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

项目摘要 青少年起病的复发性呼吸道乳头状瘤病(JORRP)是一种罕见的儿童疾病，可引起 声门(声箱)上的乳头状瘤军团导致严重的呼吸道阻塞和呼吸困难 吃饭、说话和呼吸。目前的治疗方法是手术治疗，为了将手术造成的损害降至最低， 在手术和再生过程中，细胞通常会留下来。这导致了再生和反复手术的恶性循环。 干预，一些儿童每年需要进行多达12次手术。在类似的HPV眼部感染中， 眼结膜乳头状瘤军团通过滴眼液来治疗；然而，目前还没有 声门直接局部治疗的同等选择。不幸的是，儿科临床前药物 值得注意的是，现场缺乏交付模式，包括那些可能支持定制开发的交付模式 儿科吸入疗法。开发高吞吐量、集成化的 临床前模型能准确预测儿科患者独特生理状态下的药物转运， 尤其是在声门等流动性较高的区域。这项工作的总体目标是设计一种 首次建立儿科“呼吸咽”实验模型，使我们能够直接建立 真实呼吸条件下儿科专用呼吸道药物沉积的空间分布。这 设计驱动的目标将需要儿科成像、自动化和组织模拟的集成，结合 为药物传输研究创造关键实验能力的离散工程设计方法 准确的生理动作。在目标1中，我们将开发类似的硅胶声门和体外动态声门。 模特们。我们将使用新的计算流体粒子动力学(CFPD)建模技术来捕获 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，创建一个气雾剂资料库 沉积概况和趋势。这些模拟将补充和通知体外模型的发展； 我们将利用机动、灵活的声门将技术工程设计与患者的呼吸道复制相结合 切片与粒子收集冲击器相一致，以量化粒子沉积。在目标2中，我们将增加粒子 通过利用CFPD建模来识别具有最大概率的有希望的参数来传递到声门 并随后在体外复制和询问模拟。我们将把 细胞水凝胶进入模型，以确保疾病的发展和生理环境 精确的表现，不同的厚度和包括复杂的细胞共培养将确保准确 对生理和疾病发展的模仿。这个项目将产生1)新的动态 儿科声门计算模型，2)建立儿科气雾剂输送的临床前工具，3)证据 用于治疗儿童阻塞性呼吸道疾病的可定制吸入性疗法。

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.