Engineered Tissue Constructs with Nested Vascular Networks
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Solution Overview
Problem
Current tissue engineering techniques fail to create functional, vascularized large tissue constructs, such as those needed for liver replacement, due to diffusion limitations of oxygen and nutrients, limiting their therapeutic efficacy in conditions like acute liver failure and Crigler-Najjar syndrome.
Innovation Solution
Engineered tissue constructs comprising a population of hepatocytes and optionally stromal cells, embedded in a biocompatible scaffold, are implanted to promote hepatocyte survival and function, with a focus on neovascularization and long-term liver function support.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional tissue engineering techniques are used to create large tissue constructs, then the cell mass increases, but the diffusion of oxygen and nutrients to cells within the construct is insufficient
Solution Approach 1:
The tissue construct is divided into multiple smaller units or compartments, each with its own vascular network. This segmentation allows oxygen and nutrients to diffuse efficiently to all cells while maintaining a large total cell mass. The construct can be organized as a hierarchical structure with micro-vessels serving local cell groups and macro-vessels connecting them.
Solution Approach 2:
The patent employs a nested vascular architecture where micro-vessels are embedded within tissue compartments, which are themselves organized around macro-vessels. This nested structure enables multi-scale oxygen and nutrient delivery, with smaller vessels serving immediate cellular needs while larger vessels provide bulk transport over longer distances.
2Reliability
If large tissue constructs are created to replace critical organ functions, then the therapeutic efficacy increases, but the ability to deliver cell mass of therapeutic value is hindered
Solution Approach 1:
Vascular networks are pre-formed and integrated into the tissue construct during the manufacturing process, before implantation. This preliminary vascularization ensures that oxygen and nutrient delivery pathways are established prior to placing the construct in the patient, enabling immediate support of high cell masses upon implantation.
Solution Approach 2:
The patent uses biocompatible scaffolds and matrices as intermediary structures that provide both mechanical support and vascular pathways. These intermediaries facilitate the organized arrangement of cells and vessels, enabling efficient mass transport while maintaining structural integrity during manufacturing and implantation.
3Quantity of substance
If engineered tissue constructs are made thick to provide sufficient cell mass, then the functional capacity increases, but the diffusion limit of oxygen and nutrients prevents cell survival
Solution Approach 1:
The tissue construct employs local vascularization where every region, regardless of distance from the outer surface, has access to its own micro-vascular network. This local quality ensures that oxygen and nutrient diffusion distances remain short everywhere in the construct, enabling cell survival throughout the entire thickness and volume.
Solution Approach 2:
The patent transitions from two-dimensional surface-based tissue cultures to three-dimensional volumetric constructs with internal vascular networks. By adding the third dimension of vascular penetration, the construct can maintain high cell density throughout its volume while ensuring adequate oxygen and nutrient supply to all cells.
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 engineered tissue constructs provide sustained hepatocyte survival and functional liver support for extended periods, potentially replacing the need for liver transplants and managing conditions like acute liver failure and Crigler-Najjar syndrome.
Implementation Method 1
the diffusion limit of oxygen and nutrients to cells within the construct
Data Source
AI summary
The present disclosure provides engineered tissue constructs having hepatocytes and stromal cells and methods of making and using the same (e.g., for treating 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). The engineered tissue constructs may provide a microenvironment that promotes the persistence of hepatocyte survival for at least three months.