INTRODUCTION:
UCLA researchers in the Departments of Bioengineering and Cardiology have developed a novel organ-on-a-chip platform using patient specific iPSC-derived cardiomyocytes and hepatocytes, for the general toxicity screening of drugs.
BACKGROUND:
Clinical trials are required to evaluate the effect of drugs on human patients, following preclinical studies including in vivo small and large animal models. However, these preclinical models are often unable to accurately recapitulate the complexities of human physiologic responses to therapeutics. Current methods to improve upon in vivo toxicity screening involve exposing induced pluripotent stem cell (iPSC)-derived cardiomyocytes to candidate drugs. Although these assays provide may more information regarding drug toxicity in human cells, the analysis is performed using planar and static cell cultures that fail to account for a dynamic environment or hepatic metabolism of the pharmaceuticals. Further, a mixture of iPSC-derived cardiomyocytes makes it difficult to evaluate both biological and electromechanical responses to drug exposure. These deficiencies in pharmaceutical screening in vivo must be addressed to allow for increased predictability of patient drug response and ultimately, precision medicine.
INNOVATION:
UCLA researchers have generated an ‘organ-on-a-chip’ system, wherein patient specific iPSC-derived cardiomyocytes and hepatocytes may be evaluated for toxicity to various chemotherapeutic agents with known cardiotoxicity. This innovative platform for drug screening is improved over conventional planar and static cell culture drug screening assays, as it utilizes multi-channel microfluidics system to mimic a dynamic flow system more similar to patient organs. A multisensory-integrated system allows precise measurements of biological and electromechanical properties in real-time, over an extended period of time. Nodal, atrial and left ventricular cardiomyocytes may also be individually isolated from iPSCs, to directly probe arrhythmogenic side effects and biomechanical cellular damage. This technology lays the foundation for a precision medicine approach for general screening of drug toxicity beyond chemotherapeutics in individual patients.
POTENTIAL APPLICATIONS:
• Evaluation of cardiotoxicity of common drugs used in patients undergoing chemotherapy
• General screening of drug toxicity
ADVANTAGES:
• Evaluate the effect of a drug on each individual patient, which allows for precision medicine
• Integrated bio- and mechano-sensors to monitor drug toxicity over an extended time period
• Biological parameters may be measured in real time
• Nodal, atrial and left ventricular cardiomyocytes can be isolated from iPSC individually, for probing specific responses within the heart
• Multichannel flow system mimics a dynamic flow system for drug screening, which is improved over conventional planar and static cell culture screening assays