3D printed bioresorbable sleeve device for esophageal atresia repair

项目摘要/摘要 先天性食道闭锁(EA)是一种潜在的致命性和相对常见的畸形，导致 完全不连续的食道。如果不进行治疗，患有这种疾病的新生儿将无法进食、窒息 依靠自己的唾液，最终死于继发于慢性吸入的终末期呼吸衰竭 肺炎。虽然新生儿一期手术修复可以恢复眼球两端之间的连续性 食道手术是一种挽救生命的手术，该手术对许多患者来说在技术上是困难的，而且仍然令人担忧 术后并发症发生率高，包括漏、复发性狭窄、瘘、胃食道 反流和慢性吞咽困难。此外，在新生儿的一部分(10%)中，两者之间的差距 食道末端测量&gt；3厘米(长间隙电针)，手术连接末端是不可能的，导致 住院数月，因为需要进行高度病态的食道置换手术 和/或其他复杂操作。仍然迫切需要新的治疗策略，以促进 这些新生儿的结局会更好。我们的长期目标是发展以再生医学为基础的治疗 使用3D打印(3DP)弹性材料改善吻合口的EA新生儿的策略 伤口愈合，减少并发症。这个项目的中心假设是，植入一个 外支架套筒由弹性体聚甘油-十二烷二酸(PGD)制成，并与 生物活性多肽序列可促进电针修复部位的食管吻合口愈合 吻合口的张力和增强细胞的附着。这个提案用两个具体的例子来验证这个假设 目标。在目标1中，研究人员将确定支架设计如何影响降解和生物力学 可生物吸收食管套的性能。在目标2中，研究人员将评估生物可再吸收材料 在电针修复的新生大动物模型中，食道袖子对吻合口愈合进行了优化。完成 这些目标将提出非线性弹性可吸收弹性体的概念，作为一种新的方法 细胞募集和纵向调控对局部食道组织微环境的调节 和径向力。此外，我们预计这些实验将促进3DP装置的临床移植 供儿科外科医生在手术室使用的技术，利用我们的患者临床经验 气管装置。最后，我们的方法也将为弹性体设备的开发奠定基础 作为用于长间隙电针的全厚度节段组织产生的底物。

Project Summary/Abstract Congenital esophageal atresia (EA) is a potentially lethal and relatively common malformation that results in a complete discontinuity of the esophagus. Left untreated, neonates with this condition are unable to eat, choke on their own saliva, and eventually die from end-stage respiratory failure secondary to chronic aspiration pneumonia. Although neonatal primary surgical repair, which restores continuity between the two ends of the esophagus, is a life-saving operation, the procedure is technically difficult in many patients and remains fraught with a high rate of postoperative complications, including leaks, recurrent strictures, fistulae, gastroesophageal reflux, and chronic dysphagia. Moreover, in a subset of newborns (10%) where the gap between the two esophageal ends measures >3 cm (long-gap EA), connecting the ends surgically is impossible, resulting in months of hospitalization because of the need to perform highly morbid esophageal replacement procedures and/or other complex operations. There remains a critical need for novel treatment strategies that can facilitate better outcomes in these newborns. Our long-term goal is to develop regenerative medicine-based treatment strategies for newborns with EA using 3D printed (3DP) elastomeric materials that can improve anastomotic wound healing and decrease complications. The central hypothesis of this project is that the implantation of an external scaffold sleeve made from the elastomer, poly-glycerol-dodecanedioate (PGD), and functionalized with bioactive peptide sequences can improve esophageal anastomotic healing at the EA repair site by reducing tension at the anastomosis and enhancing cell attachment. This proposal tests this hypothesis with two specific aims. In Aim 1, the investigators will determine how scaffold design affects the degradation and biomechanical properties of bioresorbable esophageal sleeves. In Aim 2, the investigators will evaluate bioresorbable esophageal sleeves optimized for anastomotic healing in a neonatal large animal model of EA repair. Completion of these Aims will have advanced the concept of nonlinear elastic resorbable elastomers as a novel approach to modulate the local esophageal tissue microenvironment through cell recruitment and modulation of longitudinal and radial forces. In addition, we anticipate that these experiments will facilitate clinical translation of 3DP device technologies for use by pediatric surgeons in the operating room, leveraging our patient clinical experience with tracheal devices. Finally, our approach will also have set the stage for the development of elastomeric devices as a substrate for the generation of full-thickness segmental tissue for long-gap EA.