Cai Hongwei, Ao Zheng, Tian Chunhui, Wu Zhuhao, Kaurich Connor, Chen Zi, Gu Mingxia, Hohmann Andrea G, Mackie Ken, Guo Feng
Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, 47405, United States.
Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, 02115, United States.
Bioact Mater. 2022 Oct 25;22:482-490. doi: 10.1016/j.bioactmat.2022.10.007. eCollection 2023 Apr.
pioids are commonly used for treating chronic pain. However, with continued use, they may induce tolerance and/or hyperalgesia, which limits therapeutic efficacy. The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied, in part, because current models cannot fully recapitulate human pathology. Here, we engineered novel human spinal microphysiological systems (MPSs) integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance. Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement. We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids, but also promotes their neuron maturation, neural activity, and functional development. We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia, as measured by altered neural activity, and downregulation of μ-opioid receptor expression of human spinal MPSs. The MPSs are scalable, cost-effective, easy-to-use, and compatible with commonly-used well-plates, thus allowing plug-and-play measurements of neural activity. We believe the MPSs hold a promising translational potential for studying human pain etiology, screening new treatments, and validating novel therapeutics for human pain medicine.
阿片类药物常用于治疗慢性疼痛。然而，持续使用时，它们可能会诱导耐受性和/或痛觉过敏，这限制了治疗效果。阿片类药物诱导的耐受性和痛觉过敏的人体机制研究明显不足，部分原因是当前模型无法完全重现人类病理学情况。在此，我们构建了新型的人体脊髓微生理系统（MPS），其集成了即插即用的神经活动传感功能，用于模拟人体伤害感受和阿片类药物诱导的耐受性。每个脊髓MPS由源自人类干细胞的扁平人体脊髓类器官和用于即插即用神经活动测量的3D打印类器官固定装置组成。我们发现，MPS的扁平类器官设计不仅减少了类器官中的缺氧和坏死情况，还促进了它们的神经元成熟、神经活动及功能发育。我们进一步证明，长时间暴露于阿片类药物会导致阿片类药物耐受性和痛觉过敏的神经化学关联，这通过神经活动的改变以及人体脊髓MPS的μ-阿片受体表达下调来衡量。这些MPS具有可扩展性、成本效益高、易于使用且与常用微孔板兼容，从而能够对神经活动进行即插即用测量。我们相信，MPS在研究人类疼痛病因、筛选新疗法以及验证人类疼痛医学的新型治疗方法方面具有广阔的转化潜力。
