Abstract

Human-on-a-Chip Systems For Use in Efficacy and Toxicological Investigations For Applications in Neurological Diseases

James Hickman, Professor, University of Central Florida

One of the primary limitations in drug discovery and toxicology research is the lack of good model systems between the single cell level and animal or human systems. This is especially true for neurodegenerative diseases such as ALS and Alzheimer’s as well as spinal cord injury. In addition, with the banning of animals for toxicology testing in many industries body-on-a-chip systems to replace animals with human mimics is essential for product development and safety testing. Our research focus is on the establishment of functional in vitro systems to address this deficit where we seek to create organs and subsystems to model motor control, muscle function, myelination and cognitive function, as well as cardiac and liver subsystems. The idea is to integrate microsystems fabrication technology and surface modifications with protein and cellular components, for initiating and maintaining self-assembly and growth into biologically, mechanically and electronically interactive functional multi-component systems. Our advances in culturing adult rat, mouse and human mammalian spinal cord, hippocampal neurons, muscle and cardiac cells in a defined serum-free medium, suggest outstanding potential for answering questions related to maturation, aging, neurodegeneration and injury. A specific embodiment of this technology is the creation of a functional human NMJ system to understand ALS. We have investigated four mutations found in ALS patients; SOD1, FUS, TDP43 and C9ORF72. The models have demonstrated variations of the disease phenotype compared to WT for NMJ stability and functional dynamics. Results of these studies will be presented as well as preliminary results for reversal of the deficits. Examples will be given of some of the more advanced human-on-a-chip systems being developed for CNS and PNS disease applications as well as the results of six workshops held at NIH to explore what is needed for validation and qualification of these systems.