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 随着患者的成长，当前使用的阀门需要更换。 具有非常高的相关死亡率（~40%）。为了满足这一临床需求，我们正在开创一种方法。 提供不断生长的心脏瓣膜植入物的全新方法，我们称之为部分心脏移植 (PHT) 与心脏移植不同，因为仅包含瓣膜的心脏部分被移植。 根据我们对免疫抑制仔猪的初步数据，我们最近进行了世界范围内的移植。 2022 年 4 月 22 日进行了首例人类部分心脏移植手术，并显示瓣膜生长。 在适当的时间进行供体部分心脏移植的比例很低，因此我们建议进行开发。 拥有主要儿科心血管医疗中心技术许可的组织库网络 我们的中心假设是玻璃化和纳米加热的 PHT。 在生长儿童中进行原位移植后可以实现其血流动力学和生物学功能。 在第一阶段的提案中有三​​个具体目标： 首先，我们提出短期保存的优化 我们对此目标的工作假设是 PHT 能够耐受更长时间的死后冷缺血。 将评估采购和冷藏对仔猪来源 PHT 的影响。 通过体外可行性评估，这将确定 PHT 采购的预期地理范围。 根据估计的冷藏旅行时间进行解剖后，我们将在第二个具体目标中进行优化。 针对 PHT 的玻璃化冷冻方案，我们的工作假设是采用无冰冷冻保存。 针对成年猪肺心病开发的组织玻璃化、快速纳米升温和细胞凋亡抑制 阀门可以针对儿科病例所需的较小 PHT 进行进一步优化。 时间、暴露条件和细胞凋亡抑制剂将通过体外活力评估来评估。 我们将建立儿科 PHT 的最佳玻璃化冷冻方案，最终目标是评估术后情况。 最佳玻璃化和纳米加热的移植物生长、小叶活力和血流动力学功能 我们对此目标的工作假设是优化的方案将允许玻璃化 PHT。 储存一个月后，其在体内的功能就像新鲜的 PHT 一样。 早期目标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 这将为未来建立 PHT 玻璃化、加温和储存方法。 临床应用。