Aerosol Ventilation for Rapid Cooling of Transplant Donor Lungs

项目摘要 美国每年进行超过2，700例肺移植手术，但 捐献的肺意味着每年有成千上万的人在等待合适的捐献者时死亡 器官.尽管目前美国大部分捐赠者的肺来自脑死亡的捐赠者， 约20%的多器官脑死亡供体可提供适合移植的肺。显著 更多的供体肺的机会在于心脏死亡后的捐赠（DCD）捐赠者，但只有 在美国，一小部分DCD供体用于肺移植， 缺血性损伤肺被认为是严重损伤的热缺血，如果他们没有 在灌注或氧合减少的60-90分钟内冷却和氧合。此外，本发明还提供了一种方法， 来自DCD供体的肺在获取前经受>60分钟的热缺血， 支气管愈合受损，原发性移植物功能障碍或再灌注损伤的风险更大。作为 例如，开发一种简单且非侵入性的冷却和充氧肺部的方法， 潜在的不受控制的DCD供体将减轻热缺血的损伤作用， 供体准备采购，并由此提供无限的肺供体供应， 未开发的捐赠者 为了增加可用的供体肺，无限科学有限责任公司开发了一种双液体 雾化通气（BAV）装置原型，其在以下情况下快速且有效地冷却肺： 死亡BAV将两种液体全氟化碳（LP）的混合物雾化，引入 雾化液滴通过呼吸机或面罩进入肺部，收集蒸发的LP蒸汽 从肺，冷凝和充氧的蒸汽，并返回冷却的LP液体到 肺通过原来的雾化方法。LP的蒸发焓提供了快速的 冷却，同时其携带氧气的能力防止缺氧性肺损伤。这款安全、易用、 便携式设备是流动的，可以在ICU和ER中使用，以非侵入性地冷却和 在死后一小时之内就可以移植肺了。 该第1阶段提案的目的是提供肺可以有效地 从37°C冷却到20°C（以减少肺部的代谢消耗，同时提供 氧气到气道）在<30分钟使用LP的组合。为了实现高效冷却， BAV，我们认为，我们需要纳入以下优化参数：液滴大小 以及它们的肺泡停留时间、LP混合物的沸点和传热流体。这将是 实现四个具体目标。目标1：创建最佳液滴尺寸和密度， 用雾化全氟戊烷有效渗透肺泡目标2：建立和评估一个 呼出的冷却系统，以回收蒸发的LP。目的3：确定以下物质的优化混合物： LP和临床相关的冷却方法，例如猪肺可以冷却17°C（至 20°C）下在30分钟内使用优化的BAV参数。目标4：修改呼吸机设置， 操纵LP液滴的肺泡停留时间。一旦获得概念证明，我们 我们将进入第二阶段，在那里我们将改进我们的原型设备，在活体动物身上进行测试， 检测组织健康状况，争取FDA批准

PROJECT SUMMARY Over 2,700 lung transplants are performed in the US each year, but a significant shortage of donor lungs means that thousands of people die each year while waiting for a suitable donor organ. Although most donor lungs in the US are currently taken from brain-dead donors, only ~20% of multiorgan brain dead donors provide suitable lungs for transplantation. A significant opportunity for more donor lungs lies with donation after cardiac death (DCD) donors, but only a tiny fraction of DCD donors in the US are used for lung transplantation due to concerns over ischemic damage. Lungs are considered significantly injured from warm ischemia if they are not cooled and oxygenated within 60–90 min of diminished perfusion or oxygenation. In addition, lungs from DCD donors subject to warm ischemia for >60 min prior to procurement have impaired bronchial healing and greater risk of primary graft dysfunction or reperfusion injury. As such, developing a simple and non-invasive method of cooling and oxygenating lungs in potential uncontrolled DCD donors would mitigate the damaging effects of warm ischemia while the donor is prepared for procurement and provide a boundless supply of lung donors from this untapped donor pool. To improve the pool of usable donor lungs, Boundless Science, LLC developed a bi-liquid aerosolized ventilation (BAV) device prototype that cools a lung quickly and efficiently following death. The BAV aerosolizes a mixture of two liquid perfluorocarbons (LP), introduces the atomized droplets into the lungs through a ventilator or mask, collects evaporated LP vapors from the lungs, condenses and oxygenates the vapor, and returns the cooled LP liquid to the lungs via the original aerosolization method. The LP’s enthalpy of vaporization provides rapid cooling while its ability to carry oxygen prevents hypoxic lung damage. This safe, easy-to-use, portable device is ambulatory and can be used in the ICU and the ER to non-invasively cool and oxygenate lungs for transplant well within an hour after death. The objective of this phase 1 proposal is to provide proof of concept that lungs can be efficiently cooled from 37°C to 20°C (to decrease metabolic consumption by the lungs while providing oxygen to the airways) in <30 min using a combination of LPs. To achieve efficient cooling with BAV, we believe that we need to incorporate the following optimized parameters: droplet size and their alveolar dwell time, boiling point of the LP mixture, and heat transfer fluid. This will be achieved using four Specific Aims. Aim 1: Create the optimal droplet size and density to effectively infiltrate alveoli with aerosolized Perfluoropentane. Aim 2: Build and evaluate an exhaled cooling system to recover the vaporized LP. Aim 3: Determine the optimized mixture of LPs and a clinically relevant cooling method such that pig lungs can be cooled by 17°C (to 20°C) in under 30 minutes using optimized BAV parameters. Aim 4: Modify ventilator settings to manipulate the alveolar dwell time of LP droplets. Once proof of concept has been obtained, we will progress to Phase II, where we will refine our prototype device, test it on live animals and test for tissue health, and pursue FDA approval.