Lessons Learned From the First-In-Human Compassionate Use of Connect-EA™ in Ten Patients With Esophageal Atresia.

INTRODUCTION: Delayed primary repair of esophageal atresia in patients with high-risk physiologic and anatomic comorbidities remains a daunting challenge with an increased risk for peri-operative morbidity and mortality via conventional repair. The Connect-EA device facilitates the endoscopic creation of a secure esophageal anastomosis. This follow-up study reports our long-term outcomes with the novel esophageal magnetic compression anastomosis (EMCA) Connect-EA device for EA repair, as well as lessons learned from the ten first-in-human cases. We propose an algorithm to maximize the advantages of the device for EA repair. METHODS: Under compassionate use approval, from June 2019 to December 2022, ten patients with prohibitive surgical or medical risk factors underwent attempted EMCA with this device. All patients underwent prior gastrostomy, tracheoesophageal fistula ligation (if necessary), and demonstrated pouch apposition prior to EMCA. RESULTS: Successful device deployment and EMCA formation were achieved in nine patients (90%). Mean time to anastomosis formation was 8 days (range 5-14) and the device was retrieved endoscopically in five (56%) cases. At median follow-up of 22 months (range 4-45), seven patients (78%) are tolerating oral nutrition. Balloon dilations (median 4, range 1-11) were performed either prophylactically for radiographic asymptomatic anastomotic narrowing (n = 7, 78%) or to treat clinically-significant anastomotic narrowing (n = 2, 22%) with no ongoing dilations at 3-month follow up post-repair. CONCLUSION: EMCA with the Connect-EA device is a safe and feasible minimally-invasive alterative for EA repair in high-risk surgical patients. Promising post-operative outcomes warrant further Phase I investigation. LEVEL OF EVIDENCE: IV, Case series of novel operative technique without comparison group.

The novel application of an emerging device for salvage of primary repair in high-risk complex esophageal atresia.

INTRODUCTION: Preservation of native esophagus is a tenet of esophageal atresia (EA) repair. However, techniques for delayed primary anastomosis are severely limited for surgically and medically complex patients at high-risk for operative repair. We report our initial experience with the novel application of the Connect-EA, an esophageal magnetic compression anastomosis device, for salvage of primary repair in 2 high-risk complex EA patients. Compassionate use was approved by the FDA and treating institutions. OPERATIVE TECHNIQUE: Two approaches using the Connect-EA are described - a totally endoscopic approach and a novel hybrid operative approach. To our knowledge, this is the first successful use of a hybrid operative approach with an esophageal magnetic compression device. OUTCOMES: Salvage of delayed primary anastomosis was successful in both patients. The totally endoscopic approach significantly reduced operative time and avoided repeat high-risk operation. The hybrid operative approach salvaged delayed primary anastomosis and avoided cervical esophagostomy. CONCLUSION: The Connect-EA is a novel intervention to achieve delayed primary esophageal repair in complex EA patients with high-risk tissue characteristics and multi-system comorbidities that limit operative repair. We propose a clinical algorithm for use of the totally endoscopic approach and hybrid operative approach for use of the Connect-EA in high-risk complex EA patients.

Disruption of cell-cell contact-mediated notch signaling via hydrogel encapsulation reduces mesenchymal stem cell chondrogenic potential: winner of the Society for Biomaterials Student Award in the Undergraduate Category, Charlotte, NC, April 15 to 18, 2015.

Cell-cell contact-mediated Notch signaling is essential for mesenchymal stem cell (MSC) chondrogenesis during development. However, subsequent deactivation of Notch signaling is also required to allow for stem cell chondrogenic progression. Recent literature has shown that Notch signaling can also influence Wnt/ß-catenin signaling, critical for MSC differentiation, through perturbations in cell-cell contacts. Traditionally, abundant cell-cell contacts, consistent with development, are emulated in vitro using pellet cultures for chondrogenesis. However, cells are often encapsulated within biomaterials-based scaffolds, such as hydrogels, to improve therapeutic cell localization in vivo. To explore the role of Notch and Wnt/ß-catenin signaling in the context of hydrogel-encapsulated MSC chondrogenesis, we compared signaling and differentiation capacity of MSCs in both hydrogels and traditional pellet cultures. We demonstrate that encapsulation within poly(ethylene glycol) hydrogels reduces cell-cell contacts, and both Notch (7.5-fold) and Wnt/ß-catenin (84.7-fold) pathway activation. Finally, we demonstrate that following establishment of cell-cell contacts and transient Notch signaling in pellet cultures, followed by Notch signaling deactivation, resulted in a 1.5-fold increase in MSC chondrogenesis. Taken together, these findings support that cellular condensation, and establishment of initial cell-cell contacts is critical for MSC chondrogenesis, and this process is inhibited by hydrogel encapsulation.