Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
Biomater Sci. 2019 Dec 17;8(1):132-147. doi: 10.1039/c9bm01005j.
Biomaterials are increasingly used for in situ vascular tissue engineering, wherein resorbable fibrous scaffolds are implanted as temporary carriers to locally initiate vascular regeneration. Upon implantation, macrophages infiltrate and start degrading the scaffold, while simultaneously driving a healing cascade via the secretion of paracrine factors that direct the behavior of tissue-producing cells. This balance between neotissue formation and scaffold degradation must be maintained at all times to ensure graft functionality. However, the grafts are continuously exposed to hemodynamic loads, which can influence macrophage response in a hitherto unknown manner and thereby tilt this delicate balance. Here we aimed to unravel the effects of physiological levels of shear stress and cyclic stretch on biomaterial-activated macrophages, in terms of polarization, scaffold degradation and paracrine signaling to tissue-producing cells (i.e. (myo)fibroblasts). Human THP-1-derived macrophages were seeded in electrospun polycaprolactone bis-urea scaffolds and exposed to shear stress (∼1 Pa), cyclic stretch (∼1.04), or a combination thereof for 8 days. The results showed that macrophage polarization distinctly depended on the specific loading regime applied. In particular, hemodynamic loading decreased macrophage degradative activity, especially in conditions of cyclic stretch. Macrophage activation was enhanced upon exposure to shear stress, as evidenced from the upregulation of both pro- and anti-inflammatory cytokines. Exposure to the supernatant of these dynamically cultured macrophages was found to amplify the expression of tissue formation- and remodeling-related genes in (myo)fibroblasts statically cultured in comparable electrospun scaffolds. These results emphasize the importance of macrophage mechano-responsiveness in biomaterial-driven vascular regeneration.
生物材料越来越多地用于原位血管组织工程，其中可吸收的纤维支架被植入作为临时载体，以局部启动血管再生。植入后，巨噬细胞浸润并开始降解支架，同时通过分泌旁分泌因子来驱动愈合级联反应，这些因子直接指导组织产生细胞的行为。新组织形成和支架降解之间的平衡必须始终保持，以确保移植物的功能。然而，移植物不断受到血流动力学负荷的影响，这些影响可能以迄今未知的方式影响巨噬细胞的反应，从而使这种微妙的平衡发生倾斜。在这里，我们旨在揭示生理水平的剪切力和循环拉伸对生物材料激活的巨噬细胞的影响，包括极化、支架降解和旁分泌信号传递到组织产生细胞（即（肌）成纤维细胞）。将人 THP-1 衍生的巨噬细胞接种在静电纺聚己内酯双脲支架上，并暴露于剪切力（约 1 Pa）、循环拉伸（约 1.04）或两者的组合中 8 天。结果表明，巨噬细胞的极化明显取决于施加的特定加载状态。特别是，血流动力学负荷降低了巨噬细胞的降解活性，尤其是在循环拉伸的情况下。暴露于剪切力会增强巨噬细胞的激活，这从促炎和抗炎细胞因子的上调得到证明。发现这些动态培养的巨噬细胞的上清液可放大静态培养在类似静电纺丝支架中的（肌）成纤维细胞中与组织形成和重塑相关的基因的表达。这些结果强调了巨噬细胞机械响应性在生物材料驱动的血管再生中的重要性。
