The Use of a Hemocompatible Porous Polymer Bread Sorbent for Removal of Pamps and Damps

Abstract

The invention concerns biocompatible polymer systems comprising at least one polymer sorbent with a plurality of pores, said polymer designed to adsorb pathogen-associated molecular pattern molecules and damage-associated molecular pattern molecules. Also disclosed herein are methods for reducing contamination in a biological substance, or treating contamination in a subject, by one or more pathogen-associated molecular pattern molecules and damage-associated molecular pattern molecules, by contacting the biological substance with an effective amount of sorbent capable of sorbing the toxin.

Claims

1-14. (canceled)

15. A method of removing (i) pathogen-associated molecular pattern molecules (PAMPS) and (ii) damage-associated molecular pattern molecules (DAMPS) from a physiological fluid comprising: contacting the physiological fluid with a polymer comprising a plurality of pores in a range of from 50 Å to 40,000 Å and having a total volume of pore sizes in a range of from about cc/g to about 5.0 cc/g dry polymer; and wherein the PAMPS and DAMPS have a molecular weight of from about 0.5 kDa to about 1,000 kDa.

16. The method of claim 15, wherein the polymer is hemocompatible.

17. The method of claim 15, wherein the polymer has a geometry that is a spherical bead.

18. The method of claim 15, wherein the PAMPs and DAMPS comprise one or more of flagellins, lipopeptides, formyl peptides, mycotoxins, exotoxins, endotoxins, lipoteichoic acid, cytolysins, superantigens, proteases, lipases, amylases, enzymes, peptides including bradykinin, activated complement, soluble receptors, soluble CD40 ligand, bioactive lipids, oxidized lipids, cellular DNA, mitochondrial DNA, pathogen or host derived RNA, cell-free hemoglobin, cell-free myoglobin, growth factors, peptidoglycans, glycoproteins, released intracellular components, cell wall or viral envelope components, Polyinosinic:polycytidylic acid (poly I:C), prions, toxins, bacterial and viral toxins, drugs, vasoactive substances, and foreign antigens.

19. The method of claim 15, wherein the polymer is made using suspension polymerization.

20. The method of claim 15, wherein the polymer is a hypercrosslinked polymer.

21. The method of claim 17, wherein the spherical bead has a biocompatible hydrogel coating.

22. The method of claim 15, wherein the polymer is formed and subsequently modified to be biocompatible.

23. The method of claim 15, wherein the polymer is housed in a container suitable to retain the polymer and for transfusion of a physiological fluid selected from whole blood, packed red blood cells, platelets, albumin, plasma and combinations thereof.

24. The method of claim 15, wherein the polymer is in a device suitable to retain the polymer and be incorporated into an extracorporeal circuit.

25. The method of claim 15, wherein free polymer (i.e. not contained) is used to treat the physiologic fluids.

26. The method of claim 15, wherein physiological fluid is selected from whole blood, packed red blood cells, platelets, albumin, plasma and combinations thereof.

27. A method of perfusion comprising: passing a physiologic fluid once through or by way of a suitable extracorporeal circuit through a device once or many times comprising a polymer comprising a plurality of pores in a range of from 50 Å to 40,000 Å and having a total volume of pore sizes in a range of from about cc/g to about 5.0 cc/g dry polymer; and removing (i) pathogen-associated molecular pattern molecules (PAMPS) and (ii) damage-associated molecular pattern molecules (DAMPS) from the physiological fluid; wherein the PAMPS and DAMPS have a molecular weight of from about 0.5 kDa to about 1,000 kDa.

