Artificial tissue constructs comprising alveolar cells and methods for using the same
Inventors
MAHMOOD, Ayesha • Kachurin, Anatoly • Warren, William • Higbee, Russell
Assignees
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Publication Number
US-9566250-B2
Publication Date
2017-02-14
Expiration Date
Abstract
The present invention comprises artificial tissue constructs that serve as in vitro models of mammalian lung tissue. The artificial tissue constructs of the present invention comprise functionally equivalent in vitro tissue scaffolds that enable immunophysiological function of the lung. The constructs can serve as novel platforms for the study of lung diseases (e.g., interstitial lung diseases, fibrosis, influenza, RSV) as well as smoke- and smoking-related diseases. The artificial tissue constructs of the present invention comprise the two components of alveolar tissue, epithelial and endothelial cell layers.
Core Innovation
The invention provides an artificial tissue construct comprising a first confluent cellular layer of alveolar primary epithelial cells and a second confluent cellular layer of alveolar primary endothelial cells. The first layer is stacked on top of and in direct contact with the second layer, or the second layer is stacked on top of and in direct contact with the first layer. This stacked, confluent bilayer design establishes direct cellular contact between alveolar epithelial and endothelial cell layers.
In some embodiments, the construct further comprises primary alveolar macrophages positioned between the epithelial and endothelial layers. The construct can be configured such that one of the layers is stacked on a biocompatible membrane, and the biocompatible membrane is selected from a group including basement membrane, extracellular matrix, collagen, laminin, proteoglycan, vitronectin, fibronectin, poly-D-lysine, and polysaccharide. The invention also includes embodiments where the biocompatible membrane is an extracellular-matrix membrane made of laminin and collagen.
The invention is presented as a functional in vitro model for immunophysiological lung responses, where immunological activity of test compounds is determined using the constructed in vitro bilayer. The disclosed immunological outputs include immunoglobulin generation, chemokine generation, cytokine generation, host-defense gene up-regulation, and CYP450 activity. The overall approach is described in the context of predictive in vitro respiratory immunology and toxicoIogy modeling.
Claims Coverage
The partial content provides one independent claim directed to the structural bilayer artificial tissue construct. Dependent claims specify additional cellular components and optional biocompatible membranes, refining how the layers are assembled and what materials or immune-related culture media constituents are included.
Stacked, directly contacted confluent alveolar epithelial and endothelial layers
An artificial tissue construct comprising a first confluent cellular layer of alveolar primary epithelial cells and a second confluent cellular layer of alveolar primary endothelial cells, wherein the first layer is stacked on top of and in direct contact with the second layer, or wherein the second layer is stacked on top of and in direct contact with the first layer.
Primary alveolar macrophages between the confluent epithelial and endothelial layers
The artificial tissue construct includes primary alveolar macrophages distributed between primary alveolar epithelial cells and primary alveolar endothelial cells, located between a first cellular layer and a second cellular layer.
Direct-contact bilayer with one layer positioned on a biocompatible membrane
The artificial tissue construct includes a first layer directly stacked on and in contact with a second layer, where the second layer is positioned on a biocompatible membrane.
Biocompatible membrane selected from specified biomaterial options
The biocompatible membrane is selected from basement membrane, extracellular matrix, collagen, laminin, proteoglycan, vitronectin, fibronectin, poly-D-lysine, or polysaccharide.
Laminin-and-collagen extracellular-matrix membrane
The biocompatible membrane is an extracellular-matrix membrane made of laminin and collagen.
Culture media including specified immune cell types with the artificial tissue construct
An in vitro cell culture using an artificial tissue construct and culture media containing one or more specified immune cell types including monocytes, CD4+ T lymphocytes, CD8+ T lymphocytes, B lymphocytes, and natural killer cells.
Across the provided independent claim and dependent claim refinements, the inventive coverage centers on a stacked, confluent alveolar epithelial/endothelial bilayer with direct contact, optionally incorporating primary alveolar macrophages and optionally placing one layer on a biocompatible membrane selected from specified biomaterial classes, including laminin-plus-collagen. Additional coverage extends to in vitro culture configurations using immune-cell-defined culture media constituents.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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