Engineered Tissue Constructs for Liver Failure Treatment
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Solution Overview
Problem
Current approaches to creating functional engineered tissues for therapeutic applications have failed to achieve the necessary scale and vascularization, making it challenging to treat diseases like acute liver failure and Crigler-Najjar syndrome effectively due to difficulties in finding suitable implantation sites within the body.
Innovation Solution
The development of engineered tissue constructs comprising a population of mammalian cells in a biocompatible scaffold, specifically implanted in extraperitoneal, extrapleural, or liver surface sites, which are designed to engraft and vascularize, using fibrin as a scaffold and potentially including endothelial cells for enhanced integration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional approaches are used to create engineered tissue constructs, then cell-based implants can be developed, but the constructs fail to achieve the necessary scale and vascularization for therapeutic efficacy
Solution Approach 1:
The tissue construct is divided into multiple discrete vessels within the scaffold, each capable of independent vascularization. This segmentation allows the large-scale construct to be populated by multiple host vessels rather than requiring a single continuous vascular network, thereby achieving therapeutic scale while maintaining vascularization feasibility
Solution Approach 2:
The invention transitions from attempting to vascularize the entire construct through a single approach to using multiple spatial dimensions and routes. Multiple vessels are distributed throughout the scaffold volume, creating a three-dimensional vascular network that can simultaneously support large-scale tissue constructs
2Quantity of substance
If engineered tissue constructs are made at larger scales for therapeutic applications, then more cells can be implanted, but vascularization becomes increasingly difficult to achieve
Solution Approach 1:
The vascularization challenge is segmented into multiple independent vessel units distributed throughout the scaffold. Each vessel serves a localized region, reducing the complexity of any single vascularization event while collectively supporting a large number of cells across the entire construct
Solution Approach 2:
The scaffold design enables self-vascularization by providing pre-formed channels that guide host vessel infiltration. The construct essentially vascularizes itself through the natural migratory behavior of endothelial cells along the scaffold channels, reducing the need for complex external vascularization procedures
3Quantity of substance
If more vessels are included in the scaffold to support larger cell masses, then vascularization capacity increases, but the scaffold design and implantation complexity increases
Solution Approach 1:
The scaffold design parameters (vessel diameter, spacing, density) are optimized to support high cell mass densities. By adjusting these physical parameters, the scaffold can accommodate larger cell masses while maintaining manageable complexity through standardized geometric patterns
Data Source
AI summary
The present disclosure provides engineered tissue constructs having a population of cells. such as hepatocytes and stromal cells. and methods of implanting the same (e.g., for treating a disease or disorder, such as acute liver failure, a urea cycle disorder, or hyperbilirubinemia (e.g., in a subject having Crigler-Najjar syndrome) in a human subject in need thereof).