28. The method of claim 27, wherein the polymer is hemocompatible.

29. The method of claim 27, wherein the polymer has a geometry that is a spherical bead.

30. The method of claim 27, wherein the PAMPs and DAMPS comprise one or more of flagellins, lipopeptides, formyl peptides, mycotoxins, exotoxins, endotoxins, lipoteichoic acid, cytolysins, superantigens, proteases, lipases, amylases, enzymes, peptides including bradykinin, activated complement, soluble receptors, soluble CD40 ligand, bioactive lipids, oxidized lipids, cellular DNA, mitochondrial DNA, pathogen or host derived RNA, cell-free hemoglobin, cell-free myoglobin, growth factors, peptidoglycans, glycoproteins, released intracellular components, cell wall or viral envelope components, Polyinosinic:polycytidylic acid (poly I:C), prions, toxins, bacterial and viral toxins, drugs, vasoactive substances, and foreign antigens.

31. The method of claim 27, wherein the polymer is made using suspension polymerization.

32. The method of claim 27, wherein the polymer is a hypercrosslinked polymer.

33. The method of claim 29, wherein the spherical bead has a biocompatible hydrogel coating.

34. The method of claim 27, wherein the polymer is formed and subsequently modified to be biocompatible.

35. The method of claim 27, wherein physiological fluid is selected from whole blood, packed red blood cells, platelets, albumin, plasma and combinations thereof.

36. A method for treating contamination with pathogen-associated molecular pattern molecules (PAMPS) and/or damage-associated molecular pattern molecules (DAMPS), comprising contacting physiological fluid of a patient with a polymer comprising a plurality of pores in a range of from 50 Å to 40,000 Å and having a total volume of pore sizes in a range of from about 0.5 cc/g to about 5.0 cc/g dry polymer; wherein the PAMPS and DAMPS have a molecular weight of from about 0.5 kDa to about 1,000 kDa.

37. The method of claim 36, wherein the polymer is hemocompatible.

38. The method of claim 36, wherein the polymer has a geometry that is a spherical bead.

39. The method of claim 36, wherein the PAMPs and DAMPS comprise one or more of flagellins, lipopeptides, formyl peptides, mycotoxins, exotoxins, endotoxins, lipoteichoic acid, cytolysins, superantigens, proteases, lipases, amylases, enzymes, peptides including bradykinin, activated complement, soluble receptors, soluble CD40 ligand, bioactive lipids, oxidized lipids, cellular DNA, mitochondrial DNA, pathogen or host derived RNA, cell-free hemoglobin, cell-free myoglobin, growth factors, peptidoglycans, glycoproteins, released intracellular components, cell wall or viral envelope components, Polyinosinic:polycytidylic acid (poly I:C), prions, toxins, bacterial and viral toxins, drugs, vasoactive substances, and foreign antigens.

40. The method of claim 36, wherein the polymer is made using suspension polymerization.

41. The method of claim 36, wherein the polymer is a hypercrosslinked polymer.

42. The method of claim 38, wherein the spherical bead has a biocompatible hydrogel coating.

43. The method of claim 36, wherein the polymer is formed and subsequently modified to be biocompatible.

44. The method of claim 36, wherein the polymer is housed in a container suitable to retain the polymer and for transfusion of a physiological fluid selected from whole blood, packed red blood cells, platelets, albumin, plasma and combinations thereof.

45. The method of claim 36, wherein the polymer is in a device suitable to retain the polymer and be incorporated into an extracorporeal circuit.

46. The method of claim 36, wherein free polymer (i.e. not contained) is used to treat the physiologic fluids.

47. The method of claim 36, wherein physiological fluid is selected from whole blood, packed red blood cells, platelets, albumin, plasma and combinations thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The accompanying drawings, which are included to provide a further understanding of the disclosure, are incorporated in and constitute a part of this specification, illustrate aspects of the disclosure and together with the detailed description serve to explain the principles of the disclosure. No attempt is made to show structural details of the disclosure in more detail than may be necessary for a fundamental understanding of the disclosure and the various ways in which it may be practiced. In the drawings:

[0022] FIGS. 1 and 2 present DAMPS and PAMPs removal data from an in vitro dynamic model, using whole blood, expressed as percentage remaining compared to the pre-circulation concentrations for modified polymer CY15065.

