Aerosol Ventilation for Rapid Cooling of Transplant Donor Lungs

用于快速冷却移植供体肺的气雾通气

• 批准号: 10481907
• 负责人: Andrew Jones
• 金额: $ 29.9万
• 依托单位: BOUNDLESS SCIENCE, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2023-11-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481907
• 关键词: Accident and Emergency department; Acute Respiratory Distress Syndrome; Aerosols; Alveolar; Alveolus; Animal Testing; Animals; Brain Death; Cardiac Death; Cessation of life; Clinical; Collection; Consumption; Country; Devices; Donor person; Environment; Exhalation; Family suidae; Fluorocarbons; General Hospitals; Goals; Grant; Health; Hour; Impairment; Intensive Care Units; Intervention; Letters; Liquid substance; Lung; Lung Transplantation; Lung diseases; Masks; Measurement; Measures; Mediating; Medical Device; Metabolic; Methods; Normal Range; North America; Operating Rooms; Organ; Organ Donor; Oxygen; Patients; Pentanes; Perfusion; Persons; Phase; Physical condensation; Preparation; Process; Protocols documentation; Proxy; Recycling; Reperfusion Injury; Respiratory Failure; Risk; Rodent Model; Safety; Science; Small Business Innovation Research Grant; System; Technology; Temperature; Testing; Time; Tissues; Transplantation; Treatment Cost; Ventilator; Warm Ischemia; Work; aerosolized; analog; clinically relevant; density; design; enthalpy; graft dysfunction; healing; improved; injured; innovation; ischemic injury; lung hypoxia; lung injury; perfluoropentane; portability; post-transplant; preservation; prevent; programs; prototype; respiratory; vapor; vaporization; ventilation

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.

项目概要 美国每年进行超过 2,700 例肺移植手术，但严重短缺 供肺意味着每年有成千上万的人在等待合适的供体期间死亡 尽管目前美国大多数供体肺均取自脑死亡供体，但只有 大约 20% 的多器官脑死亡捐献者提供了适合移植的肺部。 心脏死亡（DCD）捐献者的捐献是获得更多肺供体的机会，但只有 由于担心肺移植，美国只有一小部分 DCD 捐献者被用于肺移植 如果不是，则认为肺部因热缺血而受到严重损伤。 灌注或氧合减少后 60-90 分钟内冷却并氧合。 来自 DCD 供体的肺在采购前经历了超过 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。 因此，开发一种简单且非侵入性的方法来冷却和给肺部供氧 潜在的不受控制的 DCD 供体将减轻热缺血的破坏性影响，同时 捐赠者已做好采购准备，并由此提供无限量的肺捐赠者供应 未开发的捐助库。 为了改善可用供体肺池，Boundless Science, LLC 开发了一种双液体 雾化通气 (BAV) 设备原型可快速有效地冷却肺部 BAV 雾化两种液体全氟化碳 (LP) 的混合物，介绍了 通过呼吸机或面罩将雾化液滴吸入肺部，收集蒸发的液化石油气蒸汽 从肺部排出，对蒸气进行冷凝和充氧，并将冷却的液化石油气返回到 通过原始的雾化方法，LP 的汽化焓提供了快速的作用。 冷却的同时其携带氧气的能力可防止缺氧性肺损伤。 便携式设备是流动的，可在 ICU 和 ER 中使用，以非侵入性方式冷却和 死后一小时内为肺部充氧以进行移植。 该第一阶段提案的目标是提供肺部可以有效地 从 37°C 冷却至 20°C（以减少肺部的代谢消耗，同时提供 使用 LP 组合在 30 分钟内将氧气输送到气道，以实现高效冷却。 BAV，我们认为需要纳入以下优化参数： 液滴尺寸 以及它们的肺泡停留时间、LP 混合物的沸点和传热流体。 通过四个具体目标 1 实现：创建最佳的液滴尺寸和密度。 用雾化的全氟戊烷有效地渗透肺泡 目标 2：建立并评估 呼气冷却系统回收汽化的液化石油气 目标 3：确定优化的混合物。 LP 和临床相关的冷却方法，使猪肺可以冷却 17°C（至 使用优化的 BAV 参数在 30 分钟内达到 20°C）目标 4：将呼吸机设置修改为 一旦获得概念证明，我们就可以控制 LP 液滴的肺泡停留时间。 将进入第二阶段，我们将完善我们的原型设备，在活体动物上进行测试， 测试组织健康，并寻求 FDA 批准。