Surfactant Induced Post-Deposition Transport of Aerosols with Application to Pulmonary Drug Delivery

表面活性剂诱导的气溶胶沉积后传输及其在肺部药物输送中的应用

• 批准号: 1159369
• 负责人: Stephen Garoff
• 金额: $ 30万
• 依托单位: Carnegie-Mellon University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1159369&HistoricalAwards=false
• 关键词: Surfactant; Induced; Post; Deposition; Transport

Abstract#1159369Garoff, StephenMotivated by a new approach to enhance pulmonary aerosol drug delivery, the project will establish the fundamental mechanisms controlling surface tension gradient driven (Marangoni) flows to induce post-deposition transport of aerosol across subphases that mimic the lung airway surface liquid (ASL). While inhaled aerosol drugs can deliver substantial doses of medication directly to the lungs, altered patterns of ventilation cause inhaled drugs to deposit non-uniformly in diseased lungs. Some lung regions receive very high local doses while other regions go untreated. This demands new methods to cause post-deposition spreading in order to be effective. The research under a current NSF grant has shown that surfactant induced Marangoni stresses enhance spreading of millimeter scale drops acrosssubphases mimicking the ASL. In this renewal proposal, the PIs extend their research to address how the aerosol droplet flux to the subphase couples with individual droplet spreading dynamics to produce the maximum spreading on ASL mimic subphases.Intellectual Merit: Through the previous NSF grant, the PIs have obtained a complete picture of how millimeter scale drops of surfactant solutions spread across complex subphases and what properties control the final spread area. These results present a clear set of material selection and dosing criteria for developing successful therapies. They set the stage for the present proposal where we will determine the conditions for optimizing the final spread area from aerosol deposition of micron scale droplets. While dispersion of aerosol in a branched system such as the lung is well studied, the post-deposition spreading of the droplets is not. The research under the current grant uses single droplets and has confirmed that surfactant greatly enhances the post-deposition transport of aqueous droplet contents on aqueous polymeric subphases. However, to determine the conditions that will optimize the spreading of aerosol droplets, they address a number of fundamental issues. Do the same spreading mechanisms determined to operate at the millimeter scale operate at the 10 micron scale? How do adjacent aqueous surfactant solution drops on a complex aqueous subphase coalesce after deposition? How do the timescales of droplet deposition, spreading, and coalescence on an entangled aqueous polymeric subphase compete to control the final spread area? The research addresses two specific aims: 1) Determine the droplet scale processes and properties that control the lateral interactions of aerosol droplets after deposition on complex subphases. 2) Determine how aerosol deposition flux and total dose determine the final extent of post-deposition spreading. The project will culminate this work by developing empirical quantitative correlations for the extent of post-deposition spreading with the critical parameters and time scales identified in previous aims.Broader Impacts: Just as the earlier work in determining the fundamental spreading mechanisms of millimeter scale drops has established the basis for materials selection for surfactant-enhanced pulmonary drug delivery methods, the research here provides new options in not only the composition of aerosol formulations but also the administration protocols such as breathing patterns to optimize drug spreading to all regions of a diseased lung. Thus, the proposed research will become a formulation design tool for surfactants to be tested as self-dispersing carriers for aerosol drug delivery. This technology will benefit the treatment of any number of obstructive lung diseases, including cystic fibrosis, asthma,pneumonia and other acute or chronic pulmonary infections. While this research focuses on fundamentalphysical mechanisms of enhanced drug spreading, the team collaborates with pulmonary medicine specialists in the University of Pittsburgh School of Medicine where our new fundamental findings will guide in vivo studies. By regularly attending seminars and meetings with clinical investigators, students will be trained in a highly interdisciplinary environment. As part of the this grant, the investigators will plan a two to three day workshop to bring together the clinical and the science and engineering communities to exchange ideas on understanding and harnessing mechanisms for exogenous fluid movement in the lung. The investigators will mentor an undergraduate research student during each academic year and summer and at least two middle school students each year in the Carnegie Mellon/Colfax Physics Concepts Outreach Program.

摘要#1159369Garoff，Stephen 在增强肺部气溶胶药物输送的新方法的推动下，该项目将建立控制表面张力梯度驱动 (Marangoni) 流的基本机制，以诱导气溶胶在模拟肺气道表面液体 (ASL) 的亚相中沉积后传输。虽然吸入气雾剂药物可以将大量药物直接输送到肺部，但通气模式的改变会导致吸入药物不均匀地沉积在患病肺部。一些肺部区域接受非常高的局部剂量，而其他区域则未经治疗。这就需要新的方法来引起沉积后扩散，以便有效。目前 NSF 资助下的研究表明，表面活性剂引起的马兰戈尼应力增强了毫米级液滴在模拟 ASL 的亚相中的扩散。在这项更新提案中，PI 扩展了他们的研究，以解决气溶胶液滴通量如何与各个液滴扩散动力学相结合，以在 ASL 模拟子相上产生最大的扩散。 智力优点：通过之前的 NSF 资助，PI 已经获得了关于表面活性剂溶液的毫米级液滴如何在复杂的子相上扩散以及哪些属性控制最终扩散区域的完整图像。这些结果为开发成功的疗法提供了一套明确的材料选择和剂量标准。他们为当前的提案奠定了基础，我们将确定优化微米级液滴气溶胶沉积的最终扩散区域的条件。虽然气溶胶在肺部等分支系统中的扩散已得到充分研究，但液滴沉积后的扩散却没有得到充分研究。目前资助的研究使用单液滴，并已证实表面活性剂极大地增强了水性液滴内容物在水性聚合物亚相上的沉积后传输。然而，为了确定优化气溶胶液滴扩散的条件，他们解决了许多基本问题。确定在毫米级运行的相同扩散机制是否也可以在 10 微米级运行？沉积后，复杂的水相亚相上的相邻表面活性剂水溶液滴如何聚结？纠缠的水性聚合物亚相上的液滴沉积、铺展和聚结的时间尺度如何竞争以控制最终的铺展面积？该研究解决了两个具体目标：1）确定控制气溶胶液滴沉积在复杂亚相上后横向相互作用的液滴尺度过程和特性。 2) 确定气溶胶沉积通量和总剂量如何确定沉积后扩散的最终程度。该项目将通过开发沉积后扩散程度与之前目标中确定的关键参数和时间尺度的经验定量相关性来完成这项工作。 更广泛的影响：正如早期确定毫米级液滴基本扩散机制的工作为表面活性剂增强肺部药物输送方法的材料选择奠定了基础一样，这里的研究不仅在气溶胶的成分方面提供了新的选择 配方以及给药方案，例如呼吸模式，以优化药物扩散到患病肺部的所有区域。因此，拟议的研究将成为表面活性剂的配方设计工具，以作为气雾剂药物输送的自分散载体进行测试。这项技术将有利于治疗多种阻塞性肺部疾病，包括囊性纤维化、哮喘、肺炎和其他急性或慢性肺部感染。虽然这项研究的重点是增强药物扩散的基本物理机制，但该团队与匹兹堡大学医学院的肺医学专家合作，我们的新基本发现将指导体内研究。通过定期参加与临床研究人员的研讨会和会议，学生将在高度跨学科的环境中接受培训。作为这笔拨款的一部分，研究人员将计划举办一个两到三天的研讨会，将临床和科学与工程界聚集在一起，就理解和利用肺部外源性液体运动机制交换意见。研究人员将在每个学年和夏季指导一名本科生，并在卡内基梅隆/科尔法克斯物理概念推广计划中每年指导至少两名中学生。