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：儿童心脏瓣膜更换是一个严重的问题，因为没有心脏瓣膜 随着患者的生长。随着病人的增长，当前使用的阀需要更改 相关的死亡率非常高（约40％）。响应这种临床需求，我们正在开创 全新的方法来传递不断增长的心脏瓣膜，我们称之为部分心脏移植 （PHT）。 PHT与心脏移植不同，因为只有心脏的部分包含瓣膜 移植。根据我们在免疫抑制小猪中的初步数据，我们最近进行了世界的表演 在4/22/2022上的第一个人类部分心脏移植，展示了瓣膜的生长。但是，有机会 在恰到好处可用的供体部分心脏移植很低。因此，我们提出发展 在主要儿科心血管医疗中心拥有技术许可的组织库网络 在全国范围内准备临床应用。我们的中心假设是玻璃和纳米臂的PHT 在成长中的儿童原位移植后，可以履行其血液动力学和生物学功能。 在此阶段我的建议中，有三个具体目标：首先，我们提出了短期保存的优化 协议。我们针对此目标的工作假设是，PHT将忍受更长的验尸后缺血性 比完整的心。将评估采购和制冷对小猪衍生的PHT的影响 通过评估体外的生存能力。这将建立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。在第二个特定目标中，我们将优化 PHT的玻璃化方案。我们针对此目标的工作假设是采用无冰的冷冻保护 针对成年猪肺心脏开发的组织玻璃化，快速纳米臂和凋亡抑制 可以针对小儿病例所需的较小的PHT进一步优化阀门。不同的冷冻保护剂加载 时间，暴露条件和凋亡抑制剂将通过评估体外的生存能力进行评估。这 将建立针对小儿PHT的最佳玻璃化方案。在最终目标中，我们将评估后 最佳玻璃体和纳米臂的移植生长，传单生存力和血液动力学功能 冷冻保存的PHT。我们针对此目的的工作假设是，优化的协议将允许玻璃化PHT 像新鲜PHT一样在体内工作了一个月。在 较早的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 通过移植模型。这将为未来建立PHT玻璃化，变暖和银行业 临床应用。