Greatly Extended Subzero Ischemic Storage of Renal Allografts Using Novel Bio-inspired Next Generation Cryoprotectants

使用新型仿生下一代冷冻保护剂大大延长肾同种异体移植物的零度以下缺血储存

• 批准号: 10761617
• 负责人: Gerald Brandacher
• 金额: $ 97.12万
• 依托单位: X-THERMA INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761617
• 关键词: Animal Model; Animals; Autologous Transplantation; Back; Biological Markers; Blood Chemical Analysis; Blood donor; Breakthrough device; Chemicals; Chemistry; Clinical; Collaborations; Complete Blood Count; Creatinine; Cryopreservation; Data Set; Dimethyl Sulfoxide; Evaluation; Family suidae; Flushing; Formulation; Funding; Geography; Goals; Health Care Costs; Histology; Human; Immunohistochemistry; Injury; Injury to Kidney; Investigation; Ischemia; Kidney; Kidney Transplantation; Length of Stay; Life; Logistics; Marketing; Methods; Miniature Swine; Modality; Modeling; Monitor; Organ; Organ Preservation; Organ Preservation Solutions; Organ Size; Organ Transplantation; Patient-Focused Outcomes; Patients; Peptoids; Perfusion; Phase; Play; Postoperative Period; Preservation Technique; Process; Production; Property; Proteins; Protocols documentation; Recommendation; Recovery; Recovery of Function; Renal Blood Flow; Renal function; Reperfusion Therapy; Rewarming; Role; Serum; Small Business Innovation Research Grant; Surgeon; System; Technology; Temperature; Testing; Time; Tissue Preservation; Tissue Viability; Toxic effect; Translating; Transplantation; Universities; Urine; Weight; Wisconsin; Work; clinically relevant; commercialization; cost; improved; improved outcome; in vivo; innovation; kidney allograft; kidney preservation; medical schools; next generation; novel; post-transplant; pre-clinical; preservation; success; transplant model

Abstract: Organ preservation remains a daunting challenge. Organ specific ischemia windows of 4-24h greatly limit the field of organ transplantation to save lives and cause severe geographic restriction in the US and globally. However, by halting ischemic damage at the point of procurement, we could facilitate enhanced graft viability and thus faster patient recovery, drastically shorter hospital stays, and greatly diminished healthcare costs – all while tackling the biggest challenge of all – to increase the amount of available organs for transplant. The goal of this Direct-to-PhaseII SBIR proposal is to establish the pre-clinical use of XT-ViVo for the non- frozen, subzero ischemic preservation and transplantation of renal allografts leading to improved outcome in comparison to static cold storage and to render greatly extended CIT of up to 120h possible using practical storage and transport methods. Reducing damage during extended ischemia is of critical relevance to kidney transplantation. Indeed, the FDA has recognized this technology as a Breakthrough Device for up to 120h preservation of the kidney, which could lead to dynamic shifts to logistics of kidney transplantation. This project combines novel chemistry and expertise in tissue and organ preservation with world leaders in transplantation. We will apply novel cryoprotectants to high subzero temperature ischemic preservation of porcine kidneys followed by subsequent transplantation in an effort to significantly extend the ischemia window of human-sized organs in a clinically relevant model. The evaluation of innovative modalities that may transform current preservation strategies requires the use of translational animal models for reliable assessment of tissue viability and functional recovery post-preservation. Herein, we propose two primary aims of the proposed work. Advanced cryoprotectants will be synthesized and prepared into formulations as organ preservation solutions. The novel cryoprotectants will first be applied to the preservation of pig kidneys ex vivo, at subzero temperature. We will assess kidney survival, function, injury biomarkers, histology, and immunohistochemistry. This work will further asses the ability to greatly extend subzero ischemia time of the kidney up to 120h first ex vivo, and then using a widely-accepted preclinical large animal transplantation model for close clinical relevance to humans. Heterotopic kidney transplantation will be investigated after greatly extended ischemic storage on SLA-defined miniature swine. Animal survival and kidney function will be assessed similarly with a heightened level of detail at post-operative day 0, 1, 7, and 30 to assess both intermediate and long-term kidney function. Execution of the stated aims could result in a fundamental improvement in the field of organ transplantation and will aid acquisition of the final data set required prior to clearance and clinical for commercialization. The product will offer extension of the ischemia window, simplified use with minimal disruption of current practice, and strong cost competitiveness compared to the advanced organ perfusion systems being developed in the market today.

摘要：器官保存仍然是一个艰巨的挑战。 4-24H的器官特定缺血窗口 限制器官移植的领域以挽救生命并在美国造成严重的地理限制和 全球。但是，通过在采购时停止缺血损伤，我们可以促进增强的移植物 生存能力，因此患者康复的速度更快，医院急剧缩短，医疗保健大大降低 成本 - 在应对所有最大挑战的同时，增加了移植可用器官的数量。 这个直接到底的II SBIR提案的目的是建立XT-Vivo的临床前使用。 冷冻的，亚季节缺血性保存和肾脏同种异体移植的移植，导致结果改善 与静态冷藏的比较，并使用实用性大大扩展了最多120h的CIT 存储和运输方法。减少延长缺血期间的损害与肾脏至关重要 移植。确实，FDA已将这项技术视为最多120h的突破性设备 保存肾脏，这可能导致动态转移到肾脏移植的物流。 该项目结合了新颖的化学和组织和器官保存专业知识与世界领导者 移植。我们将将新型的冷冻保护剂应用于高亚零温度缺血性保存 猪肾脏，然后进行随后的移植，以显着扩展缺血窗口 在临床相关模型中的人尺寸器官的。评估可能改变的创新方式 当前的保存策略需要使用翻译的动物模型来可靠地评估组织 生存能力和功能恢复后保护。在此，我们提出了拟议工作的两个主要目标。 晚期的冷冻保护剂将被合成并制备为配方作为器官制备溶液。 新型的冷冻保护剂将首先应用于零温度下的猪肾脏的保存。 我们将评估肾脏生存，功能，损伤生物标志物，组织学和免疫组织化学。这项工作将 进一步的能力将肾脏的亚零缺血时间延伸到第一个离体120h，然后 使用广泛接受的临床前大动物移植模型，与人类紧密临床相关。 在SLA定义大大扩展缺血储存后，将研究异位肾脏移植 微型猪。动物的生存和肾功能将与细节水平相似地评估 在术后第0、1、7和30天，以评估中间和长期肾脏功能。 执行陈述的目标可能会导致器官移植和 将有助于获取在清算和临床商业化之前所需的最终数据集。产品 将提供缺血窗口的扩展，简化使用，而当前实践的中断最小，并且很强 与当今市场开发的先进器官灌注系统相比，成本竞争力。