Dynamic, Cellularized, 3D Printed Model Development for Aerosol Targeting in Pediatric JORRP Patients

项目摘要 青少年复发性呼吸道乳头状瘤病（JORRP）是一种罕见的疾病， 声门（声带）上的乳头状瘤军团导致严重的气道阻塞和呼吸困难， 吃饭说话和呼吸目前的治疗方法是手术，为了尽量减少手术损伤， 细胞通常在手术中被留下并再生。这导致了再生和重复手术的恶性循环 一些儿童每年需要多达12次手术。在类似的HPV眼部感染中， 眼结膜乳头状瘤军团是管理与滴眼交付;然而，目前没有 用于直接局部治疗递送到声门的等效选择。不幸的是，儿科临床前药物 外地明显缺乏交付模式，包括那些可能有助于开发定制的 小儿吸入疗法。开发高通量、集成的生物技术仍然是一个重大的挑战。 准确预测儿科患者独特生理学内药物转运的临床前模型， 特别是在诸如声门的高移动性区域中。这项工作的总体目标是设计一个 第一种实验性儿科“呼吸咽”模型，使我们能够直接建立 在实际呼吸条件下儿科特定气道中的空间药物沉积分布。这 设计驱动的目标将需要集成儿科成像、自动化和组织模拟， 离散的工程设计方法，以创建药物转运研究的关键实验能力， 准确的生理运动。在目标1中，我们将开发类似的计算机和体外动态声门 模型我们将采用新的计算流体粒子动力学（CFPD）建模技术，捕捉 声门运动我们将改变患者的几何形状、空气流速和颗粒大小， 沉积概况和趋势。这些模拟将补充和告知体外模型开发; 我们将把技术工程设计与利用机动灵活声门的患者气道复制品结合起来 切片与颗粒收集撞击器成一直线，以量化颗粒沉积。在目标2中，我们将增加粒子 通过利用CFPD建模以最大概率识别有希望的参数， 成功的靶向，随后在体外复制和询问模拟。我们将合并 细胞化水凝胶进入模型，以确保疾病的发展和生理环境， 准确地表示，不同的厚度和包括复杂的细胞共培养将确保准确的 生理和疾病发展的模仿。这个项目将产生1）新的动态 小儿声门计算模型，2）建立小儿气雾剂输送的临床前工具，以及3）证据 可定制的可吸入疗法来治疗阻塞性小儿气道疾病。

PROJECT ABSTRACT Juvenile Onset Recurrent Respiratory Papillomatosis (JORRP) is a rare disease in children that causes papillomatous legions on the glottis (voice box) leading to significant airway obstructions and difficulties with eating, speech, and breathing. The current treatment is surgery and, to minimize surgical damage, diseased cells are usually left behind in surgery and regrow. This leads to a vicious cycle of regrowth and repeated surgical intervention, with some children requiring as many as 12 surgeries each year. In an analogous HPV eye infection, ocular conjunctival papilloma legions are managed with eye drop delivery; however, there are currently no equivalent options for direct topical therapeutic delivery to the glottis. Unfortunately, pediatric preclinical drug delivery models are notably absent in the field, including those that might enable development of customized pediatric inhalation therapies. There is a significant remaining challenge to develop high-throughput, integrated preclinical models that accurately predict drug transport within the unique physiology of pediatric patients, especially in regions of high mobility such as the glottis. The overall objective of this work is to engineer a first-in-kind experimental pediatric “breathing pharyngeal” model, allowing us to directly establish spatial drug deposition profiles in pediatric-specific airways under realistic breathing conditions. This design-driven objective will require integration of pediatric imaging, automation, and tissue-mimicry, combining discrete engineering design approaches to create critical experimentally capacity for drug transport studies under accurate physiological movement. In Aim 1, we will develop analogous in silico and in vitro dynamic glottis models. We will employ novel computational fluid particle dynamics (CFPD) modeling techniques capturing glottis motion. We will vary patient geometry, air flow rates, and particle sizes, creating a library of aerosol deposition profiles and trends. These simulations will complement and inform the in vitro model development; we will integrate technological engineering designs with patient airway replicas utilizing motorized, flexible glottis sections in line with a particle collection impactor to quantify particle deposition. In Aim 2, we will increase particle delivery to the glottis by leveraging CFPD modeling to identify promising parameters with the greatest probability of successful targeting and subsequently replicate and interrogate the simulations in vitro. We will incorporate cellularized hydrogels into the model to ensure disease development and physiological environments are accurately represented, varying thickness and including a complex cellular co-culture will ensure accurate mimicry of physiological and disease development. This project will result in the generation of 1) novel dynamic pediatric glottis computational models, 2) a preclinical tool to establish pediatric aerosol delivery, and 3) evidence of customizable inhalable therapies to treat obstructive pediatric airway diseases.