Devices and methods for pharmacokinetic-based cell culture system

Abstract

Devices, in vitro cell cultures, systems, and methods are provided for microscale cell culture analogous (CCA) device.

1 . A culture system of cells grown in a microscale culture device, comprising: 
 a first chamber comprising a first cell type maintained under conditions that provide a value of at least one measurable parameter in vitro comparable to a value of at least one measurable parameter found in vivo;    a second chamber comprising a second cell type maintained under conditions that provide a value of at least one second measurable parameter comparable to a value of a second measurable parameter found in vivo;    at least one fluidic channel interconnecting the first and second chambers; and    an inlet and outlet for recirculation of culture medium.    
   
   
       2 . The culture system of  claim 1  wherein the measurable parameter comprises a pharmacokinetic parameter.  
   
   
       3 . The culture system of  claim 2  wherein the at least one pharmacokinetic parameter comprises at least one selected from the group consisting of tissue to blood volume ratio, drug residence time, measurement of interactions between cells, liquid residence time, liquid to cell ratios, metabolism by cells, shear stress, flow rate, the number of cells in the device, circulatory transit time, and liquid distribution.  
   
   
       4 . The culture system of  claim 1  wherein the first cell type and the second cell type are the same type.  
   
   
       5 . The culture system of  claim 1  wherein the first cell type and the second cell type are different cell types.  
   
   
       6 . The culture system of  claim 1  wherein the first chamber and the second chamber comprise the same geometry.  
   
   
       7 . The culture system of  claim 1  wherein the first chamber and the second chamber comprise different geometries.  
   
   
       8 . The culture system of  claim 1  comprising multiple interconnected devices.  
   
   
       9 . The culture system of  claim 1  wherein each of the chambers provides for at least two values of measurable parameters in vitro comparable to values of measurable parameters found in vivo.  
   
   
       10 . The culture system of  claim 1  further comprising a pumping mechanism that is configured to pump a fluid through the first and second chambers.  
   
   
       11 . The culture system of  claim 1  further comprising a debubbler coupled to and configured to remove bubbles from the culture system.  
   
   
       12 . The culture system of  claim 1  further comprising at least one sensor configured to obtain signals from cells in the culture system.  
   
   
       13 . The culture system of  claim 12  wherein the at least one sensor is selected from at least one of the group consisting of a biosensor and a waveguide.  
   
   
       14 . The culture system of  claim 1  wherein the device is microfabricated.  
   
   
       15 . The culture system of  claim 1  wherein the device is manufactured from a microfabricated master.  
   
   
       16 . The culture system of  claim 1  wherein at least one of the chambers provides for three-dimensional growth of cells.  
   
   
       17 . The culture system of  claim 1  wherein a cell is selected from at least one of the group consisting of healthy tissue, diseased tissue, a portion of a tissue biopsy, a portion of tissue, a portion of an artery, a portion of a vein, a portion of a gastrointestinal tract, a portion of an esophagus, a portion of a colon, a portion of an organ, a portion of a heart, a portion of a brain, a portion of a kidney, a portion of a lung, a portion of a muscle, a cell culture, an eukaryotic cell, a plant cell, an animal cell, a mammalian cell, a prokaryotic cell, a primary cell, a tumor cell, a stem cell, a genetically altered cell, a transformed cell, and an immortalized cell.  
   
   
       18 . A method for determining the effect of an input variable on a culture system of cells, the method comprising: contacting the culture system of  claim 1  with an input variable; and monitoring at least one output parameter.  
   
   
       19 . The method of  claim 18  wherein the step of monitoring the at least one output parameter comprises obtaining information from at least one sensor in the device.  
   
   
       20 . The method of  claim 18  wherein the input variable is selected from at least one of the group consisting of an organic compound, an inorganic compound, a complex sample, a pharmaceutical, environmental sample, a nutritional sample, a consumer product, a virus, liposome, nanoparticle, biodegradable polymer, radiolabeled particle or toxin, biomolecule, toxin-conjugated particle, and a stabilizing agent.  
   
   
       21 . The method of  claim 20  wherein the stabilizing agent is selected from at least one of the group consisting of albumin, polyethylene glycol, poly(ethylene-co-vinyl acetate), and poly(lactide-co-glycolide).  
   
   
       22 . A microscale culture device, comprising: 
 a first microscale chamber having a geometry simulating a first in vivo interaction with culture medium, wherein the first chamber comprises a first inlet and a first outlet for flow of the culture medium;    a second microscale chamber having a geometry simulating a second in vivo interaction with the culture medium, wherein the second chamber comprises a second inlet and a second outlet for flow of the culture medium;    a microfluidic channel interconnecting the first and second chambers; and    at least one sensor for measuring at least one physiological event in the chambers.    
   
   
       23 . The microscale culture device of  claim 22  wherein the first microscale chamber comprises biological material.  
   
   
       24 . The microscale culture device of  claim 23  wherein the biological material is selected from at least one of the group consisting of healthy tissue, diseased tissue, a portion of a tissue biopsy, a portion of tissue, a portion of an artery, a portion of a vein, a portion of a gastrointestinal tract, a portion of an esophagus, a portion of a colon, a portion of an organ, a portion of a heart, a portion of a brain, a portion of a kidney, a portion of a lung, a portion of a muscle, a cell, a cell culture, an eukaryotic cell, a plant cell, an animal cell, a mammalian cell, a prokaryotic cell, a primary cell, a tumor cell, a stem cell, a genetically altered cell, a transformed cell, and an immortalized cell.  
   
   
       25 . The microscale culture device of  claim 22  wherein the chambers are formed from a plastic material.  
   
