Title: FOOD Fabricating OesOphagus for Digestion: Regenerative Medicine application to congenital oesophageal malformation (long-gap oesophageal atresia)
Funder: Department of Health and Social Care

Abstract: 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

Lay abstract: Oesophageal atresia (OA) is a condition in which part of the gullet is absent at birth. It occurs in about 1 out of 3,500 births, and often cannot be repaired by simply surgically joining the upper and lower parts of the gullet. In such cases, alternative therapies are technically challenging and may have severe complications and poor quality of life. This project aims to build and test an artificial gullet as a treatment for children with this condition. An effective, one-off therapy would benefit children and families affected by this condition, as well as have cost savings for the NHS.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL