A Size Adjustable Pulmonary Valve Implant for Pediatric Applications

摘要 法洛四联症（Tetralogy of Fallot，ToF）是最常见的紫绀型先天性心脏病，发生率为1/3600 活产婴儿，影响到几乎10%的先天性心脏病儿童。当代 ToF的管理已经发展到婴儿早期的选择性完全手术修复， 死亡率<2%。尽管有这些进展，右心室流出道的手术扩大 仍然是一个重大挑战。到目前为止，跨环补片重建，其中涉及破坏和 肺动脉瓣环扩大是最广泛使用的修复策略。但 这种技术的关键缺陷是瓣膜装置的结构完整性的丧失，导致慢性的 严重肺功能不全纵向数据显示，严重的肺功能不全往往导致 进行性右心室扩张和双心室功能障碍，使修复的ToF患者在 晚期不良事件的显著风险，包括发生室性心律失常、双心室心脏 衰竭和心脏猝死为了避免这些有害的后期结果，大多数修复的ToF 患者最终接受肺动脉瓣置换术。临床的钟摆现在正转向 更早的瓣膜置换术，因为修复的ToF患者通常会发展 在临床症状出现前数年，右心功能明显障碍。但 不幸的现实是，幼儿的瓣膜置换选择极其有限。现有 假体经常早期失效，并且普遍不能适应儿童的身体生长。 外科医生试图通过实施保留肺动脉瓣的修复术来解决这个紧迫的问题 ToF儿童的策略。然而，来自我们机构的新数据表明，大多数ToF患者 进行瓣膜保留修复的患者会出现早期和进行性肺功能不全。瓣膜早期丢失 ToF能力仍然是当代外科管理的致命弱点，而且，至关重要的是， 未解决的问题使成千上万的患者处于严重晚期不良事件的持续风险中。 为了解决这个紧迫的临床问题，我们建议利用我们的基于模拟的工作， 一组证明静脉样瓣膜在各种血管尺寸下仍然有效，沿着 支架技术的进步和新兴的生物材料，以开发一种生长适应性肺 在初次ToF修复时植入瓣膜置换器械。我们提出两个具体目标： 目的1：设计一种可扩张的、安装支架的双叶肺动脉瓣置换器械， 能够在宽直径范围内保持功能。目标二。的可行性进行评估 体内装置扩张以适应自体肺动脉瓣环的体细胞生长， 一个成长中的绵羊模型。这一目标的实现将代表着医疗保健领域的一个范式转变 的ToF患者，并最终将受益于任何需要在生命早期进行瓣膜置换的儿童。

Abstract Tetralogy of Fallot (ToF) is the most common cyanotic congenital heart defect, occurring in 1 in every 3600 live births and affecting almost 10% of all children born with congenital heart disease. Contemporary management of ToF has evolved to elective complete surgical repair in early infancy, with perioperative mortality rates of <2%. Despite these advances, surgical augmentation of the right ventricular outflow tract remains a significant challenge. To date, transannular patch reconstruction, which involves disruption and enlargement of the pulmonary valve annulus, has been the most widely used repair strategy. However, a critical deficiency of this technique is the loss of structural integrity of the valvar apparatus, leading to chronic severe pulmonary insufficiency. Longitudinal data demonstrates severe pulmonary insufficiency often leads to progressive right ventricular dilation and biventricular dysfunction, leaving repaired ToF patients at significant risk of late adverse events, including development of ventricular arrhythmias, biventricular heart failure, and sudden cardiac death. To avoid these deleterious late outcomes, the majority of repaired ToF patients undergo eventual pulmonary valve replacement. The clinical pendulum is now shifting towards earlier valve replacement as it becomes increasingly evident that repaired ToF patients often develop significant right heart dysfunction several years before the onset of clinical symptoms. However, the unfortunate reality is that valve replacement options for small children are extremely limited. Existing prostheses often fail early, and, are universally unable to accommodate somatic growth of the child. Surgeons have attempted to address this urgent problem by implementing pulmonary valve-sparing repair strategies in children with ToF. Yet, emerging data from our institution demonstrates that most ToF patients who undergo valve-sparing repair develop early and progressive pulmonary insufficiency. Early loss of valve competency in ToF remains the Achilles heel of contemporary surgical management, and, critically, this unsolved problem leaves thousands of patients at ongoing risk of serious late adverse events. To address this urgent clinical problem, we propose to leverage promising simulation-based work from our group demonstrating venous-like valves remain competent across a wide range of vessel sizes, along with advances in stent technology and emerging biomaterials, to develop a growth-accommodating pulmonary valve replacement device to be implanted at the time of primary ToF repair. We propose two Specific Aims: Aim 1: Design an expandable, stent-mounted two-leaflet pulmonary valve replacement device that is capable of maintaining function across a wide range of diameters. Aim 2. Evaluate the feasibility of in vivo device expansion to accommodate somatic growth of the native pulmonary valve annulus in a growing ovine model. Achievement of this goal would represent a paradigm-shifting advance in the care of ToF patients, and, ultimately, would benefit any child who requires valve replacement early in life.