2. Academic Validation
  3. Geometrically-engineered human motor assembloids-on-a-chip for neuromuscular interaction readout and hypoxia-driven disease modeling

Geometrically-engineered human motor assembloids-on-a-chip for neuromuscular interaction readout and hypoxia-driven disease modeling

  • Nat Commun. 2025 Sep 30;16(1):8693. doi: 10.1038/s41467-025-63736-0.
Weihua Zhang # 1 2,  Liming Yu # 1 2,  Jie Pan # 1 2,  Jiajia Deng 1 2,  Xianqin Tong 1 2,  Bingjiao Zhao 1 2,  Wen Liu 1 2,  Liangyan Sun 1 2,  Menghan Zhang 3,  Xinxin Han 1 2,  Tingjiao Liu 1 2,  Yun Lu 4 5,  Jiao Li 6 7,  Yuehua Liu 8 9
Affiliations

Affiliations

  • 1 Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China.
  • 2 Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China.
  • 3 Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, China.
  • 4 Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China. luyun@fudan.edu.cn.
  • 5 Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China. luyun@fudan.edu.cn.
  • 6 Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China. jiaoli@fudan.edu.cn.
  • 7 Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China. jiaoli@fudan.edu.cn.
  • 8 Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China. liuyuehua@fudan.edu.cn.
  • 9 Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China. liuyuehua@fudan.edu.cn.
  • # Contributed equally.
PMID: 41028715 DOI: 10.1038/s41467-025-63736-0
Abstract

Precision medicine leverages stem cell-derived models to dissect complex interactions underlying disease-driven neuromuscular damage. However, such reductionist models form stochastic structures without external guidance, while available engineering solutions remain intricate. Here, simplified surface modification engineering is used to render spatially patterned human motor assembloids-on-a-chip by geometric confinement. The anisotropic architecture of skeletal muscle organoids (hSkM) can be conferred solely by localized mechanobiological cues within this predefined device without aligned scaffolds or adjuncts. The hSkM-orchestrated coupling of motor neuron spheroids (hMNS) promotes synergistic neuromuscular development. Furthermore, integration of optogenetic and microelectrode array mapping enables visualization of functional patterning in assembloids. Applied to oxygen deprivation model, hSkM exhibits structural anomalies, fatigable muscle remodeling and dysfunction, recapitulating muscle pathologies in intermittent hypoxia (IH)-associated respiratory disorders. Electrical activity mapping reveals the heterogeneity in neuromuscular responses to IH, indicating the neuroregulatory etiology of muscle dysfunction. Finally, we identify mitochondrial bioenergetic imbalance as a key IH target, proposing evaluation of NAD+ salvage pathway-targeting agents. Our findings provide an accessible platform with translational potential for neuromuscular physiopathology research.

Figures
Products