Systems and methods for testing drugs and drug delivery systems
A system is provided that simulates the in vivo micro-environment of three-dimensional cellular structures or bodies, such as tumors. The system simulates the pressure gradients and fluid flows of the vascular and lymphatic systems as well as the interstitial and capillary transport mechanisms between the 3D cellular structure and the vascular and lymphatic systems. The system can be used to introduce drugs or drug delivery carriers to a tumor, for example, to assess the uptake capability and effect on the tumor. The system maintains the viability of the tumor cells for a sufficiently long period of time to permit testing of several different drugs and/or delivery carriers.
1. A fluidic system for performing tests on a three-dimensional (3D) cellular structure, comprising:
a bottom panel disposed beneath said top panel, said bottom panel defining;
a reservoir open at opposite ends for flowing a fluid therethrough and sized to contain the 3D cellular structure;
at least one side channel flanking said reservoir and coextensive with at least a portion of a length of said reservoir, said at least one side channel open at its opposite ends for flowing a fluid therethrough; and
a side wall between said reservoir and a corresponding one of said at least one side channel, said side wall defining openings for fluid communication between said reservoir and said corresponding side channel, said openings sized to simulate interstitial transport to and from a lymphatic vessel of a living animal;
a top panel disposed above said bottom panel and defining a top channel open at opposite ends for flowing a fluid therethrough, said top channel at least partially coincident with said reservoir; and
a porous membrane disposed between said top channel and said reservoir at least where said channels are coincident, said porous membrane having pores sized to mimic transvascular transport through the endothelium of a blood vessel of the living animal.
2. The fluidic system of claim 1 , wherein the fluid is culture medium, human sera or blood.
3. The fluidic system of claim 1 , further comprising:
at least one first pressure source fluidly connected to an end of said at least one side channels, each first pressure source calibrated to simulate the lymphatic pressure of the living animal;
at least one second pressure source fluidly connected to an end of said reservoir and calibrated to simulate the interstitial pressure of the living animal; and
at least one third pressure source fluidly connected to said top channel and calibrated to simulate the capillary pressure of the living animal.
4. The fluidic system of claim 3 , wherein:
said at least one first pressure source is configured to maintain a pressure of about 5 mmHg in said at least one side channel;
said at least one second pressure source is configured to maintain a pressure in the range of about 5 to 150 mmHg in said reservoir; and
said at least one third pressure source is configured to maintain a pressure in the range of 10 to 40 mmHg in said first channel.
5. The fluidic system of claim 1 , further comprising a viewing window in said reservoir.
6. The fluidic system of claim 1 , wherein said membrane is coated with endothelial cells.
7. The fluidic system of claim 1 , wherein said top channel is fluidly connected to a source of nanoparticles adapted for use as a carrier for drugs to treat the cells of the 3D cellular structure.
8. The fluidic system of claim 1 , wherein said top channel has a width of about 300 μm and a height of about 50 μm.
9. The fluidic system of claim 1 , wherein said reservoir has a width of about 900 μm and a height of about 100 μm.
10. The fluidic system of claim 1 , wherein said side channels have a width of about 300 μm and a height of about 100 μm.
11. The fluidic system of claim 1 , wherein said side walls are defined by a plurality of posts defining said openings therebetween.
12. The fluidic system of claim 11 , wherein said posts have a width along the length of said wall of about 100 μm.
13. The fluidic system of claim 1 , wherein said porous membrane has pores with an effective diameter of between 1 nm and 1000 nm.
14. The fluidic system of claim 12 , further comprising a plurality of posts disposed within said reservoir.