HLS-Development of a cardiac ischemia model in an organ-on-a-chip platform

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. The commercialization potential of our system has been validated by the award of a Phase IIB SBIR to apply advanced manufacturing techniques to increase output and lower cost of production. 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 for noninvasive electronic and mechanical readouts. We have detailed an in vitro cardiac system where the two main components of function, electrical conduction and muscle force, have been reproduced in vitro. The independent measurement of these two key variables allows a detailed description of a compound’s effect on overall cardiac function and is currently being used under contract by multiple companies. Because we can measure these functional outputs independently, we can also use these readouts to give ideas on mechanism of action of a compound. We have adapted this chip based system into a platform for testing cardiac ischemia and reperfusion as published in APL Bioengineering that demonstrated an investigational compound effectively reduced ischemia/reperfusion damage in vitro. The human iPSC cardiac cells used in this device were shown to reach some aspects of functional maturation as primarily evidenced by patch clamp electrophysiological measurements indicating resting membrane potentials of -85 mV or better. We will expand this system by integrating a hemodynamic module of vascular smooth muscle cells and microvascular endothelial cells with the microfluidic system and develop continuous monitoring instrumentation. This cardiac organ-on-a-chip platform will be validated by screening compounds that act either directly on the cardiac cells or affect hemodynamics, and will be used to screen investigational compounds from our pharma partners. A microphysiological system will be developed with continuous readouts for smooth muscle cell contraction, cardiac electrical and mechanical function, fitted with environmental sensors, and integrated with an environmental chamber for inducing ischemia. We will first optimize and validate environmental conditions and protocols for inducing and measuring cardiac ischemic damage, followed by validation with ischemia drugs with published in vivo and in vitro results. The uniqueness will be the combination of Hickman’s functional modules with Shuler’s “pumpless” system, as well as continuous measurement of both cardiac and hemodynamic effects. Our team contains all of the skill sets required to construct, evaluate and commercialize the integrated system and associated components to achieve the goals.