Implantable Liver Tissue Constructs for Humanized Models
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Solution Overview
Problem
The generation of humanized and chimeric mice is an inefficient process with limited scalability, requiring complex transgenics and/or cell transplantation protocols, which are time-consuming and have low engraftment efficiency, limiting their widespread utility in studying human biology and disease.
Innovation Solution
The development of implantable scaffolds stabilized ex vivo using engineered biomaterials, such as biocompatible polymeric hydrogels, to support human parenchymal cells, allowing for rapid and reproducible generation of humanized animal models by encapsulating cells with non-parenchymal cells that promote tissue-specific functions and vascularization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cell transplantation protocols are used to create humanized mice, then human tissue function can be studied in vivo, but the process is time-consuming with low engraftment efficiency
Solution Approach 1:
The patent applies preliminary action by pre-stabilizing human parenchymal cells ex vivo using engineered biomaterials and culture conditions before transplantation. This pre-preparation of cells with enhanced stability and functionality allows for rapid engraftment in vivo without requiring lengthy transplantation protocols or host manipulation, directly resolving the contradiction between engraftment efficiency and time required.
2Adaptability or versatility
If complex transgenics are used to model human genes, then human biological processes can be studied, but the device complexity and scalability are limited
Solution Approach 1:
The patent extracts the complexity of transgenic manipulation by directly transplanting human cells that already express the desired human genes and biological processes. Instead of genetically modifying the host animal, the invention isolates and transplants pre-prepared human parenchymal cells, thereby eliminating the need for complex transgenics while maintaining the ability to study human biology.
Solution Approach 2:
The patent uses engineered biomaterials as an intermediary to deliver and stabilize human cells during transplantation. This intermediary approach simplifies the overall process by providing a protective and supportive matrix that enhances cell survival and function without requiring complex genetic manipulation of the host system.
3Reliability
If host manipulation is performed to provide repopulation advantage, then transplanted cells can engraft, but the ease of operation and scalability are reduced
Solution Approach 1:
The patent applies preliminary action by pre-stabilizing human parenchymal cells ex vivo using engineered biomaterials and culture conditions before transplantation. This pre-preparation of cells with enhanced stability and functionality allows for rapid engraftment in vivo without requiring lengthy transplantation protocols or host manipulation, directly resolving the contradiction between engraftment efficiency and time required.
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
This approach enables the creation of humanized animal models with minimal time, cost, and labor, allowing for efficient drug discovery and development by maintaining parenchymal cell function and survival in vivo for several weeks, facilitating the study of human liver responses to drugs and pathogens.
Implementation Method 1
The invention features implantable scaffolds that are stabilized ex vivo using an engineered biomaterial (e.g., a biocompatible, polymeric hydrogel, tuned with key soluble and/or adhesion-promoting factors or other important biochemical cues)
Implementation Method 2
Certain non-parenchymal cells support the parenchymal cells by influencing the environment of the co-encapsulated cells, for example, secreting cytokines and/or growth factors that influence vascularization of the constructs
Data Source
AI summary
Engineered human tissue constructs are provided that are suitable for use in making humanized animals for use in pharmaceutical development. Humanized animals having the constructs implanted in vivo are provided. Methods of making and using the tissue-engineered constructs and humanized animals are also provided.