Subzero preservation of vascular composite allografts

同种异体复合血管的低温保存

基本信息

批准号：
10664308
负责人：
JOHN C BISCHOF
金额：
$ 54.6万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10664308
关键词：
Adopted Allografting Allylamine Animal Model Animals Blood Vessels Blood capillaries Bone Marrow Bypass Calculi Cell Culture Techniques Cell Maintenance Cell Survival Cell Volumes Cells Cellular Morphology Chills Chimerism Chronic Clinical Clinical Research Clinical Trials Cryoprotective Agents Data Development Dextran Sulfate Diffusion Edema Endothelial Cells Endothelium Engineering Ensure Ethics Excision Family suidae Film Freezing Future Gel General Hospitals Goals Health Heart Hindlimb Hour Human Hydrogels Immune Immune Tolerance Immunosuppression Injury Institutes Institution Iron Ischemia Kidney Limb structure Liver Long-Term Effects Magnetic Resonance Imaging Marrow Massachusetts Measures Medicine Methods Minnesota Modeling Muscle Operative Surgical Procedures Organ Organ Transplantation Osmolalities Osmotic Shocks Outcome Perfusion Permeability Physiological Polyethylene Glycols Preparation Protocols documentation Rattus Recovery Reporting Rewarming Rodent Rodent Model Silicon Dioxide Skin Solid Technology Temperature Testing Time Tissues Toxic effect Transplant Recipients Transplantation Universities Variant Vascular Endothelial Cell Vascular resistance Work allotransplant base biomaterial compatibility calginat case control cell injury conditioning image guided in vitro testing iron oxide nanoparticle ischemic injury nanoparticle nanowarming novel polyacrylamide preconditioning preservation prevent radio frequency scale up shear stress side effect standard of care success transplant model uptake vascular injury

项目摘要

ABSTRACT. The technical feasibility of VCA transplantation was demonstrated 20 years ago and the initial clinical outcomes have been encouraging. However, the ethical calculus of lifelong immunosuppression does often preclude VCA transplantation. To avoid the side effects of long-term immunosuppression, the most promising approach is the induction of tolerance by mixed chimerism via bone-marrow co-transplantation. This is the only strategy that has shown efficacy in large animal and clinical studies of solid organ transplantation. However, current tolerance protocols in clinical trials require somewhere between 3 to 7 days to pre-condition the recipient, measured from initial donor graft recovery to recipient transplantation. Sidestepping the need for preconditioning to induce mixed chimerism does not appear easy to achieve and failed in a clinical VCA transplant case when attempted by one team. Contrary to kidneys, in VCA there is no possibility of living donation, making advance recipient conditioning clinically unrealistic. Therefore, a technology to extend graft preservation to bridge the time for recipient conditioning remains a critical necessity that would enable tolerance induction in VCA transplants. Our overall goal is to develop a high subzero preservation protocol that will prolong the viability of vascular tissues during preservation prior to transplantation, thereby creating a time window to implement tolerance induction protocols. The overarching hypothesis of this study is that alleviating osmotic shocks during cryoprotective agent (CPA) loading, reducing shear injury and toxicity to endothelial cells during loading and unloading CPAs, and bypassing uncontrolled ischemia during rewarming from subzero temperatures by nanowarming, will enable superior and extended preservation of limb allografts. This hypothesis has been formulated based on our prior data demonstrating success in supercooling of human livers showing proof of scalability; however initial attempts to directly adopt the same protocol for rat and pig limbs led to excessive edema and identification of extreme sensitivity to ischemic injury and vascular resistance compared to livers. The multi-institutional partnership assembled for this work brings together the unique expertise of two institutions: 1) subzero organ storage at the MGH Center for Engineering in Medicine & Surgery, and 2) the University of Minnesota Institute for Engineering in Medicine’s unique technology of nanowarming. Our expected contribution here is the development of a new preservation protocol for rat vascularized composite tissues that extends total storage duration from hours to days, and provides time to prepare the recipient to induce tolerance. This contribution is significant because the methods developed here could be the proof-of-concept for a protocol that is clinically practical for tolerance induction in VCA transplants, and could therefore enable their wide-spread use which is not possible currently.

摘要：VCA 移植的技术可行性在 20 年前就已得到证实并初步临床。然而，终生免疫抑制的伦理考量往往会排除 VCA 的可能性。为了避免长期免疫抑制的副作用，最有希望的方法是诱导。通过骨髓共移植的混合嵌合体的耐受性这是唯一已显示出有效性的策略。实体器官移植的大型动物和临床研究然而，目前临床试验中的耐受方案需要。从最初的供体移植物恢复到受体，需要 3 到 7 天的时间对受体进行预处理避免诱导混合嵌合体的预处理似乎并不容易实现和实现。一个团队在临床 VCA 移植案例中失败了，与肾脏相反，VCA 不存在这种可能性。活体捐赠，使得在临床上预先进行受者调理是不现实的，因此，需要一种延长移植物的技术。保存以弥补接受者调节的时间仍然是实现耐受诱导的关键必要性在 VCA 移植中。我们的总体目标是开发一种高低温保存方案，以延长血管组织的活力在移植前的保存过程中，从而创造一个时间窗口来实施耐受诱导方案。这项研究的总体假设是减轻冷冻保护剂 (CPA) 加载过程中的渗透压冲击，减少装载和卸载 CPA 过程中对内皮细胞的剪切损伤和毒性，并绕过不受控制的情况通过纳米变暖从零下温度复温期间的局部缺血，将能够实现卓越和长期的保存这一假设是根据我们先前证明肢体过冷成功的数据提出的。人类肝脏显示出可扩展性的证据；然而，初步尝试直接对大鼠和猪的肢体采用相同的方案与其他药物相比，导致过度水肿，并对缺血性损伤和血管阻力极度敏感为这项工作组建的多机构合作伙伴关系汇集了两个机构的独特专业知识： 1) 麻省总医院医学与外科工程中心的零下器官储存，以及 2) 明尼苏达大学医学工程研究所独特的纳米变暖技术。我们的预期贡献是开发一种新的大鼠血管化复合组织保存方案将总储存时间从数小时延长至数天，并为接受者提供时间以诱导耐受。贡献是重要的，因为这里开发的方法可以作为临床方案的概念验证适用于 VCA 移植中的耐受诱导，因此可以使其广泛使用，这是不可能的现在。