Marangoni Driven Spreading on Entangled Polymer Subphases with Application to Pulmonary Drug Delivery

该项目将建立基本的润湿机制，以利用表面张力梯度驱动（Marangoni）流来增强气溶胶在肺部的药物传播。虽然吸入的气雾剂药物可以将大剂量的药物直接输送到肺部，但与患病肺部相关的通气模式的改变会导致吸入的药物不均匀沉积，因此一些肺部区域接受了非常高的局部剂量的药物，而其他区域则得不到治疗。初步研究表明，在气溶胶中加入表面活性剂将使这些药物在沉积后更有效地分散。在研究中，pi将确定表面活性剂配方的特性，以优化用于气溶胶药物输送的自分散液体的功效。这项研究将建立在先前对表面活性剂替代疗法（SRT）期间外源性液体在早产儿肺部扩散机制的研究基础上，但其重点将在三个方面有所不同。首先，我们把重点放在方案的最终传播领域，而不是忽视它，较少地关注导致这种最终状态的动态机制。其次，它们确定液滴中的表面活性剂、含水溶剂和溶解或溶解的替代药物如何在表面上分布。最后，初步工作强烈表明，在扩散过程的时间尺度上存在很大的分离，因此，最终的扩散液滴状态是通过给药流体的扁平透镜上的准静态界面张力平衡来捕获的。最有效分散药物的关键是使静晶状体面积最大化。智力优势：SRT有效性的发现催生了大量关于马兰戈尼流在气道中的作用的研究。理论分析探讨了肺中转运发生的复杂亚相的分支，但实验研究集中在更简单的系统上。他们将通过实验研究这些分析对流变学复杂亚相的关键预测，这些亚相可能从根本上改变表面活性剂驱动的肺内液体扩散。此外，先前的工作强调了初始扩散阶段的动力学，但他们将重点转向了决定液体最终处置的机制，特别是作为模型药物的溶解或溶解染料。将注意力重新集中在传播公式的最终状态上，代表了一种解决问题的新颖和潜在的变革方法。更广泛的影响：拟议的研究结果将指导表面活性剂配方的选择，以测试用于气溶胶药物输送的自分散载体。这项技术将有利于治疗任何数量的阻塞性肺病，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部医学专家合作，我们的基本发现将指导体内研究。通过定期参加与临床研究者的研讨会和会议，该项目的工程和物理研究生将在一个高度跨学科的环境中接受培训。他们将在每个学年和夏季指导一名本科生和至少两名中学生参加卡内基梅隆大学/科尔法克斯物理概念推广计划。

0931057GaroffThis project will establish the fundamental wetting mechanisms required to harness surface tension gradient driven (Marangoni) flows to enhance spreading of drug delivered by aerosols in the lung. While inhaled aerosol drugs can deliver substantial doses of medication directly to the lungs, altered patterns of ventilation associated with diseased lungs cause inhaled drugs to deposit non-uniformly so that some lung regions receive very high local doses of medication while other regions go untreated. Preliminary studies suggest that the addition of surfactant to the aerosol will disperse these drugs more effectively after deposition. In the research, the PIs will identify the characteristics of surfactant formulations that optimize the efficacy of self-dispersing liquids for aerosol drug delivery. The research will build on prior research on the mechanism of spreading of exogenous fluids in the lungs of premature infants during Surfactant Replacement Therapies (SRT) but will differ in its focus in three ways. First, we focus on the final spread area of the formulation and, while not neglecting it, less on the dynamic mechanisms that lead to that final state. Second, they determine how the surfactant, the aqueous solvent, and the dissolved or solubilized surrogate drug in the droplets are distributed on the surface. Finally, the preliminary work strongly suggests a large separation in the time scales of the underlying processes in the spreading, such that the final spread droplet state is captured by a quasi-static interfacial tension balance on a flattened lens of the dosing fluid. The key to the most effective drug dispersal is to maximize the static lens area. Intellectual Merit: The discovery of effectiveness of SRT spawned considerable research into role of Marangoni flows in the airways. Theoretical analyses explored the ramifications of the complex subphases over which the transport occurs in the lungs, but experimental research focused on simpler systems. They will experimentally investigate key predictions of these analyses on rheologically complex subphases that could fundamentally alter the surfactant-driven spreading of fluids in the lung. In addition, prior work placed the emphasis on the dynamics of the initial spreading stages, but they turn the focus to the mechanisms that dictate the final disposition of the fluids, especially the dissolved or solubilized dyes that serve as model drugs. The refocusing of attention on the final state of the spread formulation represents a novel and potentially transformative approach to the problem. Broader Impacts: The results of the proposed research will guide the choice of surfactant formulations to be tested for self-dispersing carriers for aerosol drug delivery. This technology will benefit 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 fundamental physical mechanisms of enhanced drug spreading, the team collaborates with pulmonary medicine specialists in the University of Pittsburgh Medical School where our fundamental findings will guide in vivo studies. By regularly attending seminars and meetings with clinical investigators, the engineering and physics graduate students on this project will be trained in a highly interdisciplinary environment. They 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.