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Abstract：
Three-dimensional (3D) cell culture models have been extensively utilized in various mechanistic studies as well as for drug development studies as superior in vitro platforms than conventional two-dimensional (2D) cell culture models. This is especially the case in cancer biology, where 3D cancer models, such as spheroids or organoids, have been utilized extensively to understand the mechanisms of cancer development. Recently, many sophisticated 3D models such as organ-on-a-chip models are emerging as advanced in vitro models that can more accurately mimic the in vivo tissue functions. Despite such advancements, spheroids are still considered as a powerful 3D cancer model due to the relatively simple structure and compatibility with existing laboratory instruments, and also can provide orders of magnitude higher throughput than complex in vitro models, an extremely important aspects for drug development. However, creating well-defined spheroids remain challenging, both in terms of throughputs in generation as well as reproducibility in size and shape that can make it challenging for drug testing applications. In the past decades, droplet microfluidics utilizing hydrogels have been highlighted due to their potentials. Importantly, core-shell structured gel droplets can avoid spheroid-to-spheroid adhesion that can cause large variations in assays while also enabling long-term cultivation of spheroids with higher uniformity by protecting the core organoid area from external environment while the outer porous gel layer still allows nutrient exchange. Hence, core-shell gel droplet-based spheroid formation can improve the predictivity and reproducibility of drug screening assays. This review paper will focus on droplet microfluidics-based technologies for cancer spheroid production using various gel materials and structures. In addition, we will discuss emerging technologies that have the potential to advance the production of spheroids, prospects of such technologies, and remaining challenges.
摘要：
三维(3D)细胞培养模型作为优于常规二维(2D)细胞培养模型的体外平台已广泛用于各种机理研究以及药物开发研究。在癌症生物学中尤其如此，3D癌症模型，如球体或类器官，已被广泛用于了解癌症发展的机制。最近,许多复杂的3D模型，如芯片上器官模型正在成为先进的体外模型，可以更准确地模拟体内组织功能。尽管有这样的进步,由于结构相对简单且与现有实验室仪器的兼容性，球体仍然被认为是强大的3D癌症模型，并且还可以提供比复杂的体外模型更高的吞吐量，药物开发的一个极其重要的方面。然而,创建定义明确的球体仍然具有挑战性，无论是在一代的吞吐量以及在大小和形状，可以使它具有挑战性的药物测试应用的可重复性。在过去的几十年里，利用水凝胶的液滴微流体由于其潜力而被强调。重要的是,核壳结构的凝胶液滴可以避免球状体到球状体的粘附，这可能会导致分析中的大差异，同时还可以通过保护核类器官区域免受外界环境的影响来长期培养具有更高均匀性的球状体，而外部多孔凝胶层仍然允许营养交换。因此，基于核壳凝胶液滴的球体形成可以提高药物筛选试验的预测性和可重复性。本文将重点介绍使用各种凝胶材料和结构的基于液滴微流体的癌症球体生产技术。此外,我们将讨论有潜力推进球体生产的新兴技术，这些技术的前景，和剩余的挑战。
