Hydrogels have been broadly studied for applications in clinically motivated fields such as tissue regeneration, drug delivery, and wound healing, as well as in a wide variety of consumer and industry uses. While the control of mechanical properties and network structures are important in all of these applications, for regenerative medicine applications in particular, matching the chemical, topographical and mechanical properties for the target use/tissue is critical. There have been multiple alternatives developed for fabricating materials with microstructures with goals of controlling the spatial location, phenotypic evolution, and signaling of cells. The commonly employed polymers such as poly(ethylene glycol) (PEG), polypeptides, and polysaccharides (as well as others) can be processed by various methods in order to control material heterogeneity and microscale structures. We review here the more commonly used polymers, chemistries, and methods for generating microstructures in biomaterials, highlighting the range of possible morphologies that can be produced, and the limitations of each method. With a focus in liquid-liquid phase separation, methods and chemistries well suited for stabilizing the interface and arresting the phase separation are covered. As the microstructures can affect cell behavior, examples of such effects are reviewed as well. STATEMENT OF SIGNIFICANCE: Heterogeneous hydrogels with enhanced matrix complexity have been studied for a variety of biomimetic materials. A range of materials based on poly(ethylene glycol), polypeptides, proteins, and/or polysaccharides, have been employed in the studies of materials that by virtue of their microstructure, can control the behaviors of cells. Methods including microfluidics, photolithography, gelation in the presence of porogens, and liquid-liquid phase separation, are presented as possible strategies for producing materials, and their relative advantages and disadvantages are discussed. We also describe in more detail the various processes involved in LLPS, and how they can be manipulated to alter the kinetics of phase separation and to yield different microstructured materials.

中文翻译：

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生产用于生物学目标应用的微结构水凝胶的方法。

水凝胶已被广泛研究用于临床驱动领域，例如组织再生、药物输送和伤口愈合，以及各种消费者和工业用途。虽然机械性能和网络结构的控制在所有这些应用中都很重要，但特别是对于再生医学应用，匹配目标用途/组织的化学、形貌和机械性能至关重要。人们已经开发出多种替代方法来制造具有微结构的材料，其目标是控制细胞的空间位置、表型进化和信号传导。常用的聚合物如聚乙二醇（PEG）、多肽和多糖（以及其他）可以通过各种方法进行加工，以控制材料的异质性和微观结构。我们在这里回顾了更常用的聚合物、化学物质和在生物材料中生成微观结构的方法，强调了可以生成的可能形态的范围以及每种方法的局限性。重点关注液-液相分离，涵盖了非常适合稳定界面和阻止相分离的方法和化学过程。由于微观结构会影响细胞行为，因此也回顾了此类影响的例子。意义声明：已经针对各种仿生材料研究了具有增强基质复杂性的异质水凝胶。一系列基于聚乙二醇、多肽、蛋白质和/或多糖的材料已被用于研究凭借其微观结构可以控制细胞行为的材料。微流体、光刻、致孔剂存在下的凝胶化和液-液相分离等方法被提出作为生产材料的可能策略，并讨论了它们的相对优点和缺点。我们还更详细地描述了 LLPS 中涉及的各种过程，以及如何操纵它们来改变相分离的动力学并产生不同的微结构材料。