Vascularized Neural Tissue Constructs for Neurotoxicity Screening
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Solution Overview
Problem
Current in vitro models for neural tissue development and neurotoxicity testing lack critical components like blood vessels and microglia, limiting their ability to predict human developmental neurotoxicity and requiring xenogeneic materials, which introduces variability and reproducibility issues.
Innovation Solution
A method for producing vascularized neural tissue constructs using human neural progenitor cells seeded in a three-dimensional porous biomaterial, such as a hydrogel, with endothelial cells, mesenchymal cells, and primitive macrophages, which promotes differentiation and vascularization, and includes bioactive agents to modulate cell behavior, allowing for the creation of uniform, xenogeneic material-free tissue constructs that mimic human neural tissue.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If animal models are used for neurotoxicity testing, then insight into neurodevelopment mechanisms is provided, but predictive accuracy for human developmental neurotoxicity is limited due to species differences
Solution Approach 1:
The patent creates in vitro human neural tissue constructs that copy and replicate human neural tissue architecture, cell types, and developmental processes. These constructs use human pluripotent stem cell-derived cells organized into three-dimensional structures with multiple cell layers, vasculature, and extracellular matrix, providing a human-specific model that accurately predicts human developmental neurotoxicity without species translation issues
2Reliability
If simple in vitro models are used, then ease of operation is improved, but critical components like blood vessels and microglia are missing, limiting predictive capability
Solution Approach 1:
The patent implements a nested organizational structure where human pluripotent stem cell-derived cells are organized into multiple cell layers, which are embedded within a three-dimensional extracellular matrix scaffold, which itself is populated with vasculature and immune cells. This nested architecture replicates the complexity of human neural tissue while maintaining a controllable in vitro system
Solution Approach 2:
The patent uses composite tissue constructs combining multiple cell types (neural progenitor cells, endothelial cells, pericytes, microglia) with extracellular matrix materials and bioactive factors. This composite approach creates a complex tissue environment that supports realistic neural development and toxicity responses while remaining amenable to in vitro culture and screening
3Productivity
If xenogeneic materials are used in tissue constructs, then ease of manufacture is improved, but variability and reproducibility issues arise
Solution Approach 1:
The patent uses human pluripotent stem cell-derived cells throughout the tissue construct, ensuring cellular homogeneity in terms of species origin and developmental potential. This eliminates variability introduced by mixing cells from different species or sources, enhancing reproducibility while maintaining compatibility with human-specific toxicity responses
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method enables the production of highly uniform, three-dimensional vascularized neural tissue constructs that recapitulate human neural tissue complexity, facilitating efficient and reproducible screening of neurotoxic agents and predicting neurotoxicity with high accuracy, replacing the need for animal models and reducing variability.
Implementation Method 1
seeding a three-dimensional porous biomaterial with human neural progenitor cells
Implementation Method 2
The three-dimensional porous biomaterial can be a hydrogel. The hydrogel can comprise polymerized poly(ethylene glycol) (PEG) or polymerized polysaccharide
Implementation Method 3
The degradable hydrogel can be selected from the group consisting of an enzymatically degradable hydrogel, a hydrolytically degradable hydrogel
Implementation Method 4
The degradable hydrogel can be selected from the group consisting of an enzymatically degradable hydrogel, a hydrolytically degradable hydrogel
Data Source
AI summary
The present invention relates to three-dimensional (3D) tissue constructs and methods of using such 3D tissue constructs to screen for neurotoxic agents. In particular, provided herein are methods of producing and using complex, highly uniform human tissue models comprising physiologically relevant human cells, where the tissue models have the degree of sample uniformity and reproducibility required for use in quantitative high-throughput screening applications.