies, operations, hospital admissions and communication difficulties. Family life is severely impacted as infants may require full time care. Current available treatment options are ineffective with no prospect of a long term cure. Lifetime costs to NHS and society are immense. Following our success with tracheal tissue engineering in humans [2], I am uniquely placed to translate regenerative medicine for the oesophagus [3]. Plan of investigation: The overall goal of this professorship is to translate a tissue engineered functional oesophagus into patients the timeframe of the project. The novel advanced therapeutic medicinal product (ATMP) has been developed in the animal model by our team in the last few years, by combining decellularised scaffolds with tissue stem cells in order to create a robust graft with structural and functional competence. Specifically autologous muscle cells (mesangioblasts), neural crest cells and oesophageal epithelial cells will be seeded respectively onto a decellularised scaffold derived from a cadaver or onto an acellular, engineered conduit. The engineered construct will be maintained in bioreactors specifically developed to allow cell seeding and expansion. The technology developed will support a Phase I trial in patients who underwent unsuccessful reconstruction and the subsequent Phase II clinical trials in patients with long-gap oesophageal atresia. Benefits: This project aims to ultimately create a life-transforming and life-saving new therapy for babies born without a complete oesophagus. If successful, the new treatment will have profound implications, also helping individuals who have lost their oesophagus as a result of caustic ingestion or other trauma (children and adults) or cancer (adults). Moreover, using similar techniques, tissue engineering of other parts of the gut such as the small bowel will also be possible and the results obtained will ultimately translate to older children and adults with other congenital or acquired disease of the gastrointestinal tract. References: 1.Ron O, De Coppi P, Pierro A (2009) The surgical approach to esophageal atresia repair and the management of long-gap atresia: results of a survey. Semin Pediatr Surg 18: 44-49. 2. Elliott MJ, De Coppi P, Speggiorin S, Roebuck D, Butler CR, et al. (2012) Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 380: 994-1000. 3. Zani A, Pierro A, Elvassore N, De Coppi P (2009) Tissue engineering: an option for esophageal replacement? Semin Pediatr Surg 18: 57-62
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