Multi-Component Liver Spheroids for 3D NAFLD Disease Modeling
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Solution Overview
Problem
Current methods for modeling non-alcoholic fatty liver disease (NAFLD) using two-dimensional cell cultures fail to accurately depict the three-dimensional structure and architecture of the liver, lacking the complexity needed to reflect in vivo disease states and cellular interactions, and there is a need for simple and effective liver spheroid-based disease models that can mimic these conditions.
Innovation Solution
Induction of liver spheroids using a combination of inflammatory cytokines, free fatty acids, and sugars to create multi-component liver spheroids, comprising distinct liver cell types such as hepatocytes and hepatic stellate cells, to model NAFLD stages like steatosis, steatohepatitis, and fibrosis, with specific inducer treatments to mimic disease progression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If two-dimensional cell cultures are used to model NAFLD, then the experimental setup is simple, but the three-dimensional structure and architecture of the liver cannot be accurately depicted
Solution Approach 1:
The patent transitions from two-dimensional cell cultures to three-dimensional liver spheroids, enabling accurate depiction of liver architecture while maintaining experimental feasibility through standardized spheroid formation protocols
Solution Approach 2:
The patent creates simplified copies of liver tissue architecture through spheroid models that replicate the three-dimensional structure and cellular organization of the liver, allowing study of disease mechanisms without requiring complex in vivo systems
2Reliability
If multi-component liver spheroids are generated with distinct cell types, then the model accurately reflects in vivo disease states, but the complexity of preparing and maintaining the model increases
Solution Approach 1:
The patent combines multiple liver cell types (hepatocytes, hepatic stellate cells, Kupffer cells, endothelial cells) into integrated spheroid structures, enabling simultaneous representation of diverse cellular functions and disease interactions within a single model system
Solution Approach 2:
The multi-component spheroid model serves multiple functions: it models various NAFLD stages, enables drug screening, and captures cellular crosstalk, making it a versatile platform that reduces the need for multiple separate models
3Adaptability or versatility
If disease induction treatments are applied to liver spheroids, then phenotypes of different NAFLD stages are displayed, but the time required to observe disease progression increases
Solution Approach 1:
The patent pre-treats liver spheroids with disease-inducing agents before experimental analysis, enabling rapid observation of disease phenotypes without requiring prolonged incubation periods, thus accelerating the timeline for studying NAFLD progression
Data Source
AI summary
Disclosed is a method of inducing non-alcoholic steato-hepatitis in a multi-component liver spheroid. The method includes harvesting or reviving a cryopreserved sample of two or more distinct primary liver cell types and seeding a mixture of at least two or more distinct primary liver cell types to generate a multi-component liver spheroid. Disclosed are mono-component and multi component liver spheroid. The method further includes inducing steatosis in the multi-component liver spheroid through treatment of one or more steatosis inducers, inducing steatohepatitis in the multi-component liver spheroid through a combinatorial treatment of a mixture of the one or more steatosis inducers and one or more fibrosis inducers; and inducing fibrosis in the multi-component liver spheroid through treatment with one or more fibrosis inducers.