Knight Meghan B, Drew Nancy K, McCarthy Linda A, Grosberg Anna
Department of Biomedical Engineering, University of California-Irvine, Irvine, California; Center for Complex Biological Systems, University of California-Irvine, Irvine, California.
Department of Biomedical Engineering, University of California-Irvine, Irvine, California; Center for Complex Biological Systems, University of California-Irvine, Irvine, California; The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California-Irvine, Irvine, California.
Biophys J. 2016 Apr 12;110(7):1615-1624. doi: 10.1016/j.bpj.2016.03.003.
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.
心脏是一个复杂的器官，其结构和功能在多个长度尺度上紧密相连。尽管心脏组织工程领域已取得了一些进展，但目前的体外心脏组织并不能完全复制有效心脏治疗和心脏毒性研究所需的结构或功能。部分原因在于目前对心脏组织组织潜在下游效应（如基因表达水平变化）的理解存在不足。我们开发了一种新型的（据我们所知）体外工具，可用于分离和量化组织和相关下游效应对组织功能的贡献。为此，将心脏组织单层设计成镶木地板图案，以便在局部尺度（在镶木地板瓷砖内）各向异性地组织，并在整体尺度上具有任何所需的组织形式。我们假设，如果下游效应被减弱，发育力与组织之间的关系可以建模为力向量之和。利用镶木地板组织和芯片上心脏装置的体外实验平台，我们能够在收缩期和舒张期应力方面证明这一假设。因此，我们深入了解了产生的应力与整体肌原纤维组织之间的关系。此外，还证明了所开发的定量工具可用于估计由于与组织结构解耦的下游效应而导致的应力产生变化。这有可能阐明与组织结构相关的特性，这些特性会改变患病心脏或干细胞衍生组织中的力产生和泵血功能。
