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 device comprising; 
 a microscale feature comprising a biological material and a geometry simulating parts of a living body, wherein the microscale feature is configured to substantially mimic in vitro at least one measurable condition in vivo, and wherein the at least one measurable condition in vivo 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 of 14 dynes per cm 2  or less, flow rate, the number of cells in the device, circulatory transit time, and liquid distribution.    
   
   
       2 . The device of  claim 1  wherein the microscale feature is selected from at least one of the group consisting of a chamber, a channel, a flow path, a tube, a well, a scaffold, an inlet, an outlet, a valve, a membrane, a diaphragm, and a compartment.  
   
   
       3 . The device of  claim 1  wherein the microscale feature is formed in, contained in, inserted, assembled, made, or constituted in the device.  
   
   
       4 . The device of  claim 1  further comprising at least one microfluidic channel connected to the microscale feature.  
   
   
       5 . The device of  claim 1  wherein the flow of fluid through, or in proximity to the microscale feature provides the at least one measurable condition in vivo.  
   
   
       6 . The device of  claim 5  wherein the characteristics of the fluid flow are based on a mathematical model.  
   
   
       7 . The device of  claim 6  wherein the mathematical model is a physiologically-based pharmacokinetic (“PBPK”) model.  
   
   
       8 . The device of  claim 1  wherein the geometry of the microscale feature, or the device in whole or in part is based on a mathematical model or wherein the geometry of interconnection of one or more microscale features or the device in whole or in part is based on a mathematical model.  
   
   
       9 . The device of  claim 1  further comprising at least a second microscale feature configured to substantially mimic at least one measurable condition in vivo.  
   
   
       10 . The device of  claim 1  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.  
   
   
       11 . The device of  claim 1  wherein the biological material is circulating, immobilized, or adherent.  
   
   
       12 . The device of  claim 1  further comprising an array of devices wherein the devices operate separately from and in parallel with one another.  
   
   
       13 . The device of  claim 1  further comprising a fluidically coupled series of devices wherein a fluidic outlet from a first device is connected directly or indirectly to at least one fluidic inlet to one or more second devices.  
   
   
       14 . The device of  claim 13  wherein the fluidically coupled series of devices further comprises fluidic outlets from the one or more second devices to at least one fluidic inlet of one or more additional devices.  
   
   
       15 . The device of  claim 1  wherein the geometry of the microscale feature is selected from at least one of the group consisting of parallel ridges and staggered pillars.  
   
   
       16 . The device of  claim 1  further comprising a second microscale feature wherein the second microscale feature has the same or a different geometry than the first microscale feature.  
   
   
       17 . The device of  claim 1  wherein the biological material is adhered to, immobilized in, or in proximity to a portion of the microscale feature.  
   
   
       18 . The device of  claim 1  wherein a portion of the microscale feature is coated to facilitate attachment, segregation or immobilization of the biological material with at least one selected from the group consisting of a protein, collagen, poly-lysine, and MATRIGEL, a hydrogel, a scaffold, a matrix, a construct consisting of multiple layers of collagen separated by biological material, and a construct consisting of multiple layers separated by biological material, wherein one or both layers are comprised of materials selected from at least one of the group consisting of a protein, collagen, MATRIGEL, and a matrix.  
   
   
       19 . The device of  claim 1  further comprising fluid.  
   
   
       20 . The device of  claim 19  wherein the fluid flows through, or in proximity to the at least one microscale feature.  
   
   
       21 . The device of  claim 19  wherein the fluid flows re-circulated through, or in proximity to the at least one microscale feature.  
   
   
       22 . The device of  claim 1  wherein the microscale feature is configured to substantially mimic at least two measurable conditions in vivo.  
   
   
       23 . The device of  claim 1  further comprising a pumping mechanism.  
   
   
       24 . The device of  claim 23  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.  
   
   
       25 . The device  claim 1  wherein the device is microfabricated.  
   
   
       26 . The device of  claim 1  wherein the device is manufactured from a microfabricated master.  
   
