Pediatric Heart Valve with Expansion Capability

具有扩张功能的儿科心脏瓣膜

基本信息

批准号：
10157591
负责人：
Leslie Neil Sierad
金额：
$ 25.21万
依托单位：
APTUS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10157591
关键词：
3-Dimensional 3D Print Adipose tissue Adolescent Adult Age Angioplasty Animals Anticoagulation Area Autologous Autologous Transplantation Balloon Angioplasty Biochemical Biological Biomedical Engineering Bioprosthesis device Bioreactors Body Size Businesses Caliber Cardiac Surgery procedures Cardiology Cell Survival Cells Cellular biology Child Childhood Clinical Trials Congenital Heart Defects Consult Data Defect Development Devices Elements Endothelial Cells Endothelium Ensure Extracellular Matrix Face Family Family suidae Fibroblasts Frequencies Glutaral Growth Heart Abnormalities Heart Valve Prosthesis Heart Valves Homeostasis Human Implant In Vitro Infant Intervention Leadership Legal patent Life Measures Mechanics Medical Metabolism Mind Minor Modification Molecular Motion Operating Rooms Operative Surgical Procedures Patients Pharmaceutical Preparations Phase Phenotype Physiological Population Preparation Procedures Process Prosthesis Protocols documentation Quality Control Quality of life Regulatory Affairs Research Risk Safety Savings Seeds Services Severities Shapes Sheep Source South Carolina Stainless Steel Stents Sterility Structure Surface Surgeon Testing Time Tissue Engineering Tissues United States Universities Visit Visual Work aortic valve base calcification cost design efficacy validation experience first-in-human heart valve replacement hemodynamics homograft implantation improved in vitro regeneration mechanical properties member millimeter nitinol novel operation patient population pediatric patients pericardial sac preservation pressure product development prototype repair model repaired response scaffold stem cell derived tissues success thrombogenesis valve replacement

项目摘要

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.

项目摘要 - 具有扩展功能的儿科心脏瓣膜美国每年出生的近 40,000 名婴儿中检测出先天性心脏瓣膜缺陷（Alsoufi 2014）心脏瓣膜缺损的严重程度各不相同，约 25% 的病例（约 13,000 例）需要立即开放。心脏手术来更换瓣膜或其他心脏缺陷目前，还没有符合手术心脏瓣膜的假体。婴儿的大小、流量和发育需求（Alsoufi 2014）选项包括机械、生物假体、同种移植、然而，最常用的是机械瓣膜和生物瓣膜。设计时考虑到了成人（Schoen 2018），因此，外科医生必须改变手术室中瓣膜的结构。有效改变血流动力学特征并最大限度地减少血流潜力。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以及因以下原因进行的多次手术：除了生长之外，机械瓣膜还需要终生抗凝药物。生物瓣膜往往会发生结构性瓣膜退化（Schoen 2018）。作为回应，我们的团队开发了一种替代心脏瓣膜，可以随着儿童的成长而增大尺寸并且可以自我修复和建模以持续孩子的一生，这将极大地改善该患者的生活质量该研究团队由 Leslie Sierad 博士组成，具有生物反应器开发和研究方面的专业知识。 Dan Simionescu 博士拥有阀门设计、支架和细胞接种方面的专业知识，Minoo Kavarana 博士拥有 David Orr 博士在治疗先天性心脏缺陷的手术方法方面拥有丰富的专业知识，并且在以下领域拥有丰富的经验：业务发展和监管事务。为此，我们建议制造和测试尺寸可以从 12mm 增加的支架瓣膜原型通过多达 4 次球囊血管成形术干预，直径可增加至 24 毫米，每一步都会使直径增加 3 毫米。将无细胞心包作为生物组织小叶或尖瓣，并测试适当的血流动力学（具体目标 1) 第二阶段，将体外获得的人成纤维细胞和内皮细胞接种到组织中。人类脂肪组织干细胞的分化将通过“模拟”进行测试。 Aptus Bioreactors 已开发并获得专利的心脏瓣膜生物反应器中的植入和扩张（具体目标 2)。在生物反应器测试期间和之后，我们将验证瓣叶运动和血流动力学、组织力学。这些研究将为支持该设备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播种传单并在幼年羊身上植入可扩张瓣膜以验证安全性和有效性。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。