[0023] FIGS. 3 and 4 presents DAMPs and PAMPs removal data from an in vitro dynamic model, using whole blood, expressed as percentage remaining compared to the pre-circulation concentrations for polymer CY15077.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0024] As required, detailed embodiments of the present invention are disclosed herein; it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limits, but merely as a basis for teaching one skilled in the art to employ the present invention. The specific examples below will enable the invention to be better understood. However, they are given merely by way of guidance and do not imply any limitation.

[0025] The present invention may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures and examples, which form a part of this disclosure. It is to be understood that this invention is not limited to the specific materials, devices, methods, applications, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed invention. The term “plurality”, as used herein, means more than one. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

[0026] It is to be appreciated that certain features of the invention, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. Further reference to values stated in ranges includes each and every value within that range.

[0027] The following definitions are intended to assist in understanding the present invention:

[0028] Pathogen-associated molecular pattern molecules (PAMPS) are molecules derived from microorganisms that are recognized by cells of the innate immune system. These molecules have small molecular motifs conserved within a class of microbes that are recognized by toll-like receptor and pattern recognition receptors that initiate and perpetuate a pathogen-induced inflammatory response.

[0029] Damage-associated molecular pattern molecules (DAMPS) are host biomolecules released by stressed cells that initiate and perpetuate inflammation in response to trauma, ischemia, and tissue damage either in the absence or presence of pathogenic infection.

[0030] The term “biocompatible” is defined to mean the sorbent is capable of coming in contact with physiologic fluids, living tissues, or organisms, without producing unacceptable clinical changes during the time that the sorbent is in contact with the physiologic fluids, living tissues, or organisms.

[0031] The term “hemocompatible” is defined as a condition whereby a biocompatible material when placed in contact with whole blood or blood plasma results in clinically acceptable physiologic changes.

[0032] As used herein, the term “sorbent” includes adsorbents and absorbents.

[0033] For purposes of this invention, the term “sorb” is defined as “taking up and binding by absorption and adsorption”.

[0034] For the purposes of this invention, the term “perfusion” is defined as passing a physiologic fluid, once through or by way of a suitable extracorporeal circuit, through a device containing the porous polymeric adsorbent to remove toxic molecules from the fluid.

[0035] The term “hemoperfusion” is a special case of perfusion where the physiologic fluid is blood.

[0036] The term “dispersant” or “dispersing agent” is defined as a substance that imparts a stabilizing effect upon a finely divided array of immiscible liquid droplets suspended in a fluidizing medium.

[0037] The term “macroreticular synthesis” is defined as a polymerization of monomers into polymer in the presence of an inert precipitant which forces the growing polymer molecules out of the monomer liquid at a certain molecular size dictated by the phase equilibria to give solid nanosized microgel particles of spherical or almost spherical symmetry packed together to give a bead with physical pores of an open cell structure [U.S. Pat. No. 4,297,220, Meitzner and Oline, Oct. 27, 1981; R. L. Albright, Reactive Polymers, 4, 155-174(1986)].

[0038] The term “hypercrosslinked” describes a polymer in which the single repeating unit has a connectivity of more than two. Hypercrosslinked polymers are prepared by crosslinking swollen, or dissolved, polymer chains with a large number of rigid bridging spacers, rather than copolymerization of monomers. Crosslinking agents may include bis(chloromethyl) derivatives of aromatic hydrocarbons, methylal, monochlorodimethyl ether, and other bifunctional compounds that react with the polymer in the presence of Friedel-Crafts catalysts [Tsyurupa, M. P., Z. K. Blinnikova, N. A. Proskurina, A. V. Pastukhov, L. A. Pavlova, and V. A. Davankov. “Hypercrosslinked Polystyrene: The First Nanoporous Polymeric Material.” Nanotechnologies in Russia 4 (2009): 665-75.]

