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Advanced Bioelectronic and Microphysiological Systems for Functional Studies of Stem Cell-Derived Neural Models https://doi.org/10.17863/CAM.124949 Haider, Belquis 0009000594400842 Kaminski Schierle, Gabriele Malliaras, George This thesis presents an integrated bioelectronic and computational framework for functional interrogation of stem cell-derived neural models. Motivated by the staggering failure rate (exceeding 90%) of neurological drug candidates in clinical trials, the work addresses limitations in preclinical modelling by combining advanced microfabrication, flexible electronics, and human-relevant in vitro systems. The research spans: • 2D compartmentalised cultures for studying tauopathy in Alzheimer’s disease using microphysiological and bioelectronic systems; • Air-liquid interface cerebral organoids (ALI-COs), interfaced with Neuroweb, a porous, ultra-flexible microelectrode array enabling chronic electrophysiology; • NeuroMaps, a modular MATLAB-based GUI for multimodal electrophysiological analysis, integrating spike sorting, spectral decomposition, and network mapping across longitudinal measurements. Key findings include: • Material and substrate-related effects on 2D stem-cell-derived neuronal growth. • Tau-induced hyperexcitability and synaptic disruption in iNeuron-astrocyte co-cultures. • Axonal swelling and lysosomal clustering in microfluidic chips following tau exposure. • Stable long-term recordings from ALI-COs, revealing maturation-linked shifts in firing rate, synchrony, and phase-amplitude coupling. • Neuroweb enabled the detection of cross-species differences in signalling using air-liquid interface cerebral organoids and changes in oscillatory activity possibly linked to metabolic recycling. • The development of a full GUI framework for electrophysiological analysis, providing morphological and electrophysiological context to analysis. Together, these platforms advance the field of neuroengineering by enabling scalable, non-invasive, and longitudinal interrogation of complex neural tissues, with implications for disease modelling, drug screening, and personalised medicine. University of Cambridge 2025-11-14 Thesis Doctoral Doctor of Philosophy (PhD) eng SPIE Optics and Photonics Education Scholarship Trinity Henry Barlow Scholarship Cambridge Trust Cambridge Philosophical Society Churchill College Department of Chemical Engineering and Biotechnology https://www.repository.cam.ac.uk/handle/1810/395448 embargo 2027-01-15 https://www.repository.cam.ac.uk/bitstreams/9c411b49-5146-461d-9442-e815e848f756/download 82a711c8a5aa11f1a20c8bd00d0010df https://www.repository.cam.ac.uk/bitstreams/8d5d448b-c1b8-4d0f-8522-2044306efd1d/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved Bioelectronics Electrophysiology Flexible electronics In vitro brain development In vitro neural systems Microelectrode arrays Microenvironment engineering Microfabrication Microphysiological systems Multimodal Electrophysiology Analysis Neuroengineering Organoids Tauopathy