Nano Fibers for ADME/Toxicology

用于 ADME/毒理学的纳米纤维

基本信息

批准号：
7486852
负责人：
PETER X MA
金额：
$ 29.9万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7486852
关键词：
Adhesions Adsorption Albumins Animal Experiments Architecture Area Behavior Behavioral Biological Assay Biomimetics Caliber Cell Adhesion Cell Communication Cell Count Cells Chemistry Clinical Trials Collagen Condition Cultured Cells Cytochrome P450 Development Differentiation and Growth Disease Drug Compounding Effectiveness Electrostatics Evaluation Excision Excretory function Extracellular Matrix Extracellular Matrix Proteins Fiber Growth Health Hepatocyte Human In Vitro Mechanics Metabolic Metabolism Modification Morphology Organ Outcome Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Play Porosity Preclinical Drug Evaluation Process Proliferating Proteins Rattus Research Personnel Role Safety Shapes Structure Surface Surface Properties Techniques Testing Tissue Engineering Tissues Toxicology Transition Temperature United States Urea absorption base cell growth culture plates design drug discovery enzyme activity in vivo nano nanofiber novel physical property pre-clinical programs psychologic research and development response scaffold self assembly size wasting

项目摘要

DESCRIPTION (provided by applicant): The annual research and development (R&D) spending for drug discovery and development in the United States is approximately sixty billion dollars. ADME/Tox (absorption, distribution, metabolism, excretion and toxicology) studies using cell cultures have played important roles in facilitating the drug discovery and development process. However, there are many differences between the behavior of cultured cells in traditional 2D culture and their 3D counterparts in vivo, resulting in low predictability. We hypothesize that A) 3D cell-scaffold constructs are superior to 2D cell cultures for ADME/Tox studies (H1), and B) scaffolds that mimic the nano-fibrous architecture and surface chemistry of collagen enhance hepatocyte adhesion, survival/growth, and differentiated function (H2). We, therefore, propose to develop a 3D nano-fibrous scaffold for hepatocytes to adhere, maintain differentiation, and possibly proliferate. These cell-scaffold constructs (or engineered tissues), shall maintain 3D cellular interaction, should serve as closer physiological mimics of tissues/organs in vivo, and will afford more predictable outcomes in ADME/Tox studies for pharmaceutical research and development. Specific Aim 1. Develop 3D nano-fibrous scaffolds with manipulatable macro-pore architecture and pore surface morphology for cell growth and tissue formation in multi-well culture plates. Specific Aim 2. Optimize macro-pore structure of the scaffolds using in vitro hepatocyte culture assays, and demonstrate that nano-fibrous pore wall architecture is superior to control pore wall architecture as a 3D scaffold for hepatocytes to form tissue mimics. Specific Aim 3. Impart biomimetic surface properties to the internal pores of the scaffolds for optimal hepatocyte adhesion and function. Specific Aim 4. Demonstrate the advantages of multi-well culture plates containing surface-modified 3D nano-fibrous scaffolds for high-throughput efficiency, robustness and effectiveness for ADME/Tox studies. By accomplishing the above specific aims, we will advance our understanding of scaffold design for optimal hepatocyte function, and demonstrate the advantages of the 3D nano-fibrous scaffolds as a novel platform for more predictive preclinical ADME/Toxicology studies.

描述（由申请人提供）：美国的年度研发（R＆D）支出在美国进行药物发现和开发的支出约为600亿美元。使用细胞培养物的ADME/TOX（吸收，分布，代谢，排泄和毒理学）研究在促进药物发现和发育过程中起着重要作用。但是，传统2D培养物中培养细胞的行为与体内的3D对应物之间存在许多差异，从而导致可预测性较低。我们假设a）3D细胞car构建体优于ADME/TOX研究（H1）的2D细胞培养物，b）模仿胶原蛋白的纳米纤维构建和表面化学的支架增强了肝细胞粘附，生存/生长和分化功能（H2）。因此，我们建议为肝细胞开发一个3D纳米纤维的支架，以粘附，维持分化并可能增殖。这些细胞c构造（或工程组织）应保持3D细胞相互作用，应作为体内组织/器官的更紧密的生理模仿，并将在药物研究和开发的ADME/TOX研究中提供更可预测的结果。具体目标1。开发3D纳米 - 纤维型支架，具有可操纵的宏孔结构和孔隙表面形态，用于多孔培养板中的细胞生长和组织形成。特定目的2。使用体外肝细胞培养测定法优化支架的宏孔结构，并证明纳米 - 纤维孔壁结构优于控制孔隙壁结构，作为肝细胞的3D支架以形成组织模仿。特定的目标3。将仿生表面特性赋予支架的内部孔，以获得最佳的肝细胞粘附和功能。具体目标4。证明包含表面修饰3D的多孔培养板的优势用于高通量效率，稳健性和ADME/TOX研究的纳米纤维支架。通过实现上述特定目标，我们将提高对脚手架设计的理解，以实现最佳的肝细胞功能，并证明3D纳米纤维纤维脚手架的优势是作为更具预测性的临床前毒学/毒理学研究的新型平台。