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 - 带有扩展能力的小儿心脏阀每年在美国出生的近40,000名婴儿中发现先天性心脏瓣膜缺陷（Alsoufi 2014）。心脏瓣膜缺陷的严重程度可能范围范围，约有25％的病例（约13,000）需要立即开放 - 心脏手术以替代瓣膜或其他心脏缺陷。目前，没有外科心脏瓣膜假体婴儿的大小，流量和发育需求（Alsoufi 2014）。选项包括机械，生物假体，同源，或自体移植（Ross程序）阀。但是，最常用的机械和生物假体阀是考虑到成年人的设计（Schoen 2018）。那就是外科医生必须改变手术室中阀的结构有效地改变血液动力学特征并最大程度地减少流动势。另外，机械和生物假体瓣膜停滞不前，这意味着儿童经常面对患者的不匹配，并且由于他们的体细胞增长（David 2016）。在生长之外，机械阀需要终身抗凝药物生物假体阀倾向于发生结构瓣膜变性（Schoen 2018）。作为回应，我们的团队假设一个替代的心脏阀可以随着成长的孩子而增加的大小增加这可以修复和建模以持续到孩子的一生，这将大大改善该患者的生活质量人口。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和制造业，Dan Simionescu博士，具有阀门设计，脚手架和细胞播种方面的专业知识，Minoo Kavarana博士与在手术方法治疗先天性心脏缺陷方面的广泛专业知识，David Orr博士具有经验业务发展和监管事务。为此，我们建议制造和测试支架阀原型，这些原型可以从12mm增加至24毫米至最大4个气球血管成形术干预措施，每个步骤将直径增加3毫米。设计将掺入细胞心包作为生物组织小叶或尖牙，测试了适当的血液动力学（特定目标 1）。在第二阶段，组织将用人的成纤维细胞和内皮细胞播种人脂肪组织衍生干细胞的分化。活阀原型将通过“模拟”进行测试在心脏瓣膜生物反应器中的植入和膨胀已经由Aptus Bieractor开发和专利（特定目标2）。在生物反应器测试期间和之后，我们将验证瓣膜小叶运动和血流动力学，组织机械性质，细胞活力和表型。这些研究将为支持设备提供实质性的概念证明并生成数据以支持II期大型动物研究，该研究将利用自体细胞播种以及在少年绵羊中植入可扩展的瓣膜，以进行安全和有效性验证。成功完成这些研究将为确定的产品开发和人类第一临床试验树立基础。