   
       26 . The microscale culture device of  claim 25  wherein the plastic material is selected from at least one of the group consisting of polystyrene, polymethylmethacrylate, polycarbonate, polytetrafluoroethylene, polyvinylchloride, polydimethylsiloxane, and polysulfone.  
   
   
       27 . The microscale culture device of  claim 22  and further comprising a pump that is configured to pump a fluid through the first and second chambers.  
   
   
       28 . The microscale culture device of  claim 27  wherein the pump is selected from at least one of the group consisting of a peristaltic pump, diaphragm pump, and microelectromechanical pump.  
   
   
       29 . The microscale culture device of  claim 27  wherein the pump recirculates culture medium.  
   
   
       30 . The microscale culture device of  claim 22  wherein the chamber geometries are based on a mathematical model.  
   
   
       31 . The microscale culture device of  claim 30  wherein the model is a physiologically-based pharmacokinetic model.  
   
   
       32 . The microscale culture device of  claim 30  wherein the model simulates at least one selected from the group consisting of tissue to blood volume ratio, drug residence time, measurement of interactions between cells, liquid residence time, liquid to cell ratios, metabolism by cells, shear stress, flow rate, geometry, the number of cells in the device, circulatory transit time, and liquid distribution.  
   
   
       33 . The microscale culture device of  claim 22  wherein the physiological events comprise at least one selected from the group consisting of cell death, cell proliferation, differentiation, immune response, or perturbations in metabolism or signal transduction pathways.  
   
   
       34 . The microscale culture device of  claim 22  wherein pharmacokinetic data is derived from the sensor.  
   
   
       35 . The microscale culture device of  claim 22  wherein the sensor is integrated with the device and provides real-time readout of the physiological status of one or more cells in the system.  
   
   
       36 . A microscale culture device comprising: 
 a plurality of chambers connected by fluidic passages, each chamber having a geometry simulating parts of a living body; and    a pump, for circulating culture medium through the chambers to simulate the effects of compounds on the living body.    
   
   
       37 . The microscale culture device of  claim 36  wherein the pump is selected from at least one of the group consisting of a peristaltic pump, a diaphragm pump, a microelectromechanical pump, a pump integrated in the device, a pump external to the device, and a pump that recirculates the culture medium.  
   
   
       38 . The microscale culture device of  claim 36  wherein the chambers simulate interaction of the culture medium with at least two of a portion of a liver, a portion of a lung, an area of slowly perfused fluid, fat, an area of rapidly perfused fluid, a portion of a muscle, an eukaryotic cell, a plant cell, an animal cell, a mammalian cell, a prokaryotic cell, a primary cell, a tumor cell, a stem cell, a genetically altered cell, a transformed cell, and an immortalized cell.  
   
   
       39 . The microscale culture device of  claim 36  wherein one chamber simulates a lung with multiple parallel ridges of material.  
   
   
       40 . The microscale culture device of  claim 36  wherein one chamber simulates a liver with multiple staggered pillars.  
   
   
       41 . The microscale culture device of  claim 36  further comprising a processor coupled to and configured to control the microscale culture device.  
   
   
       42 . The microscale culture device of  claim 41  wherein the processor is configured to control the pump to create culture medium residence times in chambers comparable to those encountered in the living body.  
   
   
       43 . The microscale culture device of  claim 42  further comprising valves distributed along at least one fluid passage, and wherein the processor controls the valves consistent with pharmacokinetic parameter values associated with at least a part of the living body.  
   
   
       44 . The microscale culture device of  claim 36  wherein the chambers are formed on a substrate.  
   
   
       45 . The microscale culture device of  claim 41  wherein the processor is separate from and electrically coupled to the substrate.  
   
   
       46 . The culture device of  claim 41  wherein the processor is coupled to one or more sensors.  
   
   
       47 . The microscale culture device of  claim 41  further comprising a look-up table having pharmacokinetic parameter values associated with the simulated parts of the living body for use by the processor.  
   
   
       48 . A microscale culture device, comprising: 
 a lung simulating chamber;    a pump;    at least two chambers selected from the group consisting of a liver chamber that maintains cells under conditions that provide a value of at least one pharmacokinetic parameter in vitro comparable to a value of at least one pharmacokinetic parameter value found in vivo that is associated with a liver, a slowly perfused chamber, a rapidly perfused chamber and a fat chamber that maintains cells under conditions that provide a value of at least one pharmacokinetic parameter in vitro comparable to a value of at least one pharmacokinetic parameter value found in vivo that is associated with the function of fat; and    a plurality of microfluidic channels coupling the pump, and the at least two chambers serially or in parallel.    
   
   
       49 . A culture system of cells grown in a microscale culture device, comprising: 
 a first chamber comprising a first cell type maintained under first selected conditions;    a second chamber comprising a second cell type maintained under second selected conditions, wherein the first and second chambers are interconnected by fluidic channels; and    an inlet and outlet for recirculation of culture medium.    
   
   
       50 . The culture system of  claim 49  wherein the first cell type and the second cell type are the same type.  
   
   
       51 . The culture system of  claim 49  wherein the first cell type and the second cell type are different cell types.  
   
   
       52 . The culture system of  claim 49  wherein the first chamber and the second chamber comprise the same geometry.  
   
   
       53 . The culture system of  claim 49  wherein the first chamber and the second chamber comprise different geometries.  
   
   
       54 . The culture system of  claim 49  further comprising a debubbler coupled to and configured to remove bubbles from the culture system.  
   
   
       55 . The culture system of  claim 49  wherein the microscale culture device is dimensioned to provide a shear stress of 14 dynes per cm2 or less.  
   
   
       56 . The culture system of  claim 49  further comprising a pump that is configured to pump a fluid through the first and second chambers; and a processor couple to and configured to control the culture system.