Repair of iatrogenic fetal membrane defects with an adhesive tissue scaffold

描述（由申请人提供）：健康和完整的胎膜（羊膜和绒毛膜）是最佳妊娠结局所必需的。针或胎儿镜插入时对胎膜的损伤可导致医源性胎膜早产破裂，并伴有早产和随后分娩的风险显著增加。本项目的目标是开发一种独特的粘性贴片系统，用于在胎儿镜手术后密封羊膜腔入口。该系统由一个组织膜补片组成，用一根缝线系住，缝线将插入羊膜腔，然后像一把倒置的雨伞一样通过入口拉回。基于复合凝聚层的不可降解粘合剂将应用于外周，以将组织补片密封到子宫壁和胎膜上。复合凝聚层是相分离的、带相反电荷的聚电解质的致密水性流体。因此，它们具有作为粘合剂基础的几种理想性质，所述粘合剂可以施加到湿的、甚至完全浸没的基底，例如充满流体的羊膜腔中的组织。仿生粘附复合凝聚层的灵感来自沙堡蠕虫的海底胶，其由带相反电荷的聚电解质粘附蛋白组成。研究策略需要通过以下方式逐步完善粘性组织贴片的材料和机械性能：i）对胎膜和粘性贴片进行定量建模，ii）进行体外机械测试，以建立粘性贴片系统的粘性化学和材料性能之间的本构关系，以及iii）在妊娠动物模型中对粘性贴片进行临床前评价。在子宫内胎儿干预后，粘性贴片系统可显著降低早产胎膜破裂、早产和相关胎儿发病率的风险。此外，通过降低早产胎膜破裂的风险，粘合剂贴片可以为目前无法治疗的其他胎儿先天性异常的子宫内治疗的发展开辟道路。

DESCRIPTION (provided by applicant): Healthy and intact fetal membranes (amnion and chorion) are required for optimal pregnancy outcomes. Damage to the fetal membranes, incident to the insertion of a needle or fetoscope, can lead to iatrogenic preterm rupture of the membranes accompanied by a significantly increased risk of preterm labor and subsequent delivery. The goal of this project is to develop a unique adhesive patch system to seal amniotic cavity access ports following fetoscopic surgeries. The system consists of a tissue membrane patch, tethered with a suture that will be inserted into the amniotic cavity, and then drawn back through the access port like an inverted umbrella. A non-degradable adhesive, based on complex coacervates, will be applied around the circumference to seal the tissue patch to the uterine wall and fetal membranes. Complex coacervates are dense, aqueous fluids of phase-separated, oppositely charged polyelectrolytes. As such, they have several ideal properties as the foundation of adhesives that can be applied to wet, even completely submerged substrates, such as tissues in the fluid-filled amniotic cavity. The biomimetic adhesive complex coacervates were inspired by the undersea glue of sandcastle worms, which is composed of oppositely charged polyelectrolytic adhesive proteins. The research strategy entails progressive refinement of the material and mechanical properties of the adhesive tissue patch through i) quantitative modeling of fetal membranes and the adhesive patch, ii) in vitro mechanical testing to establish constitutive relationships between adhesive chemistry and the material properties of the adhesive patch system, and iii) preclinical evaluation of the adhesive patch in a pregnant animal model. The adhesive patch system could significantly reduce the risk of preterm fetal membrane rupture, preterm delivery, and associated fetal morbidity after in utero fetal interventions. Further, the adhesive patch, by reducing the risk of preterm fetal membrane rupture, could open the way for development of in utero treatments for other fetal congenital anomalies that are currently untreatable.