   
       27 . The device of  claim 1  wherein the microscale feature contains a plurality of cell types.  
   
   
       28 . The device of  claim 1  wherein at least a portion of the microscale feature contains circulating, immobilized or adherent biological material.  
   
   
       29 . The device of  claim 1  wherein the microscale feature is formed from a material selected from at least one the group consisting of plastic and silicon.  
   
   
       30 . The device of  claim 29  wherein the plastic material is selected from at least one of the group consisting of polystyrene, polymethylmethacrylate, polycarbonate, polytetrafluoroethylene, polyvinylchloride, polydimethylsiloxane, and polysulfone.  
   
   
       31 . The device of  claim 1  wherein the at least one measurable condition in vivo is associated with the function of a part of a living body.  
   
   
       32 . The device of  claim 1  wherein the geometry of interconnection of multiple microscale features or the geometry of the device in whole or in part is configured to substantially mimic at least one measurable condition in vivo.  
   
   
       33 . The device of  claim 1  wherein the microscale feature is configured to represent a tissue.  
   
   
       34 . A method comprising maintaining biological material with a microscale feature comprising a biological material and a geometry simulating parts of a living body, wherein the microscale feature is configured to substantially mimic in vitro at least one measurable condition in vivo, and wherein the at least one measurable in vivo condition is selected from at least one of the group consisting of tissue size ratio, 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 of 14 dynes per cm 2  or less, flow rate, the number of cells in the device, circulatory transit time, and liquid distribution.  
   
   
       35 . The method of  claim 34  wherein the microscale feature is selected from at least one of the group consisting of a chamber, a channel, a flow path, a tube, a well, a scaffold, an inlet, an outlet, a valve, a membrane, a diaphragm, and a compartment.  
   
   
       36 . The method of  claim 34  further comprising connecting at least one microfluidic channel to the microscale feature.  
   
   
       37 . The method of  claim 34  comprising flowing fluid through, or in proximity to the microscale feature.  
   
   
       38 . The method of  claim 37  wherein flowing the fluid through the microscale feature provides the at least one measurable condition in vivo.  
   
   
       39 . The method of  claim 37  wherein the fluid flows re-circulated through, or in proximity to the at least one microscale feature.  
   
   
       40 . The method of  claim 34  wherein the characteristics of the fluid flow are based on a mathematical model.  
   
   
       41 . The method of  claim 40  wherein the mathematical model is a physiologically-based pharmacokinetic (“PBPK”) model.  
   
   
       42 . The method of  claim 34  further comprising forming, inserting, containing, assembling, making, or constituting the microscale feature within a device.  
   
   
       43 . The method  claim 42  wherein the geometry of the microscale feature, or of the device in whole or in part is based on a mathematical model or wherein the geometry of interconnection of the microscale feature or the device in whole or in part is based on a mathematical model.  
   
   
       44 . The method of  claim 34  further comprising maintaining biological material with at least a second microscale feature configured to substantially mimic at least a second measurable in vivo condition.  
   
   
       45 . The method of  claim 34  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.  
   
   
       46 . The method of  claim 34  further comprising circulating, immobilizing, containing, or adhering the biological material.  
   
   
       47 . The method of  claim 34  further comprising an array of devices wherein one or more of the devices comprise at least one microscale feature and wherein the devices operate separately from and in parallel with one another.  
   
   
       48 . The method of  claim 34  further comprising fluidically connecting a series of devices wherein one or more of the devices comprise at least one microscale feature and wherein a fluidic outlet from a first device is connected directly or indirectly to at least one fluidic inlet to one or more second devices.  
   
   
       49 . The method of  claim 48  wherein fluidically connecting the series of devices further comprises connecting fluidic outlets from the one or more second devices to at least one fluidic inlet of one or more additional devices.  
   
   
       50 . The method of  claim 34  wherein the geometry of the microscale feature comprises at least one selected from the group consisting of parallel ridges and staggered pillars.  
   
