Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Adv. 2021 Mar 12;7(11). doi: 10.1126/sciadv.abe9446. Print 2021 Mar.
Here, we present an approach to model and adapt the mechanical regulation of morphogenesis that uses contractile cells as sculptors of engineered tissue anisotropy in vitro. Our method uses heterobifunctional cross-linkers to create mechanical boundary constraints that guide surface-directed sculpting of cell-laden extracellular matrix hydrogel constructs. Using this approach, we engineered linearly aligned tissues with structural and mechanical anisotropy. A multiscale in silico model of the sculpting process was developed to reveal that cell contractility increases as a function of principal stress polarization in anisotropic tissues. We also show that the anisotropic biophysical microenvironment of linearly aligned tissues potentiates soluble factor-mediated tenogenic and myogenic differentiation of mesenchymal stem cells. The application of our method is demonstrated by (i) skeletal muscle arrays to screen therapeutic modulators of acute oxidative injury and (ii) a 3D microphysiological model of lung cancer cachexia to study inflammatory and oxidative muscle injury induced by tumor-derived signals.
在这里，我们提出了一种方法来模拟和适应形态发生的机械调节，该方法使用收缩细胞作为体外工程组织各向异性的塑造者。我们的方法使用杂双功能交联剂来创建机械边界约束，以指导细胞负载细胞外基质水凝胶构建物的表面导向塑造。使用这种方法，我们设计了具有结构和机械各向异性的线性排列组织。开发了一种用于塑造过程的多尺度计算模型，以揭示细胞收缩性随各向异性组织中的主应力极化而增加。我们还表明，线性排列组织的各向异性生物物理微环境增强了间充质干细胞中可溶性因子介导的腱形成和肌形成分化。我们的方法的应用通过以下方式证明：（i）骨骼肌阵列筛选急性氧化损伤的治疗调节剂，以及（ii）肺癌恶病质的 3D 微生理模型研究肿瘤衍生信号诱导的炎症和氧化肌肉损伤。
