Integration of a kidney module into a 4-organ human-on-a-chip system.

点击翻译按钮获取中文摘要

Project Summary Our overall strategy for Hesperos is to utilize microphysiological systems in combination with functional readouts to establish platforms capable of sophisticated analysis of chemicals and drug candidates for toxicity and efficacy during pre-clinical testing, with initial emphasis on predictive toxicity. This is a service based company and is developing low-cost in vitro systems utilizing a novel “pumpless” microphysiological platform described in US Patent 8,748,180B2, June 10, 2014. The compartments each representing a tissue or organ are connected by a serum-free medium which mimics the blood. The pumpless integrated system, using a rocking motion to pump the serum-free cellular medium, reduces the complexity and cost of the fluidic circuit design and simplifies set-up and operation of the device. Hickman has developed microelectrode arrays and cantilever systems that are integrated on chip that allows for noninvasive electronic and mechanical readouts. We will utilize microfluidic analytical components with this system for rapid and sensitive biomarker (chemical, protein and small molecule) assessment. However, the number of biomarkers to be monitored for cell health and function will be greatly reduced in our systems from use of the functional readouts. We have constructed physiological systems that represent cardiac, muscle and liver function that are being used at Hesperos and in Hickman’s lab by pharmaceutical and cosmetic companies. We have demonstrated multi-organ toxicity in the 4-organ system composed of neuronal, cardiac, liver and muscle components. This system is the first microfluidic model to demonstrate the capacity to promote the survival and functional competence of 4 interconnected tissue modules in serum-free medium over extended culture periods. Further evidence of the commercial viability of our platform is that we have just been awarded a Phase II SBIR grant from National Center for Advancing Translational Sciences (NCATS) to apply advanced manufacturing techniques to our basic 4-organ platform in collaboration with National Institute of Standards and Technology (NIST). In this proposal we extend the 4 organ system to include a model of the human kidney as a step toward a more complete ADMETox model. Our first aim will be to design, fabricate and test a kidney module to model aspects of elimination through the kidney. We will then incorporate the kidney module with the existing 4 organ module. This requires the addition of another layer to allow flow of a dialysis stream to mimic excretion through the kidney. The kidney will have glomerulus and proximal tubule compartments. Electrodes to directly measure TEER (transepithelial electrical resistance) will be integrated into the kidney module. The existing system will measure functional readouts of force for skeletal muscle and cardiac, and electrical activity of neurons and patterned cardiomyocytes. The system will be validated with drugs and chemicals that have shown to effect kidney function.