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Breakthrough Tissue and Organ Preservation and Transplantation Using Scaled-Up Nanowarming Technology

利用大规模纳米变暖技术实现突破性组织和器官保存和移植

基本信息

批准号：
9980462
负责人：
JOHN C BISCHOF
金额：
$ 58.61万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980462
关键词：
Animal Model Animals Aorta Architecture Arteries Biocompatible Materials Biological Blood Vessels Cells Cellular Structures Convection Coupling Cryopreservation Cryopreserved Tissue Cryoprotective Agents Crystal Formation Crystallization Data Degenerative Disorder Dehydration Development Devices Electromagnetics Engineering Eye Fracture Freezing Frequencies Funding Future Glass Health Care Costs Heart Heart Transplantation Heating Hour Human Ice Kidney Life Link Liquid substance Lung Magnetic nanoparticles Magnetism Measures Methods Modeling Mus National Heart, Lung, and Blood Institute Neonatal Nitrogen Organ Organ Donations Organ Donor Organ Preservation Organ Transplantation Oryctolagus cuniculus Outcome Patients Performance Polyethylene Glycols Process Production Protocols documentation Quality Control Rattus Recovery Regenerative Medicine Rewarming Rodent Sample Size Sampling Savings Services Silicon Dioxide Speed Stabilizing Agents Structure System Techniques Technology Temperature Testing Time Tissue Engineering Tissue Preservation Tissue Transplantation Tissue Viability Tissues Toxic effect Transplantation Transportation attenuation biomaterial compatibility clinical translation cold temperature cryogenics functional restoration improved in vivo interest iron oxide nanoparticle magnetic field nanomaterials nanoparticle nanoparticle delivery nanowarming new technology novel particle prevent radio frequency response scale up success thermal stress tissue/organ preservation transplant model transplantation medicine vitreous state

项目摘要

ABSTRACT: Rewarming biomaterials from the vitrified state is a critical step in obtaining successful cryopreservation. Successful techniques for rescuing cryopreserved bulk biomaterials and organs would not only provide critical improvements for donor-organ transport, supply, and matching, but is also a missing link in the potential supply chain for engineered tissues. Typical freezing processes cause significant damage to biomaterials through ice crystal formation and cellular dehydration. However, with the aid of cryoprotectant (CPA) solutions, biospecimens can be stabilized in the vitreous (i.e. “glass” or “amorphous”) state, allowing for long-term cryopreservation. A number of groups have employed successful techniques for cooling bulk systems to the vitreous state (including entire rabbit kidneys). Rewarming these vitrified biomaterials is a greater engineering challenge, due to the critical warming rates (hundreds of oC/min) necessary to avoid devitirification (i.e. crystallization) during thaw. In addition, non-uniformity in temperature field produces thermal stresses that can crack the brittle material, and so both speed and uniformity of thaw are of critical importance. Here we propose to investigate the ability of radiofrequency heated magnetic nanoparticles, or “nanowarming,” to overcome this major limitation hindering further development of bulk cryopreservation approaches. Although electromagnetic rewarming has been tried, the direct coupling of the waves to tissue inherently results in non-uniformity in heating, which leads to cracking and differential viability. At lower radiofrequencies (RF < 1 MHz) alternating magnetic fields (AMFs) can uniformly penetrate tissues without attenuation and negligible dielectric coupling. Although these lower frequency fields will be unable to rapidly heat the tissue on their own, they are ability to produce significant heating through coupling with magnetic (e.g. iron-oxide) nanoparticles. We have already demonstrated that this approach is able to generate heating rates rapid enough to avoid devitirification (greater than 200 oC/min) and should scale independent of sample size. The objective of this study is to refine this novel nanowarming technology for use in cryopreserving biologic tissues and intact organs for transplant. To this end, in Aim 1 we will scale up the nanoparticle production process and the size of the RF heating device. In Aim 2 we will optimize CPA and nanoparticle composition and loading/unloading conditions for vitrification and nanowarming of cells and tissues (arteries). In Aim 3 we will test these optimized conditions in heart transplant models of increasing size and complexity. In summary, the focus of this proposal will be to leverage our breakthrough nanowarming technology by optimizing CPA composition and nanoparticle delivery in a scaled up system capable of vitrifying and recovering cells, arteries, and intact organs with an eye on future application for cryopreserving tissues and organs for use in human transplantation.

摘要：从玻璃化状态复温生物材料是获得成功的冷冻保存的关键步骤。拯救冷冻保存的散装生物材料和器官的成功技术不仅将提供关键的改善捐赠器官的运输，供应和匹配，但也是潜在供应中缺失的一环用于工程组织的链。典型的冷冻过程会通过冰对生物材料造成重大损害晶体形成和细胞脱水。然而，在冷冻保护剂（CPA）溶液的帮助下，生物样本可以稳定在玻璃态（即“玻璃”或“无定形”），冷冻保存许多研究小组已经采用了成功的技术来冷却大体积系统，玻璃体状态（包括整个兔肾）。重新加热这些玻璃化的生物材料是一项更伟大的工程挑战，由于关键的升温速率（数百摄氏度/分钟），以避免devitrification（即，结晶）。此外，温度场的不均匀性产生热应力，使脆性材料破裂，因此解冻的速度和均匀性都是至关重要的。在这里，我们建议研究射频加热的磁性纳米粒子的能力，或 “冷冻保存”，以克服这一主要限制阻碍进一步发展散装冷冻保存接近。尽管已经尝试过电磁复温，但波与组织的直接耦合固有地导致加热的不均匀性，这导致开裂和不同的生存能力。以较低射频（RF < 1 MHz）交变磁场（AMF）可以均匀地穿透组织，衰减和可忽略的介电耦合。虽然这些低频场将无法迅速当它们自身加热组织时，它们能够通过与磁性（例如，氧化铁）纳米颗粒。我们已经证明，这种方法能够产生加热率足够快，以避免偏差（大于200 oC/min），并应独立于样本量进行缩放。本研究的目的是改进这种新的冷冻技术，用于冷冻保存生物制品。组织和完整的器官用于移植。为此，在目标1中，我们将扩大纳米颗粒的生产工艺和RF加热装置的尺寸。在目标2中，我们将优化CPA和纳米颗粒组合物以及用于细胞和组织（动脉）的玻璃化和冷冻的装载/卸载条件。在目标3中，将在越来越大和复杂的心脏移植模型中测试这些优化条件。总之，本提案的重点将是利用我们突破性的自动化技术，在能够玻璃化的放大系统中优化CPA组合物和纳米颗粒递送，回收细胞、动脉和完整器官，着眼于未来冷冻保存组织的应用，用于人体移植的器官。