Cell Shape Control of Migration on Biomaterials

描述（由申请人提供）：体外工程组织可用于恢复和修复人体组织，可能挽救一些等待器官捐赠的患者的生命。复杂组织工程的一个主要挑战是细胞运动的方向控制。例如，不同类型的细胞以特定的方式聚集形成功能器官，毛细血管向新组织或伤口方向发芽，神经系统形成或再生过程中神经细胞向特定方向迁移。这项探索性/开发性研究探讨了一种全新方法的可行性，该方法使用具有非对称形状细胞粘附岛的微米大小的可生物降解支架来控制细胞的定向迁移。这些特殊形状的粘岛被设计成像梳子一样，一边有多个尖角，另一边有光滑的弯曲边缘。这种设计的基础来自于先前对微图纹细胞的研究，这些研究表明，粘附岛上的单细胞开始板足延伸——细胞迁移的第一步——优先在离细胞核最远的细胞周围的尖角处。因此，在这些梳状岛屿上形成图案的细胞预计会优先从具有多个尖角的侧面延伸板足。为了证明细胞迁移的连续协调，多个梳状岛屿以圆形模式排列，使岛屿的尖尖指向相邻岛屿的光滑弯曲侧。岛屿之间和梳尖之间的间隙被设置在典型的扩展板足长度以下，以允许细胞逃脱限制，并以预定的逆时针方向从一个岛屿“跳跃”到另一个岛屿。一个成功的原理证明，细胞形状，由微模式的几何形状定义，可以用来控制细胞在生物材料上的定向迁移，这将为组织工程支架的设计开辟许多新的途径。例如，这些原理可以应用于同时控制内皮细胞（毛细血管）和肝细胞（肝）向复杂支架模式的定向迁移，类似于在肝组织中发现的那样。这种方法也可以直接扩展到通过切割和扭曲生物材料片或堆叠这些微图案片的多层来形成三维支架。

DESCRIPTION (provided by applicant): Tissues engineered in vitro can be used to restore and repair human tissues, potentially saving the lives of some patients waiting for organ donation. One major challenge in engineering complex tissues is directional control of cell movement. For example, different cell types assemble in specific patterns to form functional organs, capillaries sprout in the direction of new tissues or wounds, and neural cells migrate in specific directions during formation or regeneration of nervous systems. This proposed Exploratory/Development research investigates the feasibility of a completely novel approach for controlling the directional migration of cells using biodegradable scaffolds with micron-size patterns of asymmetrically shaped cell-adhesive islands. These specially shaped adhesive islands are designed to resemble combs having multiple sharp corners on one side and a smooth curved edge on the other. The basis of this design comes from previous studies with micropatterned cells, which demonstrated that single cells patterned on adhesive islands initiate lamellipodia extension - the first step of cell migration - preferentially at sharp corners of the cell periphery furthest from the cell nucleus. Cells patterned on these comb shaped islands are thus expected to extend lamellipodia preferentially from the side with multiple sharp corners. To demonstrate continuous coordination of cell migration, multiple comb-shaped islands are arranged in a circular pattern such that the sharp tips of the islands point towards the smoothly curved side of a neighboring island. The gaps between islands and between the pointed tips of the combs are set below the typical length of extended lamellipodia to allow cells to escape confinement and "hop" from one island to another in a predetermined counter-clockwise direction. A successful proof-of-principle demonstration of how cell shape, defined by the geometry of micropatterns, can be used to control the directional migration of cells on biomaterials will open many new avenues in the design of scaffolds for tissue engineering. These principles may be applied, for example, to control simultaneously the directional migration of endothelial (capillary) and hepatocyte (liver) cells into complex scaffold patterns similar to that found in liver tissues. This methodology can also be directly extended to form three-dimensional scaffolds either by cutting and twisting sheets of biomaterials or stacking multiple layers of these micropatterned sheets.