Engineering multifaceted 3D human organ platforms for toxicity testing - PROJECT SUMMARY
This award will accelerate my long-term goal to develop microphysiological systems to improve human
pharmacological efficacy with reduced toxicity and reliance on small animal models. Models of the
cardiovascular system (vascular, myocardium, adrenal medulla) in vitro have primarily been limited to simplified
2D structures and have not evaluated for tissue-tissue interactions. As such, the structure/function relationships,
and the cell-cell interactions driven by tissue organization and innervation remain poorly understood. Thus, MPS
that recapitulates key components of the human cardiovascular system, including physiologically relevant shear
flow, oxygen saturation, bioelectric stimulation, primary human endothelial, smooth muscle, cardiomyocytes,
chromaffin cells, and human autonomic neurons would be a valuable tool for advancing scientific discovery,
healthcare, compound screening, and biomedical research. Current MPS generally utilize specialized equipment
and traditional microfabrication techniques via soft lithography with polydimethylsiloxane (PDMS), making
microfluidic plumbing difficult as well as nearly impossible control of oxygen, and potential for analyte loss.
Therefore, new fabrication approaches that deviate from PDMS are needed. Our approach here describes the
application of a laser-fabricated, cut and assembled MPS for a fully humanized system. There is a scientific
and clinical urgency for the development of new tools to identify compound toxicity and decrease new
compound attrition during clinical trials. By applying my strengths in biomaterials, organ-chip design,
bioelectronics, and neuroengineering, we will accelerate the development of robust 3D, instrumented MPS
platforms of the cardiovascular system. A fundamental issue addressed in this project will be the ability to
integrate, in a scalable platform, instrumentation for stimulation and recording of neural, adrenal, and cardiac
activity to better elucidate the impact of the autonomic nervous system and compound toxicity. We will harness
a statistical model to identify driving factors in cell fate, function, and identify sex-based differential responses in
autonomic balance on the MPS. These innovative models will integrate recent advances in stem cell
differentiation and our proven ‘cut & assemble’ fabrication method to broadly disseminate these organ platforms.
