iPSC-Derived Neural Models on Vascularized Microfluidic Chips
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Solution Overview
Problem
Current culture systems fail to effectively model sporadic forms of neurodegenerative diseases like ALS and Parkinson's disease, lacking overt cell death phenotypes and genetic markers, necessitating a more complex model to study disease pathogenesis and therapeutic targets.
Innovation Solution
Development of microphysiological models (MPS) using iPSC-derived neurons and a 'brain-on-chip' system that includes a vascularized compartment, allowing for electrophysiological and metabalomic analysis, and drug screening across the blood-brain barrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional cell culture systems are used for sporadic ALS and PD, then the models are simpler to establish, but they fail to reproduce overt cell death phenotypes and disease pathogenesis
Solution Approach 1:
The culture system is segmented into multiple compartments including neural tissue chambers, vascular chambers, and meningeal layers, allowing each component to be optimized for specific physiological functions while collectively reproducing complex disease phenotypes
Solution Approach 2:
The microphysiological system employs nested structures where neural tissues are embedded within vascularized compartments that are further enclosed by meningeal layers, creating a hierarchical organization that mimics in vivo brain architecture and enables reliable disease modeling
2Adaptability or versatility
If microphysiological models with vascularized compartments are implemented, then real-time drug screening across the blood-brain barrier is enabled, but the device complexity and manufacturing difficulty increase
Solution Approach 1:
The vascularized microphysiological platform serves multiple functions including drug screening, pharmacokinetic analysis, blood-brain barrier permeability assessment, and disease modeling, allowing a single device architecture to address diverse research needs without requiring separate specialized systems
Solution Approach 2:
The patent employs microfabricated vascular chambers and porous membranes as intermediary structures that facilitate controlled drug transport across the blood-brain barrier while maintaining physiological relevance, enabling versatile drug screening without requiring complex in vivo surgical procedures
3Manufacturing precision
If iPSC-derived neurons are cultured in static conditions, then the culture protocol is simpler, but the neurons fail to exhibit mature physiological functions and disease-relevant phenotypes
Solution Approach 1:
The culture system transitions from static to dynamic conditions through continuous media flow, mechanical stretching, and electrical stimulation, enabling neurons to mature and exhibit physiological functions that closely resemble in vivo conditions while maintaining controlled experimental parameters
Data Source
AI summary
Described herein is a microphysiological system for models of disease. Specifically, induced pluripotent stem cells (iPSCs) and iPSC-derived cells, including those obtained from disease patients, are seeded onto microfluidic “chip” devices to study cellular development and disease pathogenesis. Herein, neurodegenerative disease modeling, including Parkinson's Disease (PD) is shown to reproduce key PD pathology in a vascularized human model that contains neurons relating to PD pathology. Such compositions and methods are used for research for PD biomarkers, patient screening for PD risk assessment, and therapeutic discovery and testing. A panel of biomarkers are generated through analysis of living PD-chips by neural activity, whole transcriptomic, proteomic, and metabolomic analysis, and functional enzyme tests of media and tissue. Introducing therapeutics through a vasculature channel, coupled with blood brain barrier penetration studies can be assessed for efficacy in the human neural cells present in the PD-Chip.