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iPSC-mediated axonal regeneration and function in human brain chip

  • 김나연 (Na Yeon Kim, 서강대학교 일반대학원)

초록(요약문)

The aim of this dissertation is to develop human-relevant, controllable microphysiological platforms that accelerate functional neurodevelopment and enable systematic evaluation of neuroprotective interventions. Conventional in vitro and animal- based approaches often face key limitations, including limited physiological relevance, poor translation to human conditions, and insufficient control over the complex, multi-factorial microenvironment that governs neural differentiation and maturation. In particular, human iPSC-based neural models, while powerful, frequently require prolonged and variable differentiation processes, motivating the need for integrated and programmable stimulation strategies. This dissertation integrates microfluidics with bioelectrical and biochemical modulation to guide stem cell fate and promote maturation of human neural networks. A microfluidic electrode-array platform was established to provide aligned electrical cues within a defined microarchitecture that supports neurite guidance and structured network formation. By combining electrical stimulation with neurotrophic biochemical cues, the system enables precise, repeatable control of the neural induction environment and enhances maturation- associated features, including neurite development and synaptic interactions, beyond what is typically achieved with single-factor stimulation. Building on this controlled brain-on-chip framework, the dissertation further investigates cross-organ neuromodulation by establishing an integrated gut–brain axis platform. A perfused gut module supports stable epithelial structure and sustained microbial interaction, enabling collection and transfer of microbiome-derived metabolites and extracellular vesicles (EVs) to the neural module. Using this approach, microbiome-derived factors were shown to modulate neuronal differentiation trajectories, promote neural network development, and influence synaptic maturation in a strain-dependent manner. The dissertation also explores the potential of these platforms for disease-relevant neuroprotection assessment. In an in vitro Alzheimer’s disease model induced by amyloid-β, treatment with microbiome-derived metabolites and EVs improved axonal growth and supported recovery of neural network features, indicating their promise as non-cellular therapeutic candidates and demonstrating the utility of the platform for mechanistic studies and intervention screening under pathological conditions. Overall, this dissertation presents a controllable, human-relevant organ-on-chip framework that coordinates electrical, biochemical, and microbial cues to drive neurodevelopmental modulation and to evaluate neuroprotective strategies. The proposed platforms provide a robust foundation for studying neural regeneration and gut–brain communication mechanisms, and offer translational potential for scalable screening and personalized evaluation of neurotherapeutic candidates. Keywords: Induced pluripotent stem cell, Microfluidic chip, Electrical stimulation, Gut-brain axis, Neurodegenerative disease.

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목차

Table of Contents i
List of figures iiii
Abstract v

I. Chapter 1. Introduction 1
A. Literature Review 1
B. Scope of Thesis 5

II. Chapter 2. Synergistic effect of electrical and biochemical stimulation on human iPSC-
derived neural differentiation in a microfluidic electrode-array chip 7
A. Introduction 7
B. Materials and Methods11
C. Results and Discussion18
D. Conclusion 38

III. Chapter 3. Effect of gut microbiota-derived metabolites and extracellular vesicles on
neural development and neuroprotection in a gut-brain axis chip 40
A. Introduction 40
B. Materials and Methods43
C. Results and Discussion49
D. Conclusion 69

IV. Conclusion and Future Perspectives 72
A. Conclusion 72
B. Future Perspectives 74

References 76

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