Engineering human spinal microphysiological systems to model opioid-induced tolerance

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 matu-ration, 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 mu-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.

Automated summary

Opioids may induce tolerance and hyperalgesia, but the human mechanisms underlying these effects are not well understood. Researchers have developed a novel human spinal microphysiological system (MPS) to model human nociception and opioid-induced tolerance. This system shows promising potential for studying pain etiology, screening new treatments, and validating novel therapeutics for human pain medicine.