Substrates with patterned extracellular matrix and subcellular stiffness gradients reveal local biomechanical responses.
Substrates with patterned extracellular matrix and subcellular stiffness gradients reveal local biomechanical responses.
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DOI：
10.1002/adma.201304607
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发表时间：
2014-02-26
影响因子：
29.4
通讯作者：
Di Carlo, Dino
中科院分区：
文献类型：
--
作者：
Tseng, Peter;Di Carlo, Dino
底物硬度和细胞外基质都是多种细胞功能的关键调节因子，并在调节细胞发育中起着关键的检查点作用。细胞直接或间接感受到基质刚性，并导致信号[1]，该信号已被确定影响迁移(趋化)[2]、增殖[3]、组织结构[1]、干细胞分化[4]和表型[5，6]。细胞外基质(ECM)或细胞模式的空间限制和调控同样会扰乱细胞的行为，对细胞极性、增殖[8、9]、分裂[10]和分化[11]都有显著影响。虽然在这些分离效应的研究中有大量的技术成就，但到目前为止，还没有什么技术可以长期、同时和对齐地绘制僵硬(或力)和ECM线索的图案，特别是在亚细胞分辨率下[12]。在活体中，单个细胞和组织经常受到局部硬度、来自邻近细胞和组织的力以及基质组织(特别是在生物发育的早期阶段)的影响[13，14]，因此，在这些条件的受控组合下探索细胞的稳态反应的能力对于生物学理解和进一步开发工具以确定具有局部微环境变化的生物结构的组装都是至关重要的。存在许多技术来在基质上形成硬度和细胞外基质蛋白。硬度的图案化主要是通过在具有不同交联度的聚合物材料之间产生直接的材料界面，无论是通过在交联剂中引入化学梯度，还是通过光敏交联剂的不同曝光[2，15-19]。这从根本上也会在暴露在生物系统中的材料特性中产生梯度，因为不同交联度的地区的孔大小和表面化学可能会有很大差异。最近，几种方法已经在聚丙烯酰胺凝胶中产生了僵硬图案，而不是依赖于产生由不那么坚硬的聚合物填充和覆盖的3-d模塑刚性主干[20，21]。由于力在较软材料中的传播，具有较低高度的区域较软
Both substrate stiffness and the extracellular matrix are key regulators of a large variety of cellular functions, and act as critical checkpoints in regulating cellular development. Substrate stiffness is either directly or indirectly sensed by cells and leads to signaling [1] that has been identified to affect migration (durotaxis)[2], proliferation [3], tissue architecture [1], stem cell differentiation [4], and phenotype [5, 6]. Spatial restriction and regulation of extracellular matrix (ECM), or cell patterning, similarly perturbs cell behavior, with noted effects on cell polarity [7], proliferation [8, 9], division [10], and differentiation [11]. While numerous technological achievements abound in the study of these separated effects, as of yet, there exists few techniques allowing long-term, simultaneous and aligned patterning of stiffness (or force) and ECM cues, especially at sub-cellular resolution [12]. In vivo, both single cells and tissues are often subject to local variations in stiffness, forces from neighboring cells and tissues, and matrix organization (particularly in early stages of biological development)[13, 14], and as such, the capability to explore the steady-state response of cells under controlled combinations of such conditions is of critical importance in both biological understanding and the further development of tools to specify the assembly of biological structures with local microenvironment variations.A number of technologies exist to pattern stiffness and extracellular matrix proteins on substrates. Stiffness is patterned predominantly by generating a direct material interface between polymeric materials with different cross-linking density, whether by the introduction of chemical gradients in cross-linker, or by differential exposure of photosensitive crosslinker [2, 15–19]. This fundamentally also generates gradients in material properties exposed to the biological systems, as the pore size and surface chemistry can vary significantly across regions of varying cross-linking density. Recently, several approaches have generated stiffness patterns in polyacrylamide gels that instead rely on generating a 3-d molded rigid backbone filled and covered by the less stiff polymer [20, 21]. Because of the propagation of force through the softer material, regions with lower heights of softer
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