A Combinatorial Bioreactor for Electromechanical Conditioning of Differentiated Stem Cells

PROJECT SUMMARY The failure of a drug during the development process is extraordinarily costly and dangerousIndeedit can take upwards ofyears and $billion to develop just one drugand much of that cost is derived from other candidates that failMost of these failures occur towards the end of the development process when the costs are highest and when the drug is exposed to the most patientsOne of the most common reasons for failure is a compound s propensity for causing cardiac arrhythmias in patientsIn some rare casesthese cardiotoxic effects aren t even detected during clinical trials and are only discovered once the drug is exposed to the population at largeresulting in harm to patients and a costly withdrawal from the market placeConsequentlythe FDA has mandated that all new drugs be tested for cardiotoxic effectsbut they and the drug industry realize that current screening tools fall shortThis has led to a growing market for screening tools that are more predictive than existing technologiesHuman induced pluripotent stem cell derived cardiomyocytesiPSC CMsrepresent a promising avenue towards building high representative in vitro tissue models for preclinical drug screeningHowevermost iPSC CM models do not develop into matureadult like tissue and fail to recapitulate some in vivo drug responsesNanoSurface Biomedical is applying for PhaseSBIR funding to develop a combinatorial bioreactor system to enhance the maturation of cardiac stem cells for improved drug induced cardiotoxicity screeningThe bioreactor will generate tissues that are more functionally mature and can be fed into various down stream assaysWe hypothesize that the combination of nanoscale structural cuesmechanical stretchand electrical stimulation will improve cardiac structural and functional development to enable the collection of cardiotoxicity data with more predictive capacityTo test these hypothesesthis project will focus on the design and fabrication of a combinatorial bioreactor that can reproducibly and reliably apply the required stimuliAimNew methods of fabrication must be tested and implemented to ensure production of highly precise nanoscale architectures that promote cell developmentReliability and selection of actuators for mechanical stretch will also be undertakenThe company will develop hardware and software for in situ electrical stimulation that is applied in a spatiotemporally coordinated manner with the other external stimuliLastlythe company will develop protocols and validate the hypothesis that these combinatorial cues can enhance iPSC CM maturationAimThis will be assessed via a suite of structuralelectrophysiologicaland functional metrics combined with statistical analysisThese data will be used to assess the validity of the approach for eventual scale up during Phaseand for commercial release and market delivery in PhaseSuccessful validation of the company s combinatorial bioreactor will produce an innovative new product aimed at relieving critical deficiencies in preclinical toxicity models and reduce cost and time in the drug development process PROJECT NARRATIVE We will develop a combinatorial bioreactor capable of promoting the functional development of human derived cardiac stem cells in a controlled laboratory setting by combining structuralmechanicaland electrical developmental cuesCells and tissues developed in this device will enable more accurate and predictive screening of the toxicity and efficacy of candidate drugs on human heart tissue prior to their advancement to human trialsIn turnthis will streamline drug development protocolsleading to shorter development timesand bringing new life saving drugs to the market more quickly