The Groundbreaking UCL Study on Lab-Grown Esophagus

In a remarkable advancement from University College London (UCL) researchers, scientists have successfully engineered and implanted lab-grown esophagi into pigs, restoring their natural swallowing ability. This achievement, detailed in a recent Nature Biotechnology publication, marks the first time such a functional replacement has been demonstrated in a large animal model without the need for lifelong immunosuppression. Led by Professor Paolo De Coppi at the UCL Great Ormond Street Institute of Child Health (GOS ICH) in collaboration with Great Ormond Street Hospital (GOSH), the study addresses one of the most challenging congenital defects: long-gap esophageal atresia (LGOA).

Esophageal atresia (EA) occurs when the esophagus—the muscular tube that carries food from the mouth to the stomach—fails to develop properly, creating a gap that prevents normal swallowing. While EA affects about 1 in 2,500 to 4,000 live births globally, the long-gap variant, which constitutes around 10% of cases in the UK (approximately 18 babies annually), poses particular difficulties due to the extensive discontinuity. Babies with LGOA often require invasive surgeries early in life, highlighting the urgent need for innovative solutions from academic research institutions like UCL.

Challenges of Current Esophageal Atresia Treatments

Traditional management of LGOA involves complex procedures such as gastric pull-up, where the stomach is repositioned to connect the mouth to the digestive tract, or colonic interposition, using a segment of the colon to bridge the gap. These interventions carry significant risks, including gastroesophageal reflux, anastomotic leaks, strictures, and long-term complications like respiratory issues and potential malignancy. Survival rates have improved to over 90% in high-volume centers, but quality of life remains compromised, with many patients reliant on feeding tubes into adulthood.

Complications occur in up to 57% of cases within the first year post-repair, including recurrent strictures requiring repeated dilations. In low birth weight infants, in-hospital mortality exceeds 10%, and length of stay is prolonged. These challenges underscore the value of university-led regenerative medicine research, where tissue engineering offers a personalized, growing alternative tailored to pediatric patients.

The Science of Decellularization and Recellularization

The core innovation lies in tissue engineering: creating a bioengineered esophagus (bioengineered esophageal graft) from a decellularized scaffold. Researchers begin with donor pig esophagi, nearly identical in structure to human ones, and apply a detergent-enzymatic treatment (DET). This 10-day process uses 4% sodium deoxycholate perfusion, DNase I digestion, and rinsing to strip all cellular material while preserving the extracellular matrix (ECM)—collagen, elastin, and glycosaminoglycans—that provides structural integrity.

Next, autologous cells from the recipient pig are harvested via a simple biopsy of the rectus abdominis muscle and sheath. These yield mesoangioblast-like myogenic precursors (MABs)—pericyte-like cells expressing CD146, CD44, CD90, and CD56—and fibroblasts (FBs). In a 7:3 ratio, 120 microinjections (30 µl each, 1×10⁵ cells/µl) deliver them subadventitially into the scaffold. The graft matures in a bioreactor for one week under dynamic flow, upregulating proangiogenic genes like VEGFA and HIF1A, preparing it for vascular integration.

Implantation Procedure and Pig Model Rationale

Minipigs weighing 10 kg, mimicking newborn human size, underwent thoracotomy to resect a 2.5-cm circumferential esophageal defect. The graft was anastomosed end-to-end, supported by a biodegradable polydioxanone stent and a pleural wrap to promote vascularization from surrounding tissues. No immunosuppression was required, as the autologous cells prevent rejection. Pigs began oral feeding immediately—water on day 0, progressing to textured food—mirroring clinical protocols.

Pigs were selected for their physiological similarity to humans: comparable esophagus size, peristaltic mechanics, and growth patterns. This large-animal model bridges the gap from prior rodent and rabbit studies, providing robust preclinical data essential for regulatory approval.

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Impressive Results: Function and Regeneration

All eight pigs survived the first 30 days, with 63% (5/8) reaching the 6-month endpoint. Growth matched native curves, and swallowing was restored via secondary peristalsis, confirmed by high-resolution impedance manometry (HRIM) using saline/air boluses—mean duration 7.2 seconds. Ex vivo contractility tests showed dose-dependent responses to electrical stimulation (5-20 Hz) and carbachol (1-10 µM).

• Progressive neuromuscular regeneration: Smooth (αSMA, SM22) and skeletal muscle (MF20), nerves (PGP9.5, nNOS), and vessels increased over time.
• Histology revealed layered architecture: stratified squamous epithelium (p63, involucrin), muscularis mucosa, submucosa, and muscularis externa.
• Spatial transcriptomics (ST) and single-nucleus RNA-seq recapitulated native gene profiles, with reduced fibrosis by 6 months.
• Morbidities like polyps (n=10) and strictures (n=8) were endoscopically managed, akin to human EA repairs.

These outcomes demonstrate the graft's ability to mature in vivo, supporting normal alimentation without enteral supplementation.

Expert Perspectives on the Breakthrough

Professor Paolo De Coppi emphasized the pig model's relevance: “The pig oesophagus closely resembles the human one.” Dr. Marco Pellegrini highlighted personalization: “Using the child’s own muscle progenitor cells... it would be recognised as their own tissue.” Dr. Natalie Durkin, lead author, noted maturation: “Our grafts grew, matured and began to function like native tissue.”

Prof. Dusko Ilic (King’s College London) praised functional integration but cautioned on growth claims, noting persistent fibrosis and need for long-term studies. Andrew Barbour (University of Queensland) called it “impressive,” observing scar reduction over time. This balanced academic discourse reflects rigorous peer scrutiny.

Path to Human Trials and Clinical Translation

The 8-week production timeline fits neonatal treatment windows. UCL plans clinical trials within five years, refining automation, longer grafts, and cell tracking. For humans, cryopreserved human scaffolds or porcine ones with patient-derived MABs/FBs could enable off-the-shelf solutions that grow with the child. Funded by GOSH Charity and NIHR, this exemplifies translational research from university labs to bedside. Read the full study in Nature Biotechnology here.

Patient stories, like Casey Mcintyre’s family, underscore impact: multiple surgeries and feeding tubes could be replaced by one regenerative graft.

Historical Context in Esophageal Tissue Engineering

Esophageal tissue engineering milestones include 2014's human/mouse cell implants, 2018's polyurethane grafts in pigs showing remodeling, and 2022's Cellspan implants. This UCL work advances multi-layered, autologous constructs, overcoming stent dependence and poor muscle regeneration. Universities drive this field, from scaffold innovations to bioreactor conditioning.

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Implications for Regenerative Medicine and Academia

Beyond EA, this could treat strictures from cancer or caustic injury. It highlights stem cell therapy's potential in hollow organs, fostering interdisciplinary university collaborations (surgery, bioengineering, genomics). For more on research careers, explore opportunities at leading institutions. UCL's success positions UK higher education as a regenerative medicine hub. Detailed UCL press release here.

Expert reactions via Science Media Centre provide further insights here.

Future Directions and Ethical Considerations

Challenges include scaling for adults, ensuring longitudinal growth, and minimizing interventions. Ethical porcine sourcing and no immunosuppression align with welfare standards. Academic researchers must validate in primates before humans, with patents supporting commercialization. This UCL-GOSH synergy exemplifies how higher education fuels life-saving innovations.