Department of Biomedical Engineering, Yale University, New Haven, CT 06511, United States.
Department of Biomedical Engineering, Yale University, New Haven, CT 06511, United States.
Acta Biomater. 2023 Jan 1;155:167-181. doi: 10.1016/j.actbio.2022.11.011. Epub 2022 Nov 9.
3D in vitro tumor models have recently been investigated as they can recapitulate key features in the tumor microenvironment. Reconstruction of a biomimetic scaffold is critical in these models. However, most current methods focus on modulating local properties, e.g. micro- and nano-scaled topographies, without capturing the global millimeter or intermediate mesoscale features. Here we introduced a method for modulating the collagen I-based extracellular matrix structure by disruption of fibrillogenesis and the gelation process through mechanical agitation. With this method, we generated collagen scaffolds that are thickened and wavy at a larger scale while featuring global softness. Thickened collagen patches were interconnected with loose collagen networks, highly resembling collagen architecture in the tumor stroma. This thickened collagen network promoted tumor cell dissemination. In addition, this novel modified scaffold triggered differences in morphology and migratory behaviors of tumor cells. Altogether, our method for altered collagen architecture paves new ways for studying in detail cell behavior in physiologically relevant biological processes. STATEMENT OF SIGNIFICANCE: Tumor progression usually involves chronic tissue damage and repair processes. Hallmarks of tumors are highly overlapped with those of wound healing. To mimic the tumor milieu, collagen-based scaffolds are widely used. These scaffolds focus on modulating microscale topographies and mechanics, lacking global architecture similarity compared with in vivo architecture. Here we introduced one type of thick collagen bundles that mimics ECM architecture in human skin scars. These thickened collagen bundles are long and wavy while featuring global softness. This collagen architecture imposes fewer steric restraints and promotes tumor cell dissemination. Our findings demonstrate a distinct picture of cell behaviors and intercellular interactions, highlighting the importance of collagen architecture and spatial heterogeneity of the tumor microenvironment.
3D 体外肿瘤模型最近已被研究，因为它们可以再现肿瘤微环境中的关键特征。在这些模型中，重建仿生支架至关重要。然而，目前大多数方法主要侧重于调节局部特性，例如微观和纳米尺度的形貌，而无法捕捉全局毫米或中间介观特征。在这里，我们介绍了一种通过机械搅拌破坏纤维生成和凝胶过程来调节基于胶原蛋白 I 的细胞外基质结构的方法。通过这种方法，我们生成了厚度增加且呈波浪状的胶原支架，同时具有全局柔软度。增厚的胶原斑块与松散的胶原网络相互连接，非常类似于肿瘤基质中的胶原结构。这种增厚的胶原网络促进了肿瘤细胞的扩散。此外，这种新型改性支架还引发了肿瘤细胞形态和迁移行为的差异。总的来说，我们改变胶原结构的方法为详细研究生理相关生物过程中的细胞行为开辟了新途径。
肿瘤进展通常涉及慢性组织损伤和修复过程。肿瘤的特征与伤口愈合的特征高度重叠。为了模拟肿瘤环境，广泛使用基于胶原蛋白的支架。这些支架主要侧重于调节微尺度形貌和力学特性，与体内结构相比缺乏全局架构相似性。在这里，我们引入了一种模拟人皮肤疤痕中 ECM 结构的厚胶原束。这些增厚的胶原束又长又卷曲，同时具有全局柔软度。这种胶原结构施加的空间位阻较小，促进了肿瘤细胞的扩散。我们的研究结果描绘了细胞行为和细胞间相互作用的鲜明图景，突出了胶原结构和肿瘤微环境空间异质性的重要性。
