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 microscale culture device, comprising: 
 at least one microscale chamber dimensioned to maintain biological material under conditions that provide a value of at least one measurable parameter in vitro that is comparable to a value of at least one measurable parameter obtained in vivo, wherein the microscale chamber comprises a first inlet and a first outlet for flow of fluid;    at least one microfluidic channel in fluidic communication with the microscale chamber wherein the microfluidic channel is dimensioned to transport the fluid; and    wherein the device is dimensioned to provide a shear stress of 14 dynes per cm 2  or less.    
   
   
       2 . The device of  claim 1  wherein measurable parameter comprises a pharmacokinetic parameter.  
   
   
       3 . A device comprising: 
 at least one microscale feature dimensioned to maintain biological material under conditions that provide a value of at least one pharmacokinetic parameter in vitro that is comparable to a value of at least one pharmacokinetic parameter found in vivo; and    wherein the device is dimensioned to provide a shear stress of 14 dynes per cm 2  or less.    
   
   
       4 . The device of  claim 3  further comprising at least one microfluidic channel connected to the microscale feature.  
   
   
       5 . The device of  claim 3  wherein the fluid flows in, through, re-circulated through, or in proximity to the microscale feature.  
   
   
       6 . The device of  claim 3  wherein the shear stress is 8-14 dynes per cm 2 .  
   
   
       7 . The device of  claim 3  further comprising a pumping mechanism that is configured to provide the shear stress of 14 dynes per cm 2  or less.  
   
   
       8 . The device of  claim 7  wherein the pumping mechanism is selected from at least one of the group consisting of a pump integrated in the device, a pump external to the device, a peristaltic pump, a diaphragm pump, and a microelectromechanical pump.  
   
   
       9 . The device of  claim 3  wherein the device is microfabricated.  
   
   
       10 . The device of  claim 3  wherein the device is manufactured from a microfabricated master.  
   
   
       11 . The device of  claim 3  wherein the value of at least one measurable parameter in vitro is within 25% to the value of at least one measurable parameter found in vivo.  
   
   
       12 . The device of  claim 3  wherein the characteristics of fluid flow are based on a mathematical model.  
   
   
       13 . The device of  claim 12  wherein the mathematical model is a physiologically based pharmacokinetic (“PBPK”) model.  
   
   
       14 . The device of  claim 3  wherein the microscale feature is selected from at least one of the group consisting of a chamber, a channel, a tube, a well, a scaffold, an inlet, an outlet, a valve, a membrane, a diaphragm, or a compartment.  
   
   
       15 . The device of  claim 3  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 culture, a cell, 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.  
   
   
       16 . The device of  claim 3  wherein the microscale feature contains circulating, immobilized, or adherent biological material.  
   
   
       17 . The device of  claim 3  wherein the at least one measurable parameter is selected from at least one of 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 culture device, circulatory transit time, and liquid distribution.  
   
   
       18 . The device of  claim 3  further comprising at least a second microscale feature dimensioned to maintain the same or different biological material under conditions that provide a value of at least a second measurable parameter in vitro comparable to a value of at least a second measurable parameter found in vivo.  
   
   
       19 . A method of culturing biological material comprising: 
 maintaining biological material with at least one microscale chamber under conditions that provide a value of at least one measurable parameter in vitro that is comparable to a value of at least one measurable parameter obtained in vivo, wherein the microscale chamber comprises a first inlet and a first outlet for flow of fluid;    fluidically connecting the microscale chamber with at least one microfluidic channel wherein the microfluidic channel is dimensioned to transport the fluid; and    providing a shear stress of 14 dynes per cm 2  or less.    
   
   
       20 . The method of  claim 19  wherein the measurable parameter comprises a pharmacokinetic parameter.  
   
   
       21 . A method comprising: 
 maintaining biological material with at least one microscale feature under conditions that provide a value of at least one measurable parameter in vitro that is comparable to a value of at least one measurable parameter found in vivo; and    providing a shear stress of 14 dynes per cm 2  or less.    
   
   
       22 . The method of  claim 21  where in the measurable parameter comprises a pharmacokinetic parameter.  
   
   
       23 . The method of  claim 21  further comprising connecting at least one microfluidic channel to the microscale feature.  
   
   
       24 . The method of  claim 21  further comprising calculating the shear stress based on at least one desired value of at least one pharmacokinetic parameter.  
   
   
       25 . The method of  claim 23  further comprising altering the desired value if the shear stress exceeds an allowable value.  
   
   
       26 . The method of  claim 21  further comprising flowing the fluid in, through, re-circulated through or in proximity to the microscale feature.  
   
   
       27 . The method  claim 21  further comprising pumping the fluid so as to providing a shear stress of 14 dynes per cm 2  or less.  
   
   
       28 . The method of  claim 26  wherein the pumping of the fluid is performed by a pumping mechanism selected from at least one of the group consisting of a pump integrated in the device, a pump external to the device, a peristaltic pump, a diaphragm pump, and a microelectromechanical pump.  
   
   
       29 . The method of  claim 21  wherein the value of at least one measurable parameter in vitro is within 25% to the value of at least one measurable parameter found in vivo.  
   
   
       30 . The method of  claim 21  wherein the characteristics of fluid flow are based on a mathematical model.  
   
   
       31 . The method of  claim 29  wherein the mathematical model is a physiologically based pharmacokinetic (“PBPK”) model.  
   
   
       32 . The method of  claim 21  wherein the microscale feature is selected from at least one of the group consisting of a chamber, a channel, a tube, a well, a scaffold, an inlet, an outlet, a valve, a membrane, a diaphragm, or a compartment.  
   
   
       33 . The method of  claim 21  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 culture, a cell, 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.  
   
   
       34 . The method of  claim 21  wherein the microscale feature contains circulating, immobilized, or adherent biological material.  
   
   
       35 . The method of  claim 21  wherein the at least one measurable parameter is selected from at least one of 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 culture device, circulatory transit time, and liquid distribution.  
   
   
       36 . The method of  claim 21  further comprising maintaining the same or different biological material with at least a second microscale feature under conditions that provide a value of at least a second measurable parameter in vitro comparable to a value of at least a second measurable parameter found in vivo.  
   
   
       37 . A device comprising: 
 means for maintaining biological material with at least one microscale feature under conditions that provide a value of at least one measurable parameter in vitro that is comparable to a value of at least one measurable parameter found in vivo; and    means for providing a shear stress of 14 dynes per cm 2  or less.    
   
   
       38 . The device of  claim 37  wherein the measurable parameter is a pharmacokinetic parameter.  
   
   
       39 . A method comprising forming a microscale feature that is dimensioned to maintain biological material under conditions that provide a value of at least one measurable parameter in vitro that is comparable to a value of at least one measurable parameter found in vivo and wherein a shear stress of 14 dynes per cm 2  or less is provided.  
   
   
       40 . The method of  claim 39  wherein the measurable parameter is a pharmacokinetic parameter.  
   
   
       41 . A device comprising: 
 means for forming a microscale features that is dimensioned to maintain biological material under conditions that provide a value of at least one measurable parameter in vitro that is comparable to a value of at least one measurable parameter found in vivo; and wherein a shear stress of 14 dynes per cm 2  or less is provided.    
   
   
       42 . The method of  claim 41  wherein the measurable parameter is a pharmacokinetic parameter.