NSF Award
1804845
PI: Zhang, Xin / Charest, Joseph<br/>Proposal Number: 1804787 / 1804845<br/><br/>In order to study the negative effects of drugs or other therapeutics on human kidneys, screening methods have been developed to evaluate potential toxicity during preclinical testing. Despite current methods for preclinical screening, the occurrence of kidney injury due to drug toxicity in clinical practice remains unacceptably high, accounting for nearly 20% of all episodes of acute kidney injury. To date, a major limitation in the early determination of the toxicity of drugs is the reliance on experiments in animals whose responses to drugs often cannot predict human responses. This project aims to develop innovative devices and methods that combine the culturing of human kidney cells and impedance (a complex form of resistance)-based sensing techniques in a microfluidic system. These microfluidic systems will be developed to replicate the physiological behavior needed for studying the toxicity of drugs upon the human kidney, thus serving as an advanced drug screening method with the potential for increased accuracy and lower cost. The unique interdisciplinary nature of the research provides rich educational opportunities. K-12 students along with undergraduate and graduate students, including women and underrepresented groups, will be included in the development of the drug screening system through multiple programs designed to foster interest in science and engineering. <br/><br/>This project focuses on the development of microfluidic proximal convoluted tubule biochips as in vitro models for preclinical toxicology screening of drugs in the pharmaceutical development process. To improve the efficiency and decrease the costs associated with the screening process, microfluidic chips imbedded with human kidney cells will be developed and validated. To simulate the proximal tubule, biochips will be developed featuring a central, topographically patterned, porous membrane within this bilayer microfluidic device. Impedance sensing-based components will be integrated into this system using microfabrication techniques. Human renal proximal tubular epithelial cells (hRPTEC) and human microvascular endothelial cells (hMVEC) will be co-cultured and maintained on the chip, forming the primary sites for active clearance, reabsorption, intracellular concentration, and accumulation of drugs in the kidney. The co-cultured cells will be exposed to a series of well-known nephrotoxins of varying concentration over time. For each exposure, the impedance spectra of the model cells will be recorded and calibrated, making use of data on cell damage derived from conventional assessments of toxicity and cell viability. Beyond the application to in vitro kidney models, the insights gained from integrating impedance-sensing technology with these systems may be broadly applied towards diverse 'organ-on-a-chip' technologies as well as myriad cell-based biosensors and 'lab-on-a-chip' devices.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
