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Engineering Dynamic 3D-Bioprinted Models of Pulmonary Vascular Disease

肺血管疾病的工程动态 3D 生物打印模型

基本信息

批准号：
10549829
负责人：
Duncan J Davis-Hall
金额：
$ 3.92万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2021-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549829
关键词：
3-Dimensional 3D Print Actins Bathing Biocompatible Materials Biological Assay Biological Models Biomanufacturing Biomedical Engineering Blood Pressure Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell Survival Cells Chronic Clinical Collagen Colorado Complex Crosslinker Cues Deposition Development Dimensions Disease Disease Progression Elasticity Encapsulated Engineering Environment Exhibits Extracellular Matrix Extracellular Matrix Proteins Fellowship Fibroblasts Fibrosis Foundations Gelatin Gene Expression Genes Geometry Goals Human Hydrogels Immunohistochemistry In Vitro Laboratories Learning Light Lung Lung diseases Matrix Metalloproteinases Measures Medical Mentors Methacrylates Methods Modeling Modulus Myofibroblast Pathogenesis Pathologic Pathology Patient Isolation Patients Peptides Phenotype Physicians Physiological Physiology Polymers Population Production Proliferating Proteins Pulmonary Hypertension Pulmonary arterial remodeling Qualifying Quantitative Reverse Transcriptase PCR Reaction Research Research Personnel Right Ventricular Dysfunction Scientist Smooth Muscle Solid Structure Symptoms Syringes System Techniques Technology Testing Therapeutic Time Tissue-Specific Gene Expression Tissues Training Translational Research Ultraviolet Rays Universities Vascular Diseases Vascular remodeling bioink bioprinting cell type ethylene glycol experience experimental study human disease human model human study immunocytochemistry insight invention manufacture mechanical properties mortality new therapeutic target novel polymerization pre-doctoral pulmonary arterial hypertension pulmonary vascular disorder response right ventricular failure success symposium three dimensional cell culture three dimensional structure three-dimensional modeling time use tool

项目摘要

PROJECT SUMMARY/ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive and incurable disease, characterized by elevated pulmonary blood pressure, remodeling of the pulmonary arteries, and ultimately the development of right ventricular failure. Unfortunately, the only clinically available therapeutic treatments mitigate symptoms but do not cure the disease. Existing cell culture techniques represent a significant barrier to discovering new therapeutic targets for PAH because these systems do not adequately reproduce key aspects of human physiology, specifically, the complex 3D structure of the pulmonary vasculature and the time-dependent changes in extracellular matrix (ECM) mechanical properties that occur during disease progression. Therefore, an urgent need remains to develop new tools and technologies that enable us to study the pathogenesis of PAH over time. We propose to develop a new class of phototunable poly(ethylene glycol) (PEG)-based hydrogel biomaterials and biomanufacturing techniques that allow investigators to control the mechanical properties of the local microenvironment (i.e., stiffen) on-demand around patient-derived fibroblasts encapsulated within 3D-printed vascular models using focused light, with the goal of emulating PAH pathogenesis in vitro. The advanced biomaterial platform implemented here will provide the foundation for biological models of increasing complexity comprising multiple cell types that are cultured under flow under development in the sponsor's laboratory that reveal novel mechanistic insights into reduction of human disease. This project will bring together the applicant and a diverse mentoring team made up of bioengineers and clinician-scientists specializing in cardiovascular and pulmonary diseases to further develop the pulmonary workforce. Fellowship training will include clinical experiences through the Pulmonary Hypertension Breakthrough Initiative, presentations at research conferences and grand rounds to aid professional development, and hands-on training in Dr. Kurt Stenmark's Cardiovascular Pulmonary Research Lab to learn experimental techniques essential to understanding PAH. The completed model will provide a platform for testing and validating therapies for pulmonary hypertension, advancing translational research in this field. We propose two specific aims to demonstrate the feasibility of this approach. AIM I: Engineer a dynamic 3D- bioprinted cell culture platform with controllable modulus of elasticity. AIM II: Investigate the influence of dimensionality and material modulus on fibroblast activation using patient-derived cells. The success of Aim I will be measured through rheological characterization and cell viability assays. Aim II will measure fibroblast activation through immunohistochemistry and a concise qRT-PCR array to compare phenotypic changes among healthy patient-derived cells grown in 3D-bioprinted blood vessel mimics that emulate pathological ECM, healthy cells grown on 2D hydrogel substrates, and freshly isolated PAH patient cells.

项目总结/文摘