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 dangerous. Indeed, it can take
upwards of 10 years and $2-3 billion to develop just one drug, and much of that cost is derived from other
candidates that fail. Most 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 patients. One of the most common reasons for failure is
a compound’s propensity for causing cardiac arrhythmias in patients. In some rare cases, these cardiotoxic
effects aren’t even detected during clinical trials and are only discovered once the drug is exposed to the
population at large, resulting in harm to patients and a costly withdrawal from the market place. Consequently,
the FDA has mandated that all new drugs be tested for cardiotoxic effects, but they and the drug industry realize
that current screening tools fall short. This has led to a growing market for screening tools that are more predictive
than existing technologies. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) represent
a promising avenue towards building high-representative in vitro tissue models for preclinical drug screening.
However, most iPSC-CM models do not develop into mature, adult-like tissue and fail to recapitulate some in
vivo drug responses. NanoSurface Biomedical is applying for Phase 1 SBIR funding to develop a combinatorial
bioreactor system to enhance the maturation of cardiac stem cells for improved drug-induced cardiotoxicity
screening. The bioreactor will generate tissues that are more functionally mature and can be fed into various
down-stream assays. We hypothesize that the combination of nanoscale structural cues, mechanical stretch,
and electrical stimulation will improve cardiac structural and functional development to enable the collection of
cardiotoxicity data with more predictive capacity. To test these hypotheses, this project will focus on the design
and fabrication of a combinatorial bioreactor that can reproducibly and reliably apply the required stimuli (Aim 1).
New methods of fabrication must be tested and implemented to ensure production of highly precise nanoscale
architectures that promote cell development. Reliability and selection of actuators for mechanical stretch will also
be undertaken. The company will develop hardware and software for in situ electrical stimulation that is applied
in a spatiotemporally coordinated manner with the other external stimuli. Lastly, the company will develop
protocols and validate the hypothesis that these combinatorial cues can enhance iPSC-CM maturation (Aim 2).
This will be assessed via a suite of structural, electrophysiological, and functional metrics combined with
statistical analysis. These data will be used to assess the validity of the approach for eventual scale up during
Phase 2, and for commercial release and market delivery in Phase 3. Successful 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.
