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

用于儿科 JORRP 患者气溶胶靶向的动态、细胞化、3D 打印模型开发

基本信息

批准号：
10317899
负责人：
Emily Kolewe
金额：
$ 4.6万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317899
关键词：
3-Dimensional 3D Print 4 year old Adolescent Adult Aerosol Drug Therapy Aerosols Affect Air Air Movements Airway Disease Alpha Particles Area Automation Breathing Cells Child Childhood Clinical Coculture Techniques Collection Complement Complex Computer Models Custom Dangerousness Data Deposition Development Devices Disease Dose Drug Delivery Systems Drug Transport Eating Engineering Ensure Environment Epithelial Cells Eye Eye Infections Eyedrops Fluorescence Generations Geometry Growth Human Papillomavirus Hydrogels Image In Vitro Incidence Individual Inhalation Inhalation Therapy Inhalators Larynx Left Leg Libraries Liquid substance Location Lung Magnetic Resonance Imaging Malignant Neoplasms Measures Mechanics Medicine Modeling Motion Movement Mucous body substance Obstruction Operative Surgical Procedures Oral cavity Otolaryngologist Papilloma Particle Size Patients Pattern Pediatric Surgical Procedures Pharmaceutical Preparations Pharyngeal structure Physiological Physiology Positioning Attribute Postoperative Period Pre-Clinical Model Probability Procedures Rare Diseases Recurrent respiratory papillomatosis Repeat Surgery Speech Structure Techniques Testing Therapeutic Thick Tissues Topical application Validation Work X-Ray Computed Tomography airway obstruction career cost design dosage drug response prediction engineering design experience flexibility glottis in silico in vitro Model mimicry model development multidisciplinary next generation novel particle pediatric patients personalized therapeutic physical model pre-clinical predictive tools prevent response sex simulation standard care tool trend

项目摘要

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.

项目摘要青少年发病的复发性呼吸道乳头状瘤病 (JORRP) 是一种罕见的儿童疾病，可导致声门（声门）上的乳头状瘤群导致严重的气道阻塞和呼吸困难目前的治疗方法是手术，以尽量减少手术损伤。细胞通常会在手术中留下并重新生长，这会导致再生和重复手术的恶性循环。对于类似的 HPV 眼部感染，一些儿童每年需要进行多达 12 次手术。眼结膜乳头状瘤可以通过滴眼液来治疗，但目前还没有这种方法。不幸的是，儿科临床前药物的直接局部治疗递送的等效选择。该领域明显缺乏交付模式，包括那些可能支持定制开发的交付模式儿科吸入疗法的开发仍面临重大挑战。临床前模型可以准确预测儿科患者独特生理学内的药物转运，尤其是在声门等高活动性区域。这项工作的总体目标是设计一个首个实验性儿科“呼吸咽”模型，使我们能够直接建立在真实呼吸条件下儿科特定气道的空间药物沉积曲线。设计驱动的目标需要整合儿科成像、自动化和组织模拟，结合离散工程设计方法为药物转运研究创造关键的实验能力在目标 1 中，我们将在计算机和体外开发类似的动态声门。我们将采用新颖的计算流体粒子动力学（CFPD）建模技术来捕获。我们将改变患者的几何形状、气流速率和颗粒大小，创建气溶胶库。这些模拟将补充并指导体外模型的开发；我们将利用机动化、灵活的声门将技术工程设计与患者气道复制品相结合与颗粒收集冲击器一致的部分以量化颗粒沉积在目标 2 中，我们将增加颗粒。利用 CFPD 建模以最大概率识别有希望的参数，将药物输送到声门成功靶向并随后在体外复制和询问模拟。将细胞化水凝胶放入模型中，以确保疾病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该项目将产生 1) 新颖的动态。儿科声门计算模型，2) 建立儿科气雾剂输送的临床前工具，以及 3) 证据用于治疗阻塞性儿科气道疾病的可定制吸入疗法。