Emergent Global Contractile Force in Cardiac Tissues

Abstract

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.

Multiscale Characterization of Engineered Cardiac Tissue Architecture

“…Conversely, the force production in engineered isotropic tissues ( Fig. 3(b)) is significantly lower than expected [12,33,36]. In this work, we quantitatively confirmed that engineered isotropic tissues spontaneously assemble organize patches of 1.4 Â 10 4 lm 2 , which is the same order of magnitude as tissues composed of parquet tiles proven to be similar to globally aligned tissues ( Fig.…”

“…However, the OOP and the COOP were chosen because they are mathematically appropriate to interpret data from biological tissues. Also, the OOP and COOP can be used on all types of distributions and, by now, have been widely characterized for use in engineered cardiac tissues [4,9,12,33,36,37]. However, it is important to note that the orientational order parameter is not capable of differentiating between isotropic distributions and ones with multiple principal orientations.…”

“…It has been shown that for engineered locally anisotropic parquet tiles of $6 Â 10 4 lm 2 , with a global isotropic order, the force production is easily predicted based on a net force vector addition model [36]. Conversely, the force production in engineered isotropic tissues ( Fig.…”

“…The emergent force production in tissues also highly depends on the multiscale architecture of cardiac muscle [12,36]. It has been shown that for engineered locally anisotropic parquet tiles of $6 Â 10 4 lm 2 , with a global isotropic order, the force production is easily predicted based on a net force vector addition model [36].…”

“…The heart architecture has been extensively studied for decades [1,12,16,33,[35][36][37]. However, the complex nature of the structures that form the heart makes it challenging to quantitatively describe architecture in a consistent manner.…”