Perfused three-dimensional cell/tissue disease models
First Claim
1. An apparatus comprising an array of isolated perfusion bioreactor and reservoir pairs for culturing cells or tissues, the apparatus comprisinga fluidic manifold comprising an array of fluidically isolated perfusion bioreactor and reservoir pairs for cell or tissue culture, anda control manifold comprising common control channels actuated in parallel to simultaneously act on each pair of bioreactors and reservoirs and means for controlling timing, flow rate and volume of cell culture medium to each bioreactor and reservoir pair,wherein each fluidically isolated perfusion bioreactor and reservoir pair is connected by a fluidic channel allowing re-circulation of cell culture medium,wherein each perfusion bioreactor and reservoir pair is fluidically isolated from all other perfusion and bioreactor pairs,wherein each control channel is separated from the fluidic channel by a diaphragm valve which can be deflected into a valve displacement chamber by hydraulic or pneumatic actuation,wherein the volume of the cell culture medium pumped through the fluidic channel into either the bioreactor or the reservoir is determined by the volume of the valve displacement chamber, andwherein each perfusion bioreactor comprises a removable three-dimensional cell or tissue support structure through which the cell culture medium is perfused.
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Abstract
A system has been constructed that recapitulate the features of a capillary bed through normal human tissue. The system facilitates perfusion of three-dimensional (3D) cell monocultures and heterotypic cell co-cultures at the length scale of the capillary bed. A major feature is that the system can be utilized within a “multiwell plate” format amenable to high-throughput assays compatible with the type of robotics commonly used in pharmaceutical development. The system provides a means to conduct assays for toxicology and metabolism and as a model for human diseases such as hepatic diseases, including hepatitis, exposure-related pathologies, and cancer. Cancer applications include primary liver cancer as well as metastases. The system can also be used as a means of testing gene therapy approaches for treating disease and inborn genetic defects.
135 Citations
25 Claims
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1. An apparatus comprising an array of isolated perfusion bioreactor and reservoir pairs for culturing cells or tissues, the apparatus comprising
a fluidic manifold comprising an array of fluidically isolated perfusion bioreactor and reservoir pairs for cell or tissue culture, and a control manifold comprising common control channels actuated in parallel to simultaneously act on each pair of bioreactors and reservoirs and means for controlling timing, flow rate and volume of cell culture medium to each bioreactor and reservoir pair, wherein each fluidically isolated perfusion bioreactor and reservoir pair is connected by a fluidic channel allowing re-circulation of cell culture medium, wherein each perfusion bioreactor and reservoir pair is fluidically isolated from all other perfusion and bioreactor pairs, wherein each control channel is separated from the fluidic channel by a diaphragm valve which can be deflected into a valve displacement chamber by hydraulic or pneumatic actuation, wherein the volume of the cell culture medium pumped through the fluidic channel into either the bioreactor or the reservoir is determined by the volume of the valve displacement chamber, and wherein each perfusion bioreactor comprises a removable three-dimensional cell or tissue support structure through which the cell culture medium is perfused.
Specification