I-Wire Heart-on-a-Chip II: Biomechanical analysis of contractile, three-dimensional cardiomyocyte tissue constructs

Abstract

This companion study presents the biomechanical analysis of the “I-Wire” platform using a modified Hill model of muscle mechanics that allows for further characterization of construct function and response to perturbation. The I-Wire engineered cardiac tissue construct (ECTC) is a novel experimental platform to investigate cardiac cell mechanics during auxotonic contraction. Whereas passive biomaterials often exhibit nonlinear and dissipative behavior, active tissue equivalents, such as ECTCs, also expend metabolic energy to perform mechanical work that presents additional challenges in quantifying their properties. The I-Wire model uses the passive mechanical response to increasing applied tension to measure the inherent stress and resistance to stretch of the construct before, during, and after treatments. Both blebbistatin and isoproterenol reduced prestress and construct stiffness; however, blebbistatin treatment abolished subsequent force-generating potential while isoproterenol enhanced this property. We demonstrate that the described model can replicate the response of these constructs to intrinsic changes in force-generating potential in response to both increasing frequency of stimulation and decreasing starting length. This analysis provides a useful mathematical model of the I-Wire platform, increases the number of parameters that can be derived from the device, and serves as a demonstration of quantitative characterization of nonlinear, active biomaterials. We anticipate that this quantitative analysis of I-Wire constructs will prove useful for qualifying patient-specific cardiomyocytes and fibroblasts prior to their utilization for cardiac regenerative medicine.

I-Wire Heart-on-a-Chip I: Three-dimensional cardiac tissue constructs for physiology and pharmacology

“…This is consistent with effects of the β-adrenergic stimulation in native myocardium, wherein the phosphorylation of phospholamban and troponin I mostly contributes to enhanced diastolic relaxation [40;68]. An analysis of these effects in terms of the Hill model of muscle is presented in the companion paper [14]. …”

“…Hence, these engineered tissues represent a special class of mechanically active biomaterials. In a companion paper, we describe how the mechanical behavior of these contractile biomaterials can be further analyzed using a computational Hill model [14]. …”

3D bioprinting for cardiovascular regeneration and pharmacology

“…These tissue engineering scaffolds work to establish regenerative micro-environments within tissue constructs by providing 3D living space for CMs, leading to a more physiologically relevant model. Additionally, many standardized microfluidic−/microarray-based organ-on-chip systems have been reported for high-throughput drug discovery or toxicity testing [10,64–70]. However, there are considerable challenges to the development of microfluidic or chip cardiac models, stemming from their limited ability to fully recapitulate cardiac niche elements (especially for complex architecture and biological characteristics) as well as to precisely organize multiple-cell distributions and regulate cell behaviors/functions.…”

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

“…A much more comprehensive battery of techniques is already in regular use in the pharmaceutical industry, including genomics, transcriptomics, and proteomics. In recent MPS studies, we are seeing functional measurements such as contractility, calcium signaling, and electrophysiological responses of cardiac and skeletal muscle, 37,[69][70][71][72][73][74][75] electrical resistance and molecular permeability of barriers, [76][77][78][79][80][81][82] and metabolomic responses to inflammatory challenges. 78 In this issue, the Parker group uses a variety of measures, including gene expression profiling, to quantify factors that affect maturation of neonatal rat cardiomyocytes into a more mature phenotype.…”