Devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in the blood, generated as a result of extracorporeal blood processing

Abstract

Devices, systems, and methods reduce levels of pro-inflammatory or anti-inflammatory stimulators or mediators in blood by selective adsorption. The devices, systems, and methods are useful in situations where abnormal levels of or unregulated or excessive interaction among pro-inflammatory or anti-inflammatory stimulators or mediators occur, or during events that do induce or have the potential for inducing abnormal production of pro-inflammatory or anti-inflammatory stimulators or mediators. The devices, systems, and methods serve to prevent, control, reduce, or alleviate the severity of the inflammatory response and disease states that are associated with abnormal levels of or unregulated or excessive interaction among pro-inflammatory or anti-inflammatory stimulators or mediators.

We claim:  
     
         1 . A blood processing system comprising an extracorporeal apparatus to receive the blood drawn from an individual and to conduct separation of the blood into plasma and at least one cellular blood component, and a device communicating with the extracorporeal apparatus to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators from either plasma, or the at least one cellular blood component, or both.  
     
     
         2 . A blood processing system comprising an extracorporeal apparatus to receive the blood drawn from an individual and to conduct separation of the blood into plasma and at least one cellular blood component, and a device communicating with the extracorporeal apparatus to remove from either plasma, or the at least one cellular blood component, or both, cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators that are generated as a result of the separation of the blood.  
     
     
         3 . A system according to  claim 1  or  2  
 wherein the extracorporeal apparatus conducts the separation of the blood, at least in part, by filtration.  
 
     
     
         4 . A system according to  claim 1  or  2  
 wherein the extracorporeal apparatus conducts the separation of the blood, at least in part, by centrifugation.  
 
     
     
         5 . A system according to  claim 1  or  2  
 wherein the cellular blood component includes a red blood cell component.  
 
     
     
         6 . A system according to  claim 1  or  2  
 wherein the cellular blood component includes a platelet component.  
 
     
     
         7 . A system according to  claim 1  or  2  
 wherein the cellular blood component includes a white blood cell component.  
 
     
     
         8 . A system according to  claim 1  or  2  
 wherein the extracorporeal apparatus returns at least one cellular blood component to the individual following removal of cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         9 . A system according to  claim 1  or  2  
 wherein the extracorporeal apparatus retains at least one cellular blood component following removal of cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         10 . A system according to  claim 1  or  2  
 wherein the extracorporeal apparatus returns plasma to the individual following removal of cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         11 . A system according to  claim 1  or  2  
 wherein the extracorporeal apparatus retains plasma following removal of cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         12 . A system according to  claim 1  or  2  
 wherein the device includes an adsorption medium to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         13 . A system according to  claim 12   wherein the adsorption medium is characterized by a Biocompatibility Index of not greater than  14 .    
     
     
         14 . A system according to  claim 13   wherein the Biocompatibility Index is not greater than  7 .    
     
     
         15 . A system according to  claim 1  or  2  
 wherein the device is in an upstream flow direction from the extracorporeal apparatus.  
 
     
     
         16 . A system according to  claim 1  or  2  
 wherein the device is in a downstream flow direction from the extracorporeal apparatus.  
 
     
     
         17 . A system according to  claim 1  or  2  
 wherein the device includes an adsorption medium to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators, the adsorption medium comprising a polymeric material.  
 
     
     
         18 . A system according to  claim 17   wherein the polymeric material comprises particles prepared by polymerization or copolymerization of a monomer selected from a group consisting of styrene, ethylstyrene, α-methylstyrene, divinylbenzene, di isopropenyl benzene, trivinylbenzene, and alkyl methacrylate.    
     
     
         19 . A system according to  claim 17   wherein the polymeric material comprises particles formed from crosslinked polystyrene-type resins having a surface modified to minimize activation of blood complement system.    
     