[0039] Some preferred polymers comprise residues from one or more monomers, or containing monomers, or mixtures thereof, selected from acrylonitrile, allyl glycidyl ether, butyl acrylate, butyl methacrylate, cetyl acrylate, cetyl methacrylate, 3,4-dihydroxy-1-butene, dipentaerythritol diacrylate, dipentaerythritol dimethacrylate, dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol triacrylate, dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, 3,4-epoxy-1-butene, 1,2-epoxy-9-decene, 1,2-epoxy-5-hexene, ethyl acrylate, ethyl methacrylate, ethylstyrene, ethylvinylbezene, glycidyl methacrylate, methyl acrylate, methyl methacrylate, octyl acrylate, octyl methacrylate, pentaerythritol diacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, styrene, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane, vinyl acetate, vinylbenzyl alcohol, 4-vinyl-1-cyclohexene 1,2-epoxide, vinylformamide, vinylnaphthalene, 2-vinyloxirane, and vinyltoluene.

[0040] Some embodiments of the invention use an organic solvent and/or polymeric porogen as the porogen or pore-former, and the resulting phase separation induced during polymerization yield porous polymers. Some preferred porogens are selected from, or mixtures comprised of any combination of, benzyl alcohol, cyclohexane, cyclohexanol, cyclohexanone, decane, dibutyl phthalate, di-2-ethylhexyl phthalate, di-2-ethylhexylphosphoric acid, ethylacetate, 2-ethyl-1-hexanoic acid, 2-ethyl-1-hexanol, n-heptane, n-hexane, isoamyl acetate, isoamyl alcohol, n-octane, pentanol, poly(propylene glycol), polystyrene, poly(styrene-co-methyl methacrylate), tetraline, toluene, tri-n-butylphosphate, 1,2,3-trichloropropane, 2,2,4-trimethylpentane, and xylene.

[0041] In yet another embodiment, the dispersing agent is selected from a group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, poly(diethylaminoethyl acrylate), poly(diethylaminoethyl methacrylate), poly(dimethylaminoethyl acrylate), poly(dimethylaminoethyl methacrylate), poly(hydroxyethyl acrylate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl acrylate), poly(hydroxypropyl methacrylate), poly(vinyl alcohol), salts of poly(acrylic acid), salts of poly(methacrylic acid) and mixtures thereof.

[0042] Preferred sorbents are biocompatible. In another further embodiment, the polymer is biocompatible. In yet another embodiment, the polymer is hemocompatible. In still a further embodiment, the biocompatible polymer is hemocompatible. In still a further embodiment, the geometry of the polymer is a spherical bead.

[0043] In another embodiment, the biocompatible polymer comprises poly(N-vinylpyrrolidone).

[0044] The coating/dispersant on the poly(styrene-co-divinylbenzene) resin will imbue the material with improved biocompatibility.

[0045] In still yet another embodiment, a group of cross-linkers consisting of dipentaerythritol diacrylates, dipentaerythritol dimethacrylates, dipentaerythritol tetraacrylates, dipentaerythritol tetramethacrylates, dipentaerythritol triacrylates, dipentaerythritol trimethacrylates, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, pentaerythritol diacrylates, pentaerythritol dimethacrylates, pentaerythritol tetraacrylates, pentaerythritol tetramethacrylates, pentaerythritol triacrylates, pentaerythritol trimethacrylates, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane and mixtures thereof can be used in formation of a hemocompatible hydrogel coating.

[0046] In some embodiments, the polymer is a polymer comprising at least one crosslinking agent and at least one dispersing agent. The dispersing agent may be biocompatible. The dispersing agents can be selected from chemicals, compounds or materials such as hydroxyethyl cellulose, hydroxypropyl cellulose, poly(diethylaminoethyl acrylate), poly(diethylaminoethyl methacrylate), poly(dimethylaminoethyl acrylate), poly(dimethylaminoethyl methacrylate), poly(hydroxyethyl acrylate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl acrylate), poly(hydroxypropyl methacrylate), poly(vinyl alcohol), salts of poly(acrylic acid), salts of poly(methacrylic acid) and mixtures thereof; the crosslinking agent selected from a group consisting of dipentaerythritol diacrylates, dipentaerythritol dimethacrylates, dipentaerythritol tetraacrylates, dipentaerythritol tetramethacrylates, dipentaerythritol triacrylates, dipentaerythritol trimethacrylates, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, pentaerythritol diacrylates, pentaerythritol dimethacrylates, pentaerythritol tetraacrylates, pentaerythritol tetramethacrylates, pentaerythritol triacrylates, pentaerythritol trimethacrylates, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane and mixtures thereof. Preferably, the polymer is developed simultaneously with the formation of the coating, wherein the dispersing agent is chemically bound or entangled on the surface of the polymer.

