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

该项目将建立控制表面张力梯度驱动(Marangoni)流的基本机制，以诱导气溶胶沉积后跨亚相的传输，模拟肺呼吸道表面液体(ASL)。虽然吸入的气雾剂药物可以将大量的药物直接输送到肺部，但通风模式的改变会导致吸入的药物不均匀地沉积在患病的肺部。一些肺部区域接受了非常高的局部剂量，而另一些区域则没有得到治疗。这需要新的方法来引起沉积后扩散才能有效。目前美国国家科学基金会的一项研究表明，表面活性物质诱导的Marangoni应力增强了毫米级液滴在模拟ASL的亚相中的扩散。在这项更新建议中，PI扩展了他们的研究，以解决气溶胶液滴通量如何与单个液滴的扩散动力学相耦合，以在ASL模拟亚相上产生最大的扩散。智力优势：通过之前的NSF拨款，PI已经获得了毫米级表面活性剂溶液如何在复杂的亚相中扩散的完整图像，以及什么特性控制了最终的扩散区域。这些结果为开发成功的治疗方法提供了一套明确的材料选择和剂量标准。他们为目前的提议奠定了基础，我们将在那里确定优化微米级液滴气溶胶沉积的最终扩散面积的条件。虽然人们对气溶胶在分支系统(如肺)中的扩散进行了很好的研究，但液滴在沉积后的扩散还没有得到很好的研究。目前资助下的研究使用单个液滴，并证实表面活性剂极大地增强了水滴在水相聚合物亚相上的沉积后传输。然而，为了确定将优化气雾滴扩散的条件，它们解决了一些基本问题。决定在毫米尺度上运行的同样的散布机构在10微米尺度上运行吗？相邻的表面活性剂水溶液在沉积后如何滴在复杂的水相亚相上？在一个缠绕的水相聚合物亚相上，液滴沉积、扩散和合并的时间尺度如何竞争以控制最终的扩散区域？这项研究涉及两个具体目标：1)确定控制沉积在复杂亚相上的气溶胶液滴横向相互作用的液滴尺度、过程和性质。2)确定气溶胶沉积通量和总剂量如何决定沉积后扩散的最终程度。该项目将通过建立沉积后扩散程度与先前目标中确定的关键参数和时间尺度的经验定量关联来完成这项工作。广泛的影响：正如早期在确定毫米级液滴的基本扩散机制方面的工作为表面活性物质增强的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雾剂配方的组成方面提供了新的选择，而且在诸如呼吸模式等给药方案方面提供了新的选择，以优化药物向患病肺的所有区域的扩散。因此，拟议的研究将成为表面活性剂作为气雾剂药物传递的自分散载体进行测试的配方设计工具。这项技术将有利于治疗任何数量的阻塞性肺部疾病，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促进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部医学专家合作，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。作为这笔赠款的一部分，研究人员将计划举办一次为期两到三天的研讨会，将临床和科学和工程界聚集在一起，就理解和利用外源性液体在肺部运动的机制交换意见。调查人员将在每个学年和暑假指导一名本科生和每年至少两名参加卡内基梅隆/科尔法克斯物理概念拓展计划的中学生。

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.