Pediatric Heart Valve with Expansion Capability

项目摘要-具有扩张能力的儿科心脏瓣膜 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(阿苏菲 2014年)。心脏瓣膜缺陷的严重程度不一，约25%的病例(约1.3万例)需要立即开放- 心脏外科手术，以取代瓣膜或其他心脏缺陷。目前，还没有外科心脏瓣膜假体符合 婴儿的大小、流动和发育需求(阿尔苏菲，2014)。选项包括机械、生物假体、同种异体移植、 或自体移植(Ross手术)瓣膜。然而，最常用的机械和生物假体瓣膜是 设计时考虑到了成年人(Schoen 2018)。因此，外科医生必须改变手术室中阀门的结构。 有效地改变了血流动力学特征，最大限度地降低了血流潜力。此外，机械和生物假体 瓣膜停滞，这意味着儿童经常面临患者与假体不匹配和多次手术的结果 它们的躯体生长(David 2016)。在生长之外，机械瓣膜需要终生抗凝药物 而生物瓣膜往往会发生结构性瓣膜退化(Schoen 2018)。 作为回应，我们的团队假设一种替换的心脏瓣膜可以随着孩子的成长而增大 能够修复和塑造自己以维持孩子的一生将极大地提高患者的生活质量 人口。研究团队由Leslie Sierad博士组成，他在生物反应器开发和 制造，丹·西米尼斯库博士在瓣膜设计、支架和细胞种植方面拥有专业知识，米诺·卡瓦拉纳博士拥有 在治疗先天性心脏缺陷的外科方法方面拥有丰富的专业知识，David Orr博士在 业务发展和监管事务。 为此，我们建议制造和测试尺寸可从12 mm增加到12 mm的支架瓣膜原型 通过最多4次球囊血管成形术将直径增加到24 mm，每一步增加直径3 mm。该设计将 结合脱细胞心包作为生物组织小叶或尖端，进行适当的血流动力学测试(特定目的 1)。第二阶段，将体外获得的人成纤维细胞和内皮细胞接种于组织中。 人脂肪组织来源干细胞的分化。活阀样机将通过“模拟”进行测试。 心脏瓣膜生物反应器的植入和扩张已经由Aptus Bioretors开发并获得专利(特定 目标2)。在生物反应器测试期间和之后，我们将验证瓣叶的运动和血流动力学、组织机械 特性、细胞活力和表型。这些研究将为支持该设备提供实质性的概念证明 并产生数据以支持第二阶段的大型动物研究，该研究将利用自体细胞来种植小叶 并在幼年绵羊体内植入可膨胀瓣膜，以进行安全性和有效性验证。成功完成 这些研究将为最终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.