   
       51 . The method of  claim 34  further comprising adhering the biological material to, or immobilizing the biological material in, or in proximity to a portion of the microscale feature.  
   
   
       52 . The method of  claim 34  further comprising coating a portion of the microscale feature to facilitate attachment, segregation, or immobilization of the biological material with at least one selected from the group consisting of a protein, collagen, poly-lysine, and MATRIGEL, a hydrogel, a scaffold, a matrix, a construct consisting of multiple layers of collagen separated by biological material, and a construct consisting of multiple layers separated by biological material, wherein one or both layers are comprised of materials selected from at least one of the group consisting of a protein, collagen, MATRIGEL, and a matrix.  
   
   
       53 . The method of  claim 34  wherein the microscale feature is configured to substantially mimic at least two measurable in vivo conditions.  
   
   
       54 . The method of  claim 34  further comprising pumping fluid with a pumping mechanism.  
   
   
       55 . The method of  claim 54  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.  
   
   
       56 . The method of  claim 34  wherein the microscale feature at least one measurable in vivo condition is associated with the function of a part of a living body.  
   
   
       57 . The method of  claim 34  wherein the geometry of interconnection of multiple microscale features is configured to substantially mimic at least one measurable in vivo condition.  
   
   
       58 . The method of  claim 34  wherein the microscale feature is configured to represent a tissue.  
   
   
       59 . A method comprising forming a microscale feature comprising a biological material and a geometry simulating parts of a living body, wherein the microscale feature is configured to substantially mimic in vitro at least one measurable condition in vivo, and wherein the at least one measurable in vivo condition is selected from at least one of the group consisting of tissue size ratio, 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 of 14 dynes per cm 2  or less, flow rate, the number of cells in the device, circulatory transit time, and liquid distribution.  
   
   
       60 . The method of  claim 59  wherein the microscale feature provides for three-dimensional growth of biological material.  
   
   
       61 . The method of  claim 59  wherein the microscale feature comprises at least one selected from the group consisting of a chamber, a channel, a tube, a well, a scaffold, an inlet, an outlet, a valve, a membrane, a diaphragm, and a compartment.  
   
   
       62 . The method of  claim 59  wherein the microscale feature further comprises at least one microfluidic channel connected to the microscale feature.  
   
   
       63 . The method of  claim 59  further comprising forming the microscale feature such that when fluid flows through, or in proximity to the microscale feature, the fluid flow provides the at least one measurable in vivo condition.  
   
   
       64 . The method of  claim 63  wherein the characteristics of the fluid flow are based on a mathematical model.  
   
   
       65 . The method of  claim 64  wherein the mathematical model is a physiologically-based pharmacokinetic (“PBPK”) model.  
   
   
       66 . The method of  claim 59  further comprising forming, containing, inserting, assembling, making, or constituting the microscale feature in a device.  
   
   
       67 . The method  claim 59  wherein the geometry of the microscale feature, the device in whole or in part is based on a mathematical model or wherein the geometry of interconnection of the microscale feature or of the device in whole or in part is based on a mathematical model.  
   
   
       68 . The method of  claim 59  further comprising forming at least one second microscale feature configured to substantially mimic at least a second measurable in vivo condition.  
   
   
       69 . The method of  claim 59  further comprising forming an array of devices wherein one or more of the devices comprise at least one microscale feature and wherein the devices operate separately from and in parallel with one another.  
   
   
       70 . The method of  claim 59  further comprising fluidically connecting a series of devices wherein one or more of the devices comprise at least one microscale feature such that a fluidic outlet from a first device is connected directly or indirectly to at least one fluidic inlet to one or more second devices.  
   
   
       71 . The method of  claim 70  wherein connecting a series of devices further comprises connecting fluidic outlets from the one or more second devices to at least one fluidic inlet of one or more additional devices.  
   
   
       72 . The method of  claim 59  comprising forming the device with a microfabricated master.  
   
   
       73 . The method of  claim 59  wherein the microscale feature is configured to represent a tissue.