Organ-on-chip Model for Investigating Autonomic Innervation of the Cardiac Microenvironment

Cardiac sympathovagal imbalance is a dysfunction of the parasympathetic and sympathetic nervous systems (PSNS and SNS) that, in tandem, regulate cardiac output in response to environmental stimuli. This autonomic nervous system (ANS) imbalance increases the risk of cardiac arrhythmias and sudden cardiac failure due to an inability to modulate heart rate following overexertion or excessive stress. Therefore, there is an immediate need to understand the underlying cellular mechanisms of cardiac innervation to develop new strategies to restore ANS balance. Moving away from the complexity and variability of in vivo models, we developed an in vitro microphysiological model of the cardiac ANS. Custom “cut and assembled” microfluidic organ chips were fabricated to support the 3D culture of cardiac cells and ANS neurons within a biomimetic scaffold. Using this system, on-chip innervation of the cardiac microenvironment was confirmed via immunostaining (Figure 1). Further, we demonstrated trending differences in cardiomyocyte beating between those innervated by each ANS neuron population (PSNS vs. SNS: 37.4 ± 6.7 bpm vs. 44.8 ± 7.9 bpm, n = 8, p = 0.0716) via video microscopy and custom software (MATLAB®). Investigations to alter cardiomyocyte function to promote the innervation of different neural populations within the cardiac microenvironment are ongoing. Specifically, beat rate will be increased/decreased with pharmacological agents and innervation quantified using commercial neuron tracing software (Neurolucida®). Altogether, the development and use of this model will enable the systematic investigation of novel therapies to restore cardiac sympathovagal balance.