Rapid fabrication of collagen bundles mimicking tumor-associated collagen architectures
Rapid fabrication of collagen bundles mimicking tumor-associated collagen architectures
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DOI：
10.1016/j.actbio.2020.03.019
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发表时间：
2020-05-01
影响因子：
9.7
通讯作者：
Mills, K. L.
中科院分区：
文献类型：
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作者：
Gong, Xiangyu;Kulwatno, Jonathan;Mills, K. L.
间质胶原在实体瘤周围表达上调，呈致密、厚实、线性化、排列整齐的束状。胶原束在肿瘤进展过程中不断重塑，它们相对于肿瘤边界的方向与肿瘤的侵袭状态有关。目前，重组胶原凝胶是体外肿瘤细胞-细胞外基质相互作用的标准模型。然而，网状、致密和各向同性的纳米纤维(平均直径类似于900 nm)凝胶不能概括体内胶原束和排列的结构特征。在这里，我们提出了一种快速而简单的方法来制备I型胶原束，根据稀释剂温度和离子强度的不同，I型胶原束的平均厚度可以在大约4微米到9微米之间变化。胶原束的耐用性和多功能性通过将它们整合到两个体外模型中得到证明，在两个体外模型中，胶原束的厚度和排列方式类似于体内的不同排列。首先，通过微流控装置排列的胶原束可以引导癌细胞接触并增强它们的定向迁移。其次，生物惰性琼脂糖水凝胶中胶原束的存在被证明为癌细胞生长提供了一条途径。胶原束的独特结构特征提高了基于胶原蛋白的体外肿瘤模型的生理学相关性，以准确捕捉肿瘤细胞-细胞外基质的相互作用。意义陈述肿瘤微环境中的胶原蛋白被上调并重塑为致密、厚实和排列的与侵袭状态相关的胶原束。目前基于胶原蛋白的体外模型是基于网状、各向同性的纳米纤维凝胶，不能完全概括体内肿瘤间质胶原蛋白。我们提出了一种简单而可靠的方法，可以快速制造细胞规模的胶原束，更好地模拟肿瘤周围重塑的胶原蛋白。与纳米纤维支架相比，与这些束相互作用的癌细胞表现出截然不同的表型行为。这项工作揭示了体外肿瘤模型的微尺度结构的重要性。胶原束提供了生理上相关的胶原蛋白形态，可以很容易地结合到现有的肿瘤细胞-细胞外基质相互作用模型中。(C)2020 Acta Materialia Inc.由爱思唯尔有限公司出版。版权所有。
Stromal collagen is upregulated surrounding a solid tumor and presents as dense, thick, linearized, and aligned bundles. The collagen bundles are continually remodeled during tumor progression, and their orientation with respect to the tumor boundary has been correlated with invasive state. Currently, reconstituted-collagen gels are the standard in vitro tumor cell-extracellular matrix interaction model. The reticular, dense, and isotropic nanofiber (similar to 900 nm-diameter, on average) gels do not, however, recapitulate the in vivo structural features of collagen bundling and alignment. Here, we present a rapid and simple method to fabricate bundles of collagen type I, whose average thickness may be varied between about 4 mu m and 9 mu m dependent upon diluent temperature and ionic strength. The durability and versatility of the collagen bundles was demonstrated with their incorporation into two in vitro models where the thickness and alignment of the collagen bundles resembled various in vivo arrangements. First, collagen bundles aligned by a microfluidic device elicited cancer cell contact guidance and enhanced their directional migration. Second, the presence of the collagen bundles in a bio-inert agarose hydrogel was shown to provide a route for cancer cell outgrowth. The unique structural features of the collagen bundles advance the physiological relevance of in vitro collagen-based tumor models for accurately capturing tumor cell-extracellular matrix interactions.Statement of significanceCollagen in the tumor microenvironment is upregulated and remodeled into dense, thick, and aligned bundles that are associated with invasive state. Current collagen-based in vitro models are based on reticular, isotropic nanofiber gels that do not fully recapitulate in vivo tumor stromal collagen. We present a simple and robust method of rapidly fabricating cell-scale collagen bundles that better mimic the remodeled collagen surrounding a tumor. Interacting with the bundles, cancer cells exhibited drastically different phenotypic behaviors, compared to nanofiber scaffolds. This work reveals the importance of microscale architecture of in vitro tumor models. The collagen bundles provide physiologically relevant collagen morphologies that may be easily incorporated into existing models of tumor cell-extracellular matrix interactions. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.