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: 10818132
• 负责人: Taufiek Konrad Rajab
• 金额: $ 15.88万
• 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/10818132
• 关键词: Administrative Supplement; Adult; Apoptosis Inhibitor; Autopsy; Biological Process; Blood Group Antigens; Businesses; Cardiovascular system; Cause of Death; Child; Childhood; Clinical; Congenital Heart Defects; Cryopreservation; Data; Development; Diagnostic; Dissection; Entrepreneurship; Evaluation; Family suidae; Freezing; Functional disorder; Future; Geography; Grant; Growth; HLA Antigens; Heart; Heart Transplantation; Heart Valves; Human; Ice; Implant; In Vitro; Individual; Inhibition of Apoptosis; Ischemia; Learning; Licensing; Lung; Market Research; Medical center; Methods; Organ; Patients; Pediatrics; Phase; Postdoctoral Fellow; Preparation; Protocols documentation; Refrigeration; Research Personnel; Risk; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Technology; Temperature; Time; Tissue Banks; Tissues; Training; Translations; Transplantation; Travel; Work; clinical application; commercialization; cryogenics; heart valve replacement; hemodynamics; immunosuppressed; in vivo; infant death; mortality; nanowarming; neonatal death; novel strategies; porcine model; post-transplant; preservation; response; tool; transplant model

Abstract: This diversity administrative supplement proposal is focused on obtaining postdoctoral support for an outstanding individual, Dr. Kamala Sundararaj, to work on our Phase I STTR grant directed at translation of ice-free cryopreservation of heart valves for pediatrics and be trained in small business entrepreneurship. 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. At the conclusion of these aims it is anticipated that Dr. Sundaraj will have the necessary tools to establish herself as a successful independent investigator and become an entrepreneur.

翻译后摘要：这一多样性的行政补充建议的重点是获得博士后支持， 一个杰出的个人，博士卡马拉Sundararaj，对我们的工作第一阶段STTR赠款针对翻译 无冰冷冻保存儿科心脏瓣膜，并接受小企业创业培训。 儿童心脏瓣膜置换是一个严重的问题，因为没有心脏瓣膜植入物生长 和病人在一起目前使用的瓣膜需要随着患者的生长而改变， 相关死亡率高（~40%）。为了满足这种临床需求，我们正在开创一种全新的 这种方法提供了不断增长的心脏瓣膜植入物，我们称之为部分心脏移植（PHT）。PHT 与心脏移植不同，因为只有心脏的一部分包含瓣膜被移植。基于 根据我们在免疫抑制仔猪中的初步数据，我们最近进行了世界上第一个人类部分 2022年4月22日进行心脏移植，证实瓣膜生长。然而，捐献的部分心脏 在合适的时间进行移植的可能性很低。因此，我们建议建立一个网络， 在全国主要的儿科心血管医疗中心拥有技术许可证的组织库， 为临床应用作准备。我们的中心假设是，玻璃化和非玻璃化武装的PHTs可以实现这两个功能 生长期儿童原位移植后血流动力学和生物学功能。这项I期 建议有三个具体目标：首先，我们提出优化短期保存协议。我们 这一目标的工作假设是，PTs将耐受更长的死后冷缺血时间比完整的 心中将通过评估评估采购和冷藏对仔猪源性PHTs的影响 体外的生存能力。这将确定解剖后PHT采购的预期地理范围 根据估计的冷藏旅行时间在第二个具体目标中，我们将优化玻璃化方案 对于PHTs。我们对此的工作假设是，采用组织玻璃化的无冰冷冻保存， 为成年猪肺动脉心脏瓣膜开发的快速再活化和凋亡抑制可以进一步 针对儿科病例所需的较小PHTs进行了优化。不同的冷冻保护剂加载时间，暴露 条件下，并且通过评估体外活力来评估凋亡抑制剂。这将建立 最佳的玻璃化冷冻方案在最终目标中，我们将评估移植后的生长， 最佳玻璃化冷冻和无菌冷冻保存的PHTs的活力和血流动力学功能。我们的工作 针对该目标的假设是，优化的方案将允许储存一个月的玻璃化的PHTs 在体内的功能就像新鲜的PHTs。在早期的目标中开发的优化协议将在 猪白细胞抗原配型生长期免疫抑制仔猪PHT移植模型。这将 建立PHT玻璃化、加温和储存方法，以备将来临床应用。结束时 在这些目标中，预计Sundaraj博士将拥有必要的工具， 成功的独立调查员，成为一名企业家。

项目成果

A proposed objective scale for extracorporeal membrane oxygenation circuit thrombosis.

提出的体外膜氧合回路血栓形成客观量表。

• DOI: 10.1111/ctr.15118
• 发表时间: 2023
• 期刊: Clinical transplantation
• 影响因子: 2.1
• 作者: Konsek,Haley;Mealer,Corey;Skidmore,Savannah;Collins,Monika;Tchantchaleishvili,Vakhtang;Rajab,TaufiekKonrad
• 通讯作者: Rajab,TaufiekKonrad

Morbidity and Mortality of Heterotopic Partial Heart Transplantation in Rodent Models.

啮齿动物模型异位部分心脏移植的发病率和死亡率

• DOI: 10.3390/jcdd10060234
• 发表时间: 2023-05-26
• 期刊: Journal of cardiovascular development and disease
• 影响因子: 2.4

Donor supply for partial heart transplantation in the United States.

美国部分心脏移植的供体供应。

• DOI: 10.1111/ctr.15060
• 发表时间: 2023
• 期刊: Clinical transplantation
• 影响因子: 2.1
• 作者: Quintao,Ritchelli;Kwon,JennieH;Bishara,Katherine;Rajab,TaufiekKonrad
• 通讯作者: Rajab,TaufiekKonrad

Partial heart transplantation of atrioventricular valves in complete atrioventricular septal defect-simulation of techniques using silicone-molded heart models.

• DOI: 10.1016/j.xjtc.2023.09.028
• 发表时间: 2023-12
• 期刊: JTCVS TECHNIQUES
• 影响因子: 1.6
• 作者: Hussein, Nabil;Turek, Joseph W.;Rajab, Taufiek Konrad
• 通讯作者: Rajab, Taufiek Konrad

Semilunar valve growth and function 10 years after infant heart transplantation: Predicting long-term outcomes of partial heart transplants.

婴儿心脏移植后 10 年半月瓣的生长和功能：预测部分心脏移植的长期结果。

• DOI: 10.1111/petr.14746
• 发表时间: 2024
• 期刊: Pediatric transplantation
• 影响因子: 1.3
• 作者: Rajab,TaufiekK;Abdelrahman,Mohamed;Schwartzenburg,ElridgeJ;Aykut,Berk;Turek,JosephW;McVadon,DeaniH
• 通讯作者: McVadon,DeaniH