Joshi Indranil M, Mansouri Mehran, Ahmed Adeel, De Silva Dinindu, Simon Richard A, Esmaili Poorya, Desa Danielle E, Elias Tresa M, Brown Edward B, Abhyankar Vinay V
Department of Biomedical Engineering, Rochester Institute of Technology, Rochester, NY.
Department of Biomedical Engineering, University of Rochester, Rochester, NY.
Adv Funct Mater. 2024 Mar 25;34(13). doi: 10.1002/adfm.202308071. Epub 2023 Dec 17.
Collagen fibers in the 3D tumor microenvironment (TME) exhibit complex alignment landscapes that are critical in directing cell migration through a process called contact guidance. Previous in vitro work studying this phenomenon has focused on quantifying cell responses in uniformly aligned environments. However, the TME also features short-range gradients in fiber alignment that result from cell-induced traction forces. Although the influence of graded biophysical taxis cues is well established, cell responses to physiological alignment gradients remain largely unexplored. In this work, fiber alignment gradients in biopsy samples are characterized and recreated using a new microfluidic biofabrication technique to achieve tunable sub-millimeter to millimeter scale gradients. This study represents the first successful engineering of continuous alignment gradients in soft, natural biomaterials. Migration experiments on graded alignment show that HUVECs exhibit increased directionality, persistence, and speed compared to uniform and unaligned fiber architectures. Similarly, patterned MDA-MB-231 aggregates exhibit biased migration toward increasing fiber alignment, suggesting a role for alignment gradients as a taxis cue. This user-friendly approach, requiring no specialized equipment, is anticipated to offer new insights into the biophysical cues that cells interpret as they traverse the extracellular matrix, with broad applicability in healthy and diseased tissue environments.
三维肿瘤微环境（TME）中的胶原纤维呈现出复杂的排列格局，这在通过一种称为接触导向的过程指导细胞迁移方面至关重要。此前研究这一现象的体外工作主要集中在量化细胞在均匀排列环境中的反应。然而，TME中还存在由细胞诱导的牵引力导致的纤维排列短程梯度。尽管分级生物物理趋化线索的影响已得到充分证实，但细胞对生理排列梯度的反应在很大程度上仍未得到探索。在这项工作中，活检样本中的纤维排列梯度通过一种新的微流控生物制造技术进行表征和重现，以实现可调的亚毫米到毫米尺度的梯度。这项研究代表了在柔软的天然生物材料中首次成功构建连续排列梯度。在分级排列上进行的迁移实验表明，与均匀和无序的纤维结构相比，人脐静脉内皮细胞（HUVECs）表现出更高的方向性、持久性和速度。同样，图案化的MDA-MB-231聚集体表现出向纤维排列增加方向的偏向性迁移，表明排列梯度作为一种趋化线索发挥了作用。这种无需专门设备的用户友好方法，有望为细胞在穿越细胞外基质时所解读的生物物理线索提供新的见解，在健康和患病组织环境中具有广泛的适用性。
