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

• 批准号: 10514527
• 负责人: Emily Kolewe
• 金额: $ 1.43万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514527
• 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

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 青少年发作复发性呼吸乳头状瘤病（JORRP）是儿童的一种罕见疾病，导致 Glotis（语音盒）上的乳头状腿，导致气道对象和困难 饮食，言语和呼吸。当前的治疗是手术，为了最大程度地减少手术损伤，解散了 细胞通常在手术和改革中留下。这导致了一个奇妙的改革循环和重复的外科手术 干预，一些孩子每年需要多达12次手术。在类似的HPV眼感染中， 眼睛结膜乳头状瘤腿通过眼滴输送来管理；但是，目前没有 直接局部治疗输送到Glotis的等效选择。不幸的是，小儿临床前药物 该领域中的交付模型明显不存在，包括可以开发自定义的模型 小儿吸入疗法。开发高通量，集成的剩余挑战 准确预测儿科患者独特生理中药物转运的临床前模型， 特别是在高流动性的地区，例如Glotis。这项工作的总体目的是设计 首次实验性实验性小儿“呼吸咽”模型，使我们能够直接建立 在逼真的呼吸条件下，小儿特异性气道中的空间药物沉积概况。这 设计驱动的目标将需要将小儿成像，自动化和组织成像整合在一起 离散的工程设计方法，以创造关键的实验能力，以便在药物运输研究下 准确的身体运动。在AIM 1中，我们将在硅和体外动态气孔中发展出类似 型号。我们将采用新颖的计算流体粒子动力学（CFPD）建模技术捕获 Glotis运动。我们将改变患者的几何形状，空气流速和粒径，形成气雾剂库 沉积概况和趋势。这些模拟将完成并告知体外模型的开发； 我们将利用电动，灵活的Glottis将技术工程设计与患者气道复制品集成 与粒子收集撞击器一致的部分以量化粒子沉积。在AIM 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承诺参数来传递到Glotis 成功的靶向靶向并随后重复并审问体外模拟。我们将合并 细胞化水凝胶进入模型，以确保疾病发展和物理环境是 准确地表示，厚度变化，包括复杂的蜂窝培养将确保准确 模仿身体和疾病的发展。该项目将产生1）新型动态 小儿气门计算模型，2）建立小儿气溶胶的临床前工具，3）证据 可定制的吸入疗法治疗阻塞性小儿气道疾病。