     
         20 . A system according to  claim 17   wherein the polymeric material comprises particles formed from a porous hydrophobic divinylbenzene copolymer having a surface modified to include surface exposed functional groups selected from the group of polymers of 2-hydroxyethyl methacrylate, N-vinylpyrrolidine, N-vinylcaprolactame and N-acrylamide.    
     
     
         21 . A system according to  claim 17   wherein the polymeric material comprises particles formed by polymerization of aromatic divinyl compounds or their copolymerization with aromatic monovinyl compounds in the presence of porogens or mixtures of porogens with properties close to those of θ-solvents.    
     
     
         22 . A blood processing system comprising an extracorporeal apparatus to oxygenate the blood drawn from an individual and return the oxygenated blood to the individual, and a device communicating with the apparatus to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators from the oxygenated blood.  
     
     
         23 . A blood processing system comprising an extracorporeal apparatus to oxygenate the blood drawn from an individual and return the oxygenated blood to the individual, and a device communicating with the apparatus to remove from the oxygenated blood cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators that are generated as a result of extracorporeal processing.  
     
     
         24 . A system according to  claim 22  or  23  
 wherein the device includes an adsorption medium to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         25 . A system according to  claim 24   wherein the adsorption medium is characterized by a Biocompatibility Index of not greater than 14.    
     
     
         26 . A system according to  claim 25   wherein the Biocompatibility Index is not greater than 7.    
     
     
         27 . A system according to  claim 22  or  23  
 wherein the device is in an upstream flow direction from the extracorporeal apparatus.  
 
     
     
         28 . A system according to  claim 22  or  23  
 wherein the device is in a downstream flow direction from the extracorporeal apparatus.  
 
     
     
         29 . A system according to  claim 22  or  23  
 wherein the device includes an adsorption medium to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators, the adsorption medium comprising a polymeric material.  
 
     
     
         30 . A system according to  claim 29   wherein the polymeric material comprises particles prepared by polymerization or copolymerization of a monomer selected from a group consisting of styrene, ethylstyrene, α-methylstyrene, divinylbenzene, di isopropenyl benzene, trivinylbenzene, and alkyl methacrylate.    
     
     
         31 . A system according to  claim 29   wherein the polymeric material comprises particles formed from crosslinked polystyrene-type resins having a surface modified to minimize activation of blood complement system.    
     
     
         32 . A system according to  claim 29   wherein the polymeric material comprises particles formed from a porous hydrophobic divinylbenzene copolymer having a surface modified to include surface exposed functional groups selected from the group of polymers of 2-hydroxyethyl methacrylate, N-vinylpyrrolidine, N-vinylcaprolactame and N-acrylamide.    
     
     
         33 . A system according to  claim 29   wherein the polymeric material comprises particles formed by polymerization of aromatic divinyl compounds or their copolymerization with aromatic monovinyl compounds in the presence of porogens or mixtures of porogens with properties close to those of θ-solvents.    
     
     
         34 . A blood processing system comprising an extracorporeal apparatus to remove waste from the blood drawn from an individual and return waste-depleted blood to the individual, and a device communicating with the apparatus to remove from the waste-depleted blood cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators that are generated as a result of extracorporeal processing.  
     
     
         35 . A system according to  claim 34   wherein the apparatus removes waste by hemofiltration.    
     
     
         36 . A system according to  claim 34   wherein the apparatus removes waste by dialysis.    
     
     
         37 . A system according to  claim 34   wherein the device includes an adsorption medium to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.    
     
     
         38 . A system according to  claim 37   wherein the adsorption medium is characterized by a Biocompatibility Index of not greater than 14.    
     
     
         39 . A system according to  claim 38   wherein the Biocompatibility Index is not greater than 7.    
     
     
         40 . A system according to  claim 34   wherein the device is in an upstream flow direction from the extracorporeal apparatus.    
     
     
         41 . A system according to  claim 34   wherein the device is in a downstream flow direction from the extracorporeal apparatus.    
     
