Evaluation of growth potential of ice-free vitrified heart valves in a pediatric porcine model.

评估小儿猪模型中无冰玻璃化心脏瓣膜的生长潜力。

• 批准号: 10696568
• 负责人: Taufiek Konrad Rajab
• 金额: $ 45.22万
• 依托单位: TISSUE TESTING TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696568
• 关键词: Adult; Allografting; Animal Model; Apoptosis Inhibitor; Autologous Transplantation; Autopsy; Biological Process; Blood Group Antigens; Blood flow; Cardiovascular system; Cause of Death; Cell Survival; Child; Childhood; Clinical; Congenital Heart Defects; Cryopreservation; Data; Development; Disease model; Dissection; Donor person; Engineering; Ensure; Evaluation; Family suidae; Functional disorder; Future; Geography; Goals; Growth; HLA Antigens; Heart; Heart Transplantation; Heart Valves; Human; Ice; Immunosuppression; Implant; In Vitro; Infant; Inhibition of Apoptosis; Ischemia; Licensing; Lung; Mechanics; Medical center; Methods; Names; Organ Transplantation; Outcome; Parents; Patients; Phase; Preparation; Protocols documentation; Refrigeration; Regenerative Medicine; Repeat Surgery; Risk; Source; Technology; Temperature; Time; Tissue Banks; Tissue Donors; Tissue Engineering; Tissue Viability; Tissues; Transplant Recipients; Transplantation; Travel; Ventricular Dysfunction; aortic valve replacement; clinical application; clinical translation; commercialization; cryogenics; experience; heart valve replacement; hemodynamics; homograft; human tissue; immunosuppressed; in vivo; in vivo Model; infant death; innovation; mortality; nanowarming; neonatal death; neonate; novel strategies; operation; porcine model; post-transplant; preservation; repaired; response; technology platform; transplant model; trauma care; valve replacement

Abstract: Heart valve replacement in children is a serious problem because there are no heart valve implants that grow with the patient. The valves that are currently employed need to be changed as the patient grows with a very high associated mortality rate (~40%). In response to this clinical need, we are pioneering an entirely new approach to deliver growing heart valve implants, which we are calling partial heart transplantation (PHT). PHT differs from heart transplantation because only the part of the heart containing a valve is transplanted. Based on our preliminary data in immunosuppressed piglets, we recently performed the world’s first human partial heart transplant on 4/22/2022 with demonstrated valve growth. However, the chance of a donor partial heart transplant being available at just the right time is low. Therefore, we propose development of a network of tissue banks with technology licenses at major pediatric cardiovascular medical centers nationwide in preparation for clinical application. Our central hypothesis is that vitrified and nanowarmed PHTs can fulfill both their hemodynamic and biological functions after orthotopic transplantation in growing children. In this Phase I proposal there are three specific aims: First we propose optimization of short-term preservation protocols. Our working hypothesis for this aim is that PHTs will tolerate longer post-mortem cold ischemic times than intact hearts. The impact of procurement and refrigeration on piglet-derived PHTs will be evaluated by assessment of viability in vitro. This will establish the anticipated geographic range for PHT procurement after dissection based upon estimated refrigerated travel time. In the second specific aim we will optimize vitrification protocols for PHTs. Our working hypothesis for this aim is that ice-free cryo-preservation employing tissue vitrification, rapid nanowarming and apoptosis inhibition developed for adult porcine pulmonary heart valves can be further optimized for smaller PHTs required for pediatric cases. Different cryoprotectant loading times, exposure conditions, and apoptosis inhibitors will be evaluated by assessment of viability in vitro. This will establish the optimal vitrification protocol for pediatric PHTs. In the final aim we will evaluate post- transplant growth, leaflet viability and hemodynamic function of optimally vitrified and nanowarmed cryopreserved PHTs. Our working hypothesis for this aim is that optimized protocols will allow vitrified PHTs that were banked for one month to function in vivo like fresh PHTs. The optimized protocols developed in the earlier aims will be evaluated in a swine leukocyte antigen matched growing immunosuppressed piglet PHT model by transplantation. This will establish the PHT vitrification, warming, and banking methods for future clinical application.

摘要：儿童心脏瓣膜置换术是一个严重的问题，因为没有心脏瓣膜植入物。 随着病人的成长而成长。目前使用的瓣膜需要随着患者的成长而改变。 相关死亡率很高(~40%)。为了回应这一临床需求，我们正在开创一种 一种全新的移植心脏瓣膜的方法，我们称之为部分心脏移植 (PHT)。PHT与心脏移植不同，因为只有心脏中含有瓣膜的部分才是 被移植了。基于我们对免疫抑制仔猪的初步数据，我们最近进行了世界上 2022年4月22日，第一例人类部分心脏移植，显示瓣膜生长。然而，一次 捐赠者的部分心脏移植在正确的时间进行是很低的。因此，我们建议发展 在主要的儿科心血管医学中心拥有技术许可证的组织银行网络 为临床应用做准备。我们的中心假设是玻璃化和纳米武器的PHTs 在生长中的儿童原位移植后，可以同时满足血流动力学和生物学功能。 在这个第一阶段的方案中，有三个具体的目的：一是提出优化短期保全 协议。我们的工作假设是PHTs可以耐受死后更长时间的冷缺血 时代胜过完整的心。将评估采购和冷藏对仔猪来源的PHTs的影响 通过体外存活能力的评估。这将为PHT采购确定预期的地理范围 根据估计的冷藏旅行时间进行解剖后。在第二个具体目标中，我们将优化 PHTs的玻璃化冷冻方案。我们关于这个目标的工作假设是，无冰冷冻保存采用 成年猪肺组织玻璃化冷冻、快速纳米温控及细胞凋亡抑制研究进展 阀门可以进一步优化，以满足儿科病例所需的较小的PHTs。不同的防冻剂加入量 时间、暴露条件和细胞凋亡抑制物将通过体外活性评估进行评估。这 将建立儿童PHTs的最佳玻璃化冷冻方案。在最终目标中，我们将对 最佳玻璃化冷冻和纳米化冷冻的移植生长、叶活力和血流动力学功能 冷冻保存的PHTs。我们对这一目标的工作假设是，优化的方案将允许玻璃化的PHTs 它们被储存一个月，在体内发挥作用，就像新鲜的PHTs一样。中开发的优化协议 早期的AIMS将在猪白细胞抗原匹配的生长免疫抑制仔猪PHT中进行评估 移植造模。这将为未来建立PHT玻璃化、升温和银行处理方法 临床应用。