Dr. Natalie Durkin - Best of the Best in Pediatric Surgery 2025

All right, so we're on to our next presentation. We have an interesting situation that we've had in the past where we have one presenter who has chosen as best paper from two societies. So we have Dr. Natalie Durkin and first we're going to do her UPSU presentation. Natalie is from Great Ormond Street in the UK and the first presentation she's going to present is muscle regeneration and contractile function in tissue engineered asophagus. Are we ready for patients? Thank you very much for the opportunity to present our work today. These are our disclosures. So we all know long-term suffrage illiteracy can be extremely challenging to treat with significant long-term comorbidity associated with current surgical options. We've sought to address this by considering whether a tissue engineered asophage ill substitute could be the solution to bridging this gap. And the way we envisage this working is this at routine gastrocymiformation and long-gap patient. We would take a biopsy of rectus abdominis muscle. Icelatinics van methenkymal cells before injecting them back into a pre-prepared, size-matched decelinarized porcelainousophagus, maturing this inner bioreactor and transplanting it back into the patient. So the aim of this work was to demonstrate the feasibility, safety and efficacy of this approach in a large animal model. Using this protocol we produced autologous tissue engineered grafts in eight mini-pigs and transplanted them to replace two and a half centimeter thoracicusophageal defects, with intra-luminal biodegradable sense to support patency and vascularizing floral wraps. The production of grafts in two months from biopsy to transplant shows that this approach is feasible within clinically relevant timescales. After surgery we monitored animals for up to six months with a plant-stentic change at three months upon stegradation. Safety was assessed by morbidity and the primary outcome of six months survival, with function assessed by animal growth, completeness of epithelium-onendoscopy and the presence of perisalysis on high-resolution impedance monometry at endpoint. The first thing to say is that animals recovered remarkably well from thoracotomy, mobilising within minutes of surgery and eating on day one with no requirement for gastrocomy or entral feeding. UMPLAND in DOSCOPIE was required for three main events, firstly for embodied obstruction which occurred in three animals from eating their bedding and required emergency endoscopic removal. Remarkably, even though we had to do this as early as three days post-op, we had no incidence of anaesthmotic geek. Secondly, seven animals required UMPLAND at DOSCOPIE for epithelial hyperplastic polyp formation which was respected in five and resolved by two months. Interestingly, despite not feeding any epithelial cells on our graft implantation, polypestology from day 17 showed the presence of a stratified epithelium and a supporting vasculature which had already developed on the graft. Finally, all animals had at least one episode of symptomatic structure after stentic degradation or early migration, but crucially these were all amenable to endoscopic balloon dilutation and re-application of stent. Despite the requirement for intervention, growth of our animals was in line with the non-operated age-matched controls from the Elegard farm. And facilitated 100% 30-day survival and 63% 6 months of survival with early endpoints in three animals, one in three months due to recurrent stent migration and restrictions in the number of endoscopic interventions allowed within our licence. But what was really striking is that when we look at a summary of all endoscopic interventions required within the study, we can see that if animals reach the four-month time point, no further endoscopy was required prior to euthanasia, potentially indicating that grafts were able to maintain their own patency from this point. And what did endoscopy look like? Well, at six months we could see a patent-unistimosis in continuous epithelium and it was really difficult to identify the graft, which was only clear from the presence of non-absorbable sutures. Really excitingly, at endpoint, high-resolution impedance minimum tree showed secondary parisalysis in all animals at three and six months, demonstrated by this representative trace at the bottom of the screen, with the graft highlighted by the red box. And this was then validated exebo by isometric contractility testing on rings of tissue where both chemical and electrical stimulation induced the dose-dependent response of smooth muscle contraction within our graft. So if we have this functional information that our graft is contracting, can we validate this with histology? Well the answer is yes we can. This immunofluorescence shows samples at three and six months with an increasing number and complexity of smooth and skeletal muscle fibres with smooth muscle in red and skeletal muscle in green. And then we have the over time, which is shown in more detail today in the Baptist presentation. So to conclude, we hope to have shown you that our tissue engineered grafts are safe for the treatment of circumferential and soft agility effects in vivo and produceable within clinically relevant time frames. Mobility resembled that which is well recognised in long-gap and soft agility of patients and was all treatable endoscopically. Finally, we've shown you that our graft is functional by six months, facilitating both animal growth and the entruller autonomy. And we believe this paved the way for clinical translation into humans. Finally, I must say an enormous thank you to the colossal number of people it takes to undertake a project as this magnitude. And of course, see you for listening. We would welcome your comments and questions. Natalie, thank you so much. Thank you. And I'm going to ask Dr. Dirkin. It's really exciting to see this close to getting to our patients that really need it, especially those longer-term pig patients that you took care of that had the excellent outcomes in terms of the contractility, histology, and what it looked like in endoscopy. So my question was about the pigs that didn't make it to the end of the study. So you mentioned maybe stent migration or issues that could have been treated endoscopically. Can you just elaborate a little bit more on why those had to get euthanized and would that be something we could actually treat in a pediatric patient? Yeah. So unfortunately, there were three pigs that didn't make it to six months, one at one month and two at three months. And it was essentially a logistical issue. Originally, we'd only planned to do three endoscopies in the entire study. And then within the first three days, one animal ate their bedding. And then by, by like day, 21, three animals had eaten their bedding. So that was already one unplanned emergency endoscopy. And what we found, which I didn't show today, is that those who had polyps, these polyps, they were significantly worse than the animals who'd eaten their bedding interestingly and much more symptomatic. So we then had to intervene quite two more times for symptoms. And we sort of reset these polyps, but weren't really sure whether that was going to help. And then we, by, in the first one that we did that in, it was already one month we'd done three endoscopies. And so within our license, we had already reached the maximum number of endoscopies. We then put an application into increase the number of endoscopies during the study. And therefore we were allowed to continue with the other ones beyond the three in the total length. Does that make sense? So you anticipate the endopediatic patient that they would be available to endoscopy there? Also, endopediatic. They'll have a, they'll have a gastroastomy. They'll probably be defunctioned. The symptoms will be less severe if they're not, these pigs were eating from the day after the operation. So we anticipate that not to be such a significant issue. And also, yes, then migration is a very well recognised problem specifically in pigs. And it was very troublesome in the experimental model. So there are better methods for sizing stents and the children grow more slowly than these many pigs did. Natalie, thank you so much.