     
         42 . A system according to  claim 34   wherein the device includes an adsorption medium to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators, the adsorption medium comprising a polymeric material.    
     
     
         43 . A system according to  claim 42   wherein the polymeric material comprises particles prepared by polymerization or copolymerization of a monomer selected from a group consisting of styrene, ethylstyrene, a-methylstyrene, divinylbenzene, di isopropenyl benzene, trivinylbenzene, and alkyl methacrylate.    
     
     
         44 . A system according to  claim 42   wherein the polymeric material comprises particles formed from crosslinked polystyrene-type resins having a surface modified to minimize activation of blood complement system.    
     
     
         45 . A system according to  claim 42   wherein the polymeric material comprises particles formed from a porous hydrophobic divinylbenzene copolymer having a surface modified to include surface exposed functional groups selected from the group of polymers of 2-hydroxyethyl methacrylate, N-vinylpyrrolidine, N-vinylcaprolactame and N-acrylamide.    
     
     
         46 . A system according to  claim 42   wherein the polymeric material comprises particles formed by polymerization of aromatic divinyl compounds or their copolymerization with aromatic monovinyl compounds in the presence of porogens or mixtures of porogens with properties close to those of θ-solvents.    
     
     
         47 . A blood processing method comprising the steps of 
 conveying the blood drawn from an individual to an extracorporeal apparatus,    operating the extracorporeal apparatus to conduct separation of the blood into plasma and at least one cellular blood component, and    removing cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators from either plasma, or the at least one cellular blood component, or both.    
     
     
         48 . A blood processing method comprising the steps of 
 conveying the blood drawn from an individual to an extracorporeal apparatus,    operating the extracorporeal apparatus to conduct separation of the blood into plasma and at least one cellular blood component, and    removing from either plasma, or the at least one cellular blood component, or both, cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators that are generated as a result of the separation of the blood.    
     
     
         49 . A method according to  claim 47  or  48  
 wherein the extracorporeal apparatus conducts the separation of the blood, at least in part, by filtration.  
 
     
     
         50 . A method according to  claim 47  or  48  
 wherein the extracorporeal apparatus conducts the separation of the blood, at least in part, by centrifugation.  
 
     
     
         51 . A method according to  claim 47  or  48  
 wherein the cellular blood component includes a red blood cell component.  
 
     
     
         52 . A method according to  claim 47  or  48  
 wherein the cellular blood component includes a platelet component.  
 
     
     
         53 . A method according to  claim 47  or  48  
 wherein the cellular blood component includes a white blood cell component.  
 
     
     
         54 . A method according to  claim 47  or  48  
 further including returning at least one cellular blood component to the individual following removal of cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         55 . A method according to  claim 47  or  48  
 further including retaining at least one cellular blood component following removal of cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         56 . A method according to  claim 47  or  48  
 further including returning plasma to the individual following removal of cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         57 . A method according to  claim 47  or  48  
 further including retaining plasma following removal of cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         58 . A method according to  claim 47  or  48  
 wherein the removing step includes use of an adsorption medium to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         59 . A method according to  claim 58   wherein the adsorption medium comprises a polymeric material.    
     
     
         60 . A method according to  claim 59   wherein the polymeric material comprises particles prepared by polymerization or copolymerization of a monomer selected from a group consisting of styrene, ethylstyrene, α-methylstyrene, divinylbenzene, di isopropenyl benzene, trivinylbenzene, and alkyl methacrylate.    
     
     
         61 . A method according to  claim 59   wherein the polymeric material comprises particles formed from crosslinked polystyrene-type resins having a surface modified to minimize activation of blood complement system.    
     
     
         62 . A method according to  claim 59   wherein the polymeric material comprises particles formed from a porous hydrophobic divinylbenzene copolymer having a surface modified to include surface exposed functional groups selected from the group of polymers of 2-hydroxyethyl methacrylate, N-vinylpyrrolidine, N-vinylcaprolactame and N-acrylamide.    
     
