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Mammary fibroblasts remodel fibrillar collagen microstructure in a biomimetic nanocomposite hydrogel

机译:乳腺成纤维细胞在仿生纳米复合水凝胶中改造纤维胶原微观结构

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Architecture and microstructure of type I collagen fibers constitute central regulators of tumor invasion with aligned fibers providing a route for migration of stromal and cancer cells. Several different aspects of fibrillar collagen, such as stiffness, density, thickness, and pore size, may regulate migration of cancer cells, but determining effects of any one parameter requires clear decoupling of physical properties of collagen networks. The objective of this work is to develop and apply an in vitro three-dimensional (3D) tumor-extra cellular matrix (ECM) model with tunable physical parameters to define how stromal fibroblasts modulate collagen microstructure to control migration of breast cancer cells. We incorporated two different types of polyhedral oligomeric silsesquioxane (POSS) nano-molecules into a collagen/alginate matrix to induce different mechanisms of gelling. The resultant biomimetic, nanocomposite hydrogels show different collagen fibrillar microstructures while maintaining constant overall matrix stiffness, density, and porosimetry. Spheroids of human mammary fibroblasts embedded in these 3D matrices remodel the collagen network to varying extents based on differences in underlying matrix microstructures. The remodeled collagen matrix shows oriented, thicker fibrillar tracks, facilitating invasion of tumor cells. By decoupling effects of matrix stiffness and architecture, our nanocomposite hydrogels serve as robust platforms to investigate how biophysical properties of tumor environments control key processes regulating tumor progression in breast cancer and other malignancies.
机译:I型胶原纤维的建筑和微观结构构成肿瘤侵袭的中央调节因子,其对齐纤维提供用于迁移基质和癌细胞的途径。纤维状胶原的几种不同方面,例如刚度,密度,厚度和孔径,可以调节癌细胞的迁移,但是任何一个参数的测定效果需要清除胶原网络的物理性质的清除去耦。本作作品的目的是通过可调谐物理参数开发和应用体外三维(3D)肿瘤 - 额外的细胞基质(ECM)模型,以定义基质成纤维细胞如何调节胶原微观结构以控制乳腺癌细胞的迁移。我们将两种不同类型的多面体低聚倍半硅氧烷(POSS)纳米分子纳入胶原/藻酸盐基质中,以诱导不同的胶凝机制。所得型纳米复合水凝胶显示出不同的胶原纤维状微观结构,同时保持恒定的总基质刚度,密度和孔隙率。嵌入在这些3D基质中的人乳腺成纤维细胞的球状体基于底层基质微结构的差异来将胶原网络重塑到变化的范围。改造的胶原蛋白基质显示取向,较厚的纤维状轨道,促进肿瘤细胞的侵袭。通过去耦效应基质刚度和架构,我们的纳米复合水凝胶用作鲁棒平台,以研究肿瘤环境的生物物理性质如何控制乳腺癌和其他恶性肿瘤中调节肿瘤进展的关键过程。

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