Human Spinal Organoid-on-a-Chip to Model Nociceptive Circuitry for Pain Therapeutics Discovery
Human Spinal Organoid-on-a-Chip to Model Nociceptive Circuitry for Pain Therapeutics Discovery
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DOI：
10.1021/acs.analchem.1c04641
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发表时间：
2021-12-20
影响因子：
7.4
通讯作者：
Guo, Feng
中科院分区：
文献类型：
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作者：
Ao, Zheng;Cai, Hongwei;Guo, Feng
针对人类伤害感受回路的新疼痛疗法的发现是一个新兴的、令人兴奋的和有益的领域。然而，目前用于评估前瞻性新疗法的模型[例如，动物和二维（2D）体外培养物]不能完全概括人伤害感受神经元和背角神经元生物学的复杂性，从而显著限制了新型疼痛治疗剂的开发。在这里，我们报告了人类脊髓类器官芯片装置，用于模拟人类伤害性神经元和背角中间神经元在伤害性回路中的生物学和电生理学。我们的装置可以通过将膜与三维（3D）打印的类器官保持器集成来简单地制造。通过结合气液界面培养和脊髓类器官方案，我们的装置可以将人类干细胞分化为具有脊髓背侧中间神经元和感觉神经元的人类感觉脊髓类器官。通过容易地从培养孔板转移到多电极阵列（MEA）系统，我们的装置还允许即插即用测量类器官活性以测试伤害感受调节剂（例如，芥末油、辣椒素、绒蚁毒等）。我们的类器官芯片器件具有成本效益、可扩展性、易于使用且与传统孔板兼容，允许即插即用测量脊髓类器官电生理学。通过将人类感觉脊髓类器官与我们的类器官芯片设备相结合，我们的方法可能具有筛选和验证人类疼痛药物发现的新疗法的潜力。
The discovery of new pain therapeutics targeting human nociceptive circuitry is an emerging, exciting, and rewarding field. However, current models for evaluating prospective new therapeutics [e.g., animals and two-dimensional (2D) in vitro cultures] fail to fully recapitulate the complexity of human nociceptive neuron and dorsal horn neuron biology, significantly limiting the development of novel pain therapeutics. Here, we report human spinal organoid-on-a-chip devices for modeling the biology and electrophysiology of human nociceptive neurons and dorsal horn interneurons in nociceptive circuitry. Our device can be simply made through the integration of a membrane with a three-dimensional (3D)-printed organoid holder. By combining air-liquid interface culture and spinal organoid protocols, our devices can differentiate human stem cells into human sensori-spinal-cord organoids with dorsal spinal cord interneurons and sensory neurons. By easily transferring from culture well plates to the multiple-electrode array (MEA) system, our device also allows the plug-and-play measurement of organoid activity for testing nociceptive modulators (e.g., mustard oil, capsaicin, velvet ant venom, etc.). Our organoid-on-a-chip devices are cost-efficient, scalable, easy to use, and compatible with conventional well plates, allowing the plug-and-play measurement of spinal organoid electrophysiology. By the integration of human sensory-spinal-cord organoids with our organoid-on-a-chip devices, our method may hold the promising potential to screen and validate novel therapeutics for human pain medicine discovery.