? 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. ? ? ?
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