Liver Microtissue Encapsulation for Liver Failure Treatment
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Solution Overview
Problem
Current methods for producing liver microtissue from induced pluripotent stem cells are complex, costly, and difficult to scale up, limiting their effectiveness in treating liver failure due to poor cell integration and functionality.
Innovation Solution
A bioengineered three-dimensional liver microtissue is developed, comprising at least 3 different phenotypes of liver cells, including immature and mature hepatocytes, cholangiocytes, and mesenchymal stem cells, encapsulated in a closed microcompartment, which promotes integration and metabolic activity similar to a healthy liver, with CYP3A4 activity and albumin production indicators.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If guided differentiation protocols are used to produce hepatocytes from pluripotent stem cells, then an inexhaustible source of hepatocytes is obtained, but the production cost is very high (around 9.7 million dollars for autologous liver grafts)
Solution Approach 1:
The invention divides the liver into functional microtissues containing 10-100 cells each, encapsulated in separate microcompartments. This segmentation allows independent production, quality control, and integration of small functional units, reducing overall production cost while maintaining hepatic functionality. Each microtissue can be produced using standardized protocols from pluripotent stem cells at lower cost than whole organ grafts.
2Productivity
If isolated hepatocytes are transplanted to treat liver failure, then a large number of patients can be treated, but the hepatocytes show poor survival, integration and expansion in vivo
Solution Approach 1:
The invention nests multiple hepatocytes and supporting cell types within a hierarchical structure of microcompartments. This nested arrangement creates a protective microenvironment that mimics the native liver architecture, improving cell survival and integration. The microcompartments act as protective containers that maintain cellular functionality and reduce rejection while allowing expansion and long-term survival in the host liver.
3Quantity of substance
If primary hepatocytes are cultured in vitro, then hepatocytes can be obtained for transplantation, but the cells undergo dedifferentiation and lose mature hepatocyte characteristics
Solution Approach 1:
The invention performs preliminary differentiation of pluripotent stem cells into mature hepatocytes within the microcompartment before transplantation. This preliminary action occurs in a controlled microenvironment that preserves mature hepatocyte characteristics and functionality. The microcompartment structure enables staged differentiation and maturation, ensuring cells reach full functional maturity before being transplanted, thereby avoiding dedifferentiation issues.
4Reliability
If complex protocols with multiple steps are used to produce liver cells, then functional characteristics are improved, but the process complexity and total cost increase
Solution Approach 1:
The invention merges multiple cell types (hepatocytes, cholangiocytes, stellate cells, Kupffer cells) and their supporting microenvironment into integrated microtissues within single microcompartments. This merging approach produces functionally complete liver units in one process rather than requiring separate protocols for each cell type, thereby reducing overall process complexity while maintaining or improving functional characteristics through synergistic interactions.
Data Source
AI summary
The invention relates to a liver microtissue, preferably, the liver microtissue having the largest dimension between 500 and 700 μm, and the liver microtissue expressing CYP3A4 monooxygenase with an activity of at least 75,000 RLU per million cells and producing at least 18 ag of urea per million cells per 24 hours. The invention also relates to a method for producing the liver microtissue from pluripotent stem cells, and uses of the liver microtissue in treatment and/or prevention of liver failure.