Pediatric Heart Valve with Expansion Capability

项目总结-具有扩张能力的小儿心脏瓣膜 每年在美国出生的近40，000名婴儿中检测到先天性心脏瓣膜缺陷（Alsoufi 2014）。心脏瓣膜缺损的严重程度不等，约25%的病例（约13，000例）需要立即开放。 心脏手术以替换瓣膜或其他心脏缺陷。目前，没有外科心脏瓣膜假体符合 婴儿的大小，流量和发育需求（Alsoufi 2014）。选择包括机械，生物假体，同种移植， 或自体移植（Ross手术）瓣膜。然而，最常用的机械和生物瓣膜是 为成人设计（Schoen 2018）。因此，外科医生必须在手术室中改变瓣膜的结构 有效地改变血液动力学曲线并使流动潜力最小化。此外，机械和生物假体 瓣膜是停滞的，这意味着儿童经常面临病人-假体不匹配和多次手术， 他们的躯体生长（大卫2016）。在生长之外，机械瓣膜需要终身抗凝药物治疗 生物瓣膜往往会发生结构性瓣膜退化（Schoen 2018）。 作为回应，我们的团队假设，随着孩子的成长， 并且可以自我修复和塑造，使其持续孩子的一生，这将极大地提高病人的生活质量 人口该研究团队由Leslie Sierad博士组成，具有生物反应器开发方面的专业知识， Dan Simionescu博士在瓣膜设计，支架和细胞接种方面具有专业知识，Minoo Kavarana博士 大卫奥尔博士在治疗先天性心脏病的手术方法方面拥有丰富的专业知识， 业务发展及规管事务。 为此，我们建议制造和测试支架瓣膜原型，其尺寸可从12 mm增加到 通过多达4次球囊血管成形术介入，每一步直径增加3 mm。 将脱细胞心包作为生物组织瓣叶或瓣尖，测试适当的血液动力学（特定目的 1）。在第二阶段，组织将与通过体外获得的人成纤维细胞和内皮细胞一起接种。 人脂肪组织来源的干细胞的分化。活阀原型将通过“模拟”进行测试 在Aptus生物反应器已经开发并获得专利的心脏瓣膜生物反应器中植入和扩增（特定 目标2）。在生物反应器试验期间和之后，我们将确认瓣叶运动和血液动力学、组织力学 特性、细胞活力和表型。这些研究将为支持该器械提供实质性的概念证明 并生成支持II期大型动物研究的数据，该研究将利用自体细胞接种瓣叶 并在幼年绵羊中植入可扩张瓣膜以进行安全性和有效性验证。成功完成 这些研究将为确定的产品开发和首次人体临床试验奠定基础。

PROJECT SUMMARY - PEDIATRIC HEART VALVE WITH EXPANSION CAPABILITY Congenital heart valve defects are detected in nearly 40,000 infants born in the United States each year (Alsoufi 2014). The heart valve defect can range in severity, with about 25% of cases (about 13,000) requiring immediate open- heart surgery to replace the valve or other heart defects. Currently, there is no surgical heart valve prosthesis that meets the size, flow, and developmental needs of infants (Alsoufi 2014). Options include mechanical, bioprosthetic, homograft, or autograft (Ross procedure) valves. However, the most commonly used, mechanical and bioprosthetic valves, are designed with adults in mind (Schoen 2018). Thus, surgeons must alter the structure of the valve in the operating room effectively altering the hemodynamic profile and minimizing the flow potential. In addition, mechanical and bioprosthetic valves are stagnant, meaning that children often face patient-prosthesis mismatch and multiple operations as a result of their somatic growth (David 2016). Outside of growth, mechanical valves require life-long anticoagulation medication and bioprosthetic valves tend to undergo structural valve degeneration (Schoen 2018). In response, our team hypothesized that a replacement heart valve that can increase in size with a growing child and that can repair and model itself to last the child’s lifetime will greatly improve the quality of life of this patient population. The research team is composed of Dr. Leslie Sierad with expertise in bioreactor development and manufacturing, Dr. Dan Simionescu with expertise in valve design, scaffolds and cell seeding, Dr. Minoo Kavarana with extensive expertise in surgical approaches to treatment of congenital heart defects, and Dr. David Orr with experience in business development and regulatory affairs. To this end, we are proposing to manufacture and test stent valve prototypes that can increase in size from 12mm to 24mm through up to 4 balloon angioplasty interventions, each step increasing the diameter by 3 mm. The design will incorporate acellular pericardium as the biological tissue leaflets or cusps, tested for proper hemodynamics (specific Aim 1). In the second stage, the tissues will be seeded with human fibroblasts and endothelial cells obtained by in vitro differentiation of human adipose-tissue derived stem cells. The living valve prototype will be tested through “mock” implantation and expansion in a heart valve bioreactor already developed and patented by Aptus Bioreactors (specific Aim 2). During and after bioreactor testing, we will validate valve leaflets motions and hemodynamics, tissue mechanical properties, cell viability and phenotype. These studies will provide substantial proof of concept in support of the device and generate data in support of a Phase II large animal study which will utilize autologous cells for seeding of the leaflets and implantation of the expandable valves in juvenile sheep for safety and efficacy validation. Successful completion of these studies will set the basis for definitive product development and first-in-human clinical trials.