Abstract
Heart‐on‐chip is an unprecedented technology for recapitulating key biochemical and biophysical cues in cardiac pathophysiology. Several designs have been proposed to improve its ability to mimic the native tissue and establish it as a reliable research platform. However, despite mimicking one of most vascularized organs, reliable strategies to deliver oxygen and substrates to densely packed constructs of metabolically demanding cells remain unsettled. Herein, we describe a new heart‐on‐chip platform with precise fluid control, integrating an on‐chip peristaltic pump, allowing automated and fine control over flow on channels flanking a 3D cardiac culture. The application of distinct flow rates impacted on temporal dynamics of microtissue structural and transcriptional maturation, improving functional performance. Moreover, a widespread transcriptional response was observed, suggesting flow‐mediated activation of critical pathways of cardiomyocyte structural and functional maturation and inhibition of cardiomyocyte hypoxic injury. In conclusion, the present design represents an important advance in bringing engineered cardiac microtissues closer to the native heart, overcoming traditional bulky off‐chip fluid handling systems, improving microtissue performance, and matching oxygen and energy substrate requirements of metabolically active constructs, avoiding cellular hypoxia. Distinct flow patterns differently impact on microtissue performance and gene expression program.
Highlights
MethodsMiniaturized in vitro models offer unprecedent opportunities to unravel the rules that govern biological organization (Visone et al, 2016)
The volumetric flow rate was calculated as a cylindrical volume as a function of the distance traveled by the fluid front per time
This study describes a heart‐on‐chip platform able to culture and perfuse 3D constructs under controlled flow profiles
Summary
Miniaturized in vitro models offer unprecedent opportunities to unravel the rules that govern biological organization (Visone et al, 2016). Heart‐on‐chip technology has gained attention overtime due to its potential to guide tissue development by providing biochemical and biophysical signals tailored to recapitulate the complex native myocardial tissue faithfully (Marsano et al, 2016; Mathur et al, 2015; Visone et al, 2018). Advances of heart‐on‐chip technology have been pursued by introducing key physiological stimuli, namely, mechanical (Marsano et al, 2016) and electrical (Visone et al, 2018), positively impacting microtissue maturation and performance. In vitro cardiac models, often represented by high‐density three‐dimensional (3D) constructs of metabolically demanding cells, must ensure adequate delivery of oxygen and energy substrates to avoid cellular stress and enhance system reproducibility
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