The inability of biomaterial scaffolds to functionally integrate into surrounding tissue is one of the major roadblocks to developing new biomaterials and tissue-engineering scaffolds. Despite considerable advances, current approaches to engineering cell-surface interactions fall short in mimicking the complexity of signals through which surrounding tissue regulates cell behavior. Cells adhere and interact with their extracellular environment via integrins, and their ability to activate associated downstream signaling pathways depends on the character of adhesion complexes formed between cells and their extracellular matrix. In particular, alpha5beta1 and alphavbeta3 integrins are central to regulating downstream events, including cell survival and cell-cycle progression. In contrast to previous findings that alphavbeta3 integrins promote angiogenesis, recent evidence argues that alphavbeta3 integrins may act as negative regulators of proangiogenic integrins such as alpha5beta1. This suggests that fibronectin is critical for scaffold vascularization because it is the only mammalian adhesion protein that binds and activates alpha5beta1 integrins. Cells are furthermore capable of stretching fibronectin matrices such that the protein partially unfolds, and recent computational simulations provide structural models of how mechanical stretching affects fibronectin function. We propose a model whereby excessive tension generated by cells in contact to biomaterials may in fact render fibronectin fibrils nonangiogenic and potentially inhibit vascularization. The model could explain why current biomaterials independent of their surface chemistries and textures fail to vascularize.

中文翻译：

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组织工程难题：分子视角。

生物材料支架不能在功能上整合到周围组织中是开发新的生物材料和组织工程支架的主要障碍之一。尽管取得了长足的进步，目前用于工程化细胞表面相互作用的方法仍无法模仿周围组织调节细胞行为的信号复杂性。细胞通过整联蛋白粘附并与其细胞外环境相互作用，它们激活相关下游信号通路的能力取决于细胞与其细胞外基质之间形成的粘附复合物的特征。特别是，alpha5beta1和alphavbeta3整合素对于调节下游事件（包括细胞存活和细胞周期进程）至关重要。与先前的发现alphavbeta3整合素促进血管生成相反，最近的证据表明alphavbeta3整合素可能充当促血管生成整合素的负调节剂，例如alpha5beta1。这表明纤连蛋白对于支架血管形成至关重要，因为纤连蛋白是唯一结合并激活α5β1整联蛋白的哺乳动物粘附蛋白。细胞还能够拉伸纤连蛋白基质，从而使蛋白质部分展开，并且最近的计算模拟提供了机械拉伸如何影响纤连蛋白功能的结构模型。我们提出了一种模型，通过该模型，与生物材料接触的细胞所产生的过度张力实际上可能使纤连蛋白原纤维无血管生成作用，并可能抑制血管生成。