Stem cell-derived β cells offer an alternative to primary islets for biomedical discoveries as well as a potential surrogate for islet transplantation. The expense and challenge of obtaining and maintaining functional stem cell-derived β cells calls for a need to develop better high-content and high-throughput culture systems. Microphysiological systems (MPS) are promising high-content in vitro platforms, but scaling for high-throughput screening and discoveries remain a challenge. Traditionally, simultaneous multiplexing of liquid handling and cell loading poses a challenge in the design of high-throughput MPS. Furthermore, although MPS for islet β culture/testing have been developed, studies on multi-day culture of stem-cell derived β cells in MPS have been limited. We present a scalable, multiplexed islet β MPS device that incorporates microfluidic gradient generators to parallelize fluid handling for culture and test conditions. We demonstrated the viability and functionality of the stem cell-derived enriched β clusters (eBCs) for a week, as assessed by the ∼2 fold insulin release by the clusters to glucose challenge. To show the scalable multiplexing for drug testing, we demonstrated the loss of stimulation index after long-term exposure to logarithmic concentration range of glybenclamide. The MPS cultured eBCs also confirmed a glycolytic bottleneck as inferred by insulin secretion responses to metabolites methyl succinate and glyceric acid. Thus, we present an innovative culture platform for eBCs with a balance of high-content and high-throughput characteristics.

中文翻译：

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用于干细胞来源的胰岛 β 细胞的多重微流体平台

干细胞衍生的 β 细胞为生物医学发现提供了原代胰岛的替代品，并为胰岛移植提供了潜在的替代品。获得和维持功能性干细胞来源的 β 细胞的费用和挑战要求开发更好的高含量和高通量培养系统。微生理系统 (MPS)在体外有望实现高含量平台，但扩展高通量筛选和发现仍然是一个挑战。传统上，液体处理和细胞加载的同时多路复用对高通量 MPS 的设计提出了挑战。此外，虽然已经开发了用于胰岛 β 培养/测试的 MPS，但对 MPS 中干细胞来源的 β 细胞的多日培养的研究是有限的。我们提出了一种可扩展的多路复用胰岛 β MPS 设备，该设备结合了微流体梯度发生器以并行处理培养和测试条件下的流体。我们展示了干细胞衍生的富集 β 簇 (eBC) 一周的活力和功能，这是通过簇释放约 2 倍的胰岛素来评估葡萄糖挑战的。为了展示药物测试的可扩展多路复用，我们证明了长期暴露于对数浓度范围的格列本脲后刺激指数的损失。MPS 培养的 eBCs 也证实了糖酵解瓶颈，正如胰岛素分泌对代谢物琥珀酸甲酯和甘油的反应所推断的那样。因此，我们为 eBCs 提供了一个具有高内容和高通量特性平衡的创新文化平台。