The heart is a complex organ whose structure and function are intricately linked at multiple length scales. Although several advancements have been achieved in the field of cardiac tissue engineering, current in vitro cardiac tissues do not fully replicate the structure or function necessary for effective cardiac therapy and cardiotoxicity studies. This is partially due to a deficiency in current understandings of cardiac tissue organization's potential downstream effects, such as changes in gene expression levels. We developed a novel (to our knowledge) in vitro tool that can be used to decouple and quantify the contribution of organization and associated downstream effects to tissue function. To do so, cardiac tissue monolayers were designed into a parquet pattern to be organized anisotropically on a local scale, within a parquet tile, and with any desired organization on a global scale. We hypothesized that if the downstream effects were muted, the relationship between developed force and tissue organization could be modeled as a sum of force vectors. With the in vitro experimental platforms of parquet tissues and heart-on-a-chip devices, we were able to prove this hypothesis for both systolic and diastolic stresses. Thus, insight was gained into the relationship between the generated stress and global myofibril organization. Furthermore, it was demonstrated that the developed quantitative tool could be used to estimate the changes in stress production due to downstream effects decoupled from tissue architecture. This has the potential to elucidate properties coupled to tissue architecture, which change force production and pumping function in the diseased heart or stem cell-derived tissues.

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Given standard pulses of free Ca 2þ , we fit the tension data of single and paired pulses with a model that permits cooperativity owing to cycling crossbridges but not Ca 2þ -bound Tn. The model produces time courses of Ca 2þ -bound Tn and the position of the Tm-Tn complex that follow single and paired transients of the meridional 1/38.5 nm À1 reflection intensity changes for both overlap and nonoverlap preparations. The model predicts that a fraction of Ca 2þ -bound Tn correlates in time and amplitude with the tension transient. This fraction represents Tn positioned away from possible interaction with actin by cycling crossbridges acting cooperatively on the position of Tm in the thin filament. Thus, this most parsimonious model of cooperativity is also the one most capable of explaining experimental observations.