     
         63 . A method according to  claim 59   wherein the polymeric material comprises particles formed by polymerization of aromatic divinyl compounds or their copolymerization with aromatic monovinyl compounds in the presence of porogens or mixtures of porogens with properties close to those of θ-solvents.    
     
     
         64 . A blood processing method comprising the steps of 
 conveying the blood drawn from an individual to an extracorporeal apparatus,    operating the extracorporeal apparatus to oxygenate the blood, and    removing cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators from the oxygenated blood.    
     
     
         65 . A blood processing method comprising the steps of 
 conveying the blood drawn from an individual to an extracorporeal apparatus,    operating the extracorporeal apparatus to oxygenate the blood, and    removing from the oxygenated blood cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators that are generated as a result of extracorporeal processing.    
     
     
         66 . A method according to  claim 64  or  65  
 wherein the removing step includes use of an adsorption medium to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.  
 
     
     
         67 . A method according to  claim 66   wherein the adsorption medium comprises a polymeric material.    
     
     
         68 . A method according to  claim 67   wherein the polymeric material comprises particles prepared by polymerization or copolymerization of a monomer selected from a group consisting of styrene, ethylstyrene, α-methylstyrene, divinylbenzene, di isopropenyl benzene, trivinylbenzene, and alkyl methacrylate.    
     
     
         69 . A method according to  claim 67   wherein the polymeric material comprises particles formed from crosslinked polystyrene-type resins having a surface modified to minimize activation of blood complement system.    
     
     
         70 . A method according to  claim 67   wherein the polymeric material comprises particles formed from a porous hydrophobic divinylbenzene copolymer having a surface modified to include surface exposed functional groups selected from the group of polymers of 2-hydroxyethyl methacrylate, N-vinylpyrrolidine, N-vinylcaprolactame and N-acrylamide.    
     
     
         71 . A method according to  claim 67   wherein the polymeric material comprises particles formed by polymerization of aromatic divinyl compounds or their copolymerization with aromatic monovinyl compounds in the presence of porogens or mixtures of porogens with properties close to those of θ-solvents.    
     
     
         72 . A blood processing method comprising 
 conveying the blood drawn from an individual to an extracorporeal apparatus,    operating the extracorporeal apparatus to remove waste from the blood and return waste-depleted blood to the individual, and    removing from the waste-depleted blood cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators that are generated as a result of extracorporeal processing.    
     
     
         73 . A method according to  claim 72   wherein the apparatus removes waste by hemofiltration.    
     
     
         74 . A method according to  claim 72   wherein the apparatus removes waste by dialysis.    
     
     
         75 . A method according to  claim 72   wherein the removing step includes use of an adsorption medium to remove cytokines or other species of pro-inflammatory or anti-inflammatory stimulators or mediators.    
     
     
         76 . A method according to  claim 75   wherein the adsorption medium comprises a polymeric material.    
     
     
         77 . A method according to  claim 76   wherein the polymeric material comprises particles prepared by polymerization or copolymerization of a monomer selected from a group consisting of styrene, ethylstyrene, α-methylstyrene, divinylbenzene, di isopropenyl benzene, trivinylbenzene, and alkyl methacrylate.    
     
     
         78 . A method according to  claim 76   wherein the polymeric material comprises particles formed from crosslinked polystyrene-type resins having a surface modified to minimize activation of blood complement system.    
     
     
         79 . A method according to  claim 76   wherein the polymeric material comprises particles formed from a porous hydrophobic divinylbenzene copolymer having a surface modified to include surface exposed functional groups selected from the group of polymers of 2-hydroxyethyl methacrylate, N-vinylpyrrolidine, N-vinylcaprolactame and N-acrylamide.    
     
     
         80 . A method according to  claim 76   wherein the polymeric material comprises particles formed by polymerization of aromatic divinyl compounds or their copolymerization with aromatic monovinyl compounds in the presence of porogens or mixtures of porogens with properties close to those of θ-solvents.