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Biohybrid robots have been developed for biomedical applications and industrial robotics. However, the biohybrid robots have limitations to be applied in neurodegenerative disease research due to the absence of a central nervous system. In addition, the organoids‐on‐a‐chip has not yet been able to replicate the physiological function of muscle movement in the human motor system, which is essential for evaluating the accuracy of the drugs used for treating neurodegenerative diseases. Here, a human motor system‐based biohybrid robot‐on‐a‐chip composed of a brain organoid, multi‐motor neuron spheroids, and muscle bundle on solid substrateis proposed to evaluate the drug effect on neurodegenerative diseases for the first time. The electrophysiological signals from the cerebral organoid induced the muscle bundle movement through motor neuron spheroids. To evaluate the drug effect on Parkinson's disease (PD), a patient‐derived midbrain organoid is generated and incorporated into a biohybrid robot‐on‐a‐chip. The drug effect on PD is successfully evaluated by measuring muscle bundle movement. The muscle bundle movement of PD patient‐derived midbrain organoid‐based biohybrid robot‐on‐a‐chip is increased from 4.5 ± 0.99 µm to 18.67 ± 2.25 µm in response to levodopa. The proposed human motor system‐based biohybrid robot‐on‐a‐chip can serve as a standard biohybrid robot model for drug evaluation. [ABSTRACT FROM AUTHOR]

Brain organoids are being recognized as valuable tools for drug evaluation in neurodegenerative diseases due to their similarity to the human brain's structure and function. However, a critical challenge is the lack of selective and sensitive electrochemical sensing platforms to detect the response of brain organoids, particularly changes in the neurotransmitter concentration upon drug treatment. This study introduces a 3D concave electrode patterned with a mesoporous Au nanodot for the detection of electrochemical signals of dopamine in response to drugs in brain organoids for the first time. The mesoporous Au nanodot-patterned film was fabricated using laser interference lithography and electrochemical deposition. Then, the film was attached to a polymer-based 3D concave mold to obtain a 3D concave electrode. Midbrain organoids generated from Parkinson's disease (PD) patient-derived iPSCs with gene mutations (named as PD midbrain organoid) or normal midbrain organoids were positioned on the developed 3D concave electrode. The 3D concave electrode showed a 1.4 times higher electrochemical signal of dopamine compared to the bare gold electrode. And the dopamine secreted from normal midbrain organoids or PD midbrain organoids on the 3D concave electrode could be detected electrochemically. After the treatment of PD midbrain organoids with levodopa, the drug for PD, the increase in dopamine level was detected due to the activation of dopaminergic neurons by the drug. The results suggest the potential of the proposed 3D concave electrode combined with brain organoids as a useful tool for assessing drug efficacy. This sensing system can be applied to a variety of organoids for a comprehensive drug evaluation.