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

Project SummaryFor HLSour 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 testingwith initial emphasis on predictive toxicityThis is a service based company and is developing low cost in vitro systems utilizing a novelpumplessmicrophysiological platform described in US PatentBThe commercialization potential of our system has been validated by the recent award of a Phase II SBIR to apply advanced manufacturing techniques to increase output and lower cost of productionThe pumpless integrated systemusing a rocking motion to pump the serum free cellular mediumreduces the complexity and cost of the fluidic circuit design and simplifies set up and operation of the deviceHickman has developed microelectrode arrays and cantilever systems that are integrated on chip that allows for noninvasive electronic and mechanical readoutsWe have detailed an in vitro cardiac system where the two main components of functionelectrical conduction and muscle forcehave been reproduced in vitroStancescu et alThe independent measurement of these two key variables allows a detailed description of a compounds effect on overall cardiac function and is currently being used under contract by multiple companiesBecause we can measure these functional outputs independentlywe can also use these readouts to give ideas on mechanism of action of a compoundTwo different sources of cardiomyocytes were used in these studiesiPSCs that are composed of primary cardiomyocytes and cardiomyocytes from embryonic stem cells that contained the three major cell types from the heartThe cardiac cells were shown to reach some aspects of functional maturation as primarily evidenced by patch clamp electrophysiological measurements indicating resting membrane potentials ofmV or betterWe will adapt this chip based system to create a microfluidic based cardiac ischemia modelThis cardiac organ on a chip platform will be validated by screening compounds that can restore function after ischemia in this Phase I SBIRIn follow on grants we will look at mechanisms of tissue restorationscreen for cardioprotective compounds as welland extend the acute experiments to include chronic measurementsA microphysiological system will be developed with functional readouts for cardiac electrical and mechanical functionfitted with environmental sensorsand integrated with an environmental chamber for inducing ischemiaWe will first optimize and validate environmental conditions and protocols for inducing and measuring cardiac ischemic damagefollowed by validation with ischemia drugs with published in vivo resultsThe uniqueness will be the combination of Hickman s functional modules with Shuler s innovative low costpumplesssystemOur team contains all of the skill sets required to constructevaluate and commercialize the integrated system and associated components to achieve the goals Project Narrative Public Health RelevanceThe overall strategy for Hesperos is to utilize organ on a chip systems and sensors to model human physiology and pharmacologyThis proposal will extend a cardiac system that models electrical activity and force generation to enable reproduction of ischemic events and then modulate the extent of injury with bioactive compoundsThis system can be utilized in drug discovery and toxicity studies and shows potential of decreasing the cost of the drug development process which should lead to less expensive drugs for the public at large