Department of Biomedical Engineering, University of Michigan, MI, USA.
Department of Biomedical Engineering, University of Michigan, MI, USA.
Acta Biomater. 2023 Dec;172:123-134. doi: 10.1016/j.actbio.2023.10.025. Epub 2023 Oct 23.
Engineered heart tissues (EHTs) present a potential solution to some of the current challenges in the treatment of heart disease; however, the development of mature, adult-like cardiac tissues remains elusive. Mechanical stimuli have been observed to improve whole-tissue function and cardiomyocyte (CM) maturation, although our ability to fully utilize these mechanisms is hampered, in part, by our incomplete understanding of the mechanobiology of EHTs. In this work, we leverage experimental data, produced by a mechanically tunable experimental setup, to introduce a tissue-specific computational modeling pipeline of EHTs. Our new modeling pipeline generates simulated, image-based EHTs, capturing ECM and myofibrillar structure as well as functional parameters estimated directly from experimental data. This approach enables the unique estimation of EHT function by data-based estimation of CM active stresses. We use this experimental and modeling pipeline to study different mechanical environments, where we contrast the force output of the tissue with the computed active stress of CMs. We show that the significant differences in measured experimental forces can largely be explained by the levels of myofibril formation achieved by the CMs in the distinct mechanical environments, with active stress showing more muted variations across conditions. The presented model also enables us to dissect the relative contributions of myofibrils and extracellular matrix to tissue force output, a task difficult to address experimentally. These results highlight the importance of tissue-specific modeling to augment EHT experiments, providing deeper insights into the mechanobiology driving EHT function. STATEMENT OF SIGNIFICANCE: Engineered heart tissues (EHTs) have the potential to revolutionize the way heart disease is treated. However, developing mature cardiomyocytes (CM) in these tissues remains a challenge due, in part, to our incomplete understanding of the fundamental biomechanical mechanisms that drive EHT development. This work integrates the experimental data of an EHT platform developed to study the influence of mechanics in CM maturation with computational biomechanical models. This approach is used to augment conclusions obtained in-vitro - by measuring quantities such as cell stress and strain - and to dissect the relevance of each component in the whole tissue performance. Our results show how a combination of specialized in-silico and in-vitro approaches can help us better understand the mechanobiology of EHTs.
工程心脏组织 (EHT) 为治疗心脏病的一些当前挑战提供了潜在的解决方案；然而，成熟的成人样心脏组织的开发仍然难以捉摸。机械刺激已被观察到可改善整个组织功能和心肌细胞 (CM) 的成熟度，尽管我们充分利用这些机制的能力受到阻碍，部分原因是我们对 EHT 的机械生物学的理解不完整。在这项工作中，我们利用机械可调实验装置产生的实验数据，引入了 EHT 的组织特异性计算建模管道。我们的新建模管道生成模拟的基于图像的 EHT，捕获 ECM 和肌原纤维结构以及直接从实验数据估计的功能参数。这种方法通过基于数据的 CM 主动应力估计来实现 EHT 功能的独特估计。我们使用这种实验和建模管道来研究不同的机械环境，其中我们将组织的力输出与计算出的 CM 主动应力进行对比。我们表明，在不同的机械环境中，CM 中肌原纤维形成的水平可以很大程度上解释测量实验力的显著差异，而主动应力在整个条件下的变化更为温和。所提出的模型还使我们能够剖析肌原纤维和细胞外基质对组织力输出的相对贡献，这是一项难以通过实验解决的任务。这些结果强调了组织特异性建模对增强 EHT 实验的重要性，为推动 EHT 功能的机械生物学提供了更深入的见解。
工程心脏组织 (EHT) 有潜力彻底改变心脏病的治疗方式。然而，由于部分原因是我们对驱动 EHT 发育的基本生物力学机制的理解不完整，因此在这些组织中开发成熟的心肌细胞 (CM) 仍然是一个挑战。这项工作整合了一个用于研究力学对 CM 成熟影响的 EHT 平台的实验数据与计算生物力学模型。这种方法用于增强在体外测量细胞应力和应变等数量得出的结论，并剖析整个组织性能中每个组件的相关性。我们的结果表明，专门的计算机模拟和体外方法的组合如何帮助我们更好地理解 EHT 的机械生物学。