[0047] In still another embodiment, the biocompatible polymer coating is selected from a group consisting of poly(diethylaminoethyl methacrylate), poly(dimethylaminoethyl methacrylate), poly(hydroxyethyl acrylate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl acrylate), poly(hydroxypropyl methacrylate), poly(N-vinylpyrrolidone), poly(vinyl alcohol), salts of poly(acrylic acid), salts of poly(methacrylic acid) and mixtures thereof.

[0048] In still another embodiment, the biocompatible oligomer coating is selected from a group consisting of poly(diethylaminoethyl methacrylate), poly(dimethylaminoethyl methacrylate), poly(hydroxyethyl acrylate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl acrylate), poly(hydroxypropyl methacrylate), poly(N-vinylpyrrolidone), poly(vinyl alcohol), salts of poly(acrylic acid), salts of poly(methacrylic acid) and mixtures thereof.

[0049] Some present biocompatible sorbent compositions are comprised of a plurality of pores. The biocompatible sorbents are designed to adsorb a broad range of toxins from less than kDa to 1,000 kDa. While not intending to be bound by theory, it is believed the sorbent acts by sequestering molecules of a predetermined molecular weight within the pores. The size of a molecule that can be sorbed by the polymer will increase as the pore size of the polymer increases. Conversely, as the pore size is increased beyond the optimum pore size for adsorption of a given molecule, adsorption of said protein may or will decrease.

[0050] In certain methods, the solid form is porous. Some solid forms are characterized as having a pore structure having a total volume of pore sizes in the range of from 50 Å to greater than 0.5 cc/g and less than 5.0 cc/g dry polymer.

[0051] In one embodiment, the sorbent has a pore structure wherein at least ⅓ of the pore volume in pores having diameters between 50 Å and 40,000 Å is in pores having diameters between 100 Å and 1,000 Å.

[0052] In another embodiment, the sorbent has a pore structure wherein at least ½ of the pore volume in pores having diameters between 50 Å and 40,000 Å is in pores having diameters between 1000 Å and 10,000 Å.

[0053] In still another embodiment, the sorbent has a pore structure wherein at least 1/3 of the pore volume in pores having diameters between 50 Å and 40,000 Å is in pores having diameters between 10,000 Å and 40,000 Å.

[0054] In certain embodiments, the polymers can be made in bead form having a diameter in the range of 0.1 micrometers to 2 centimeters. Certain polymers are in the form of powder, beads or other regular or irregularly shaped particulates.

[0055] In some embodiments, the plurality of solid forms comprises particles having a diameter in the range for 0.1 micrometers to 2 centimeters.

[0056] In some methods, the undesirable molecules include PAMPs and DAMPS comprised of one or more of flagellins, lipopeptides, formyl peptides, mycotoxins, exotoxins, cytolysins, superantigens, proteases, lipases, amylases, enzymes, peptides including bradykinin, activated complement, soluble receptors, soluble CD40 ligand, bioactive lipids, oxidized lipids, cell-free hemoglobin, cell-free myoglobin, growth factors, glycoproteins, prions, toxins, bacterial and viral toxins, drugs, vasoactive substances, foreign antigens, and antibodies.

[0057] In one embodiment, the polymers of this invention are made by suspension polymerization in a formulated aqueous phase with free radical initiation in the presence of aqueous phase dispersants that are selected to provide a biocompatible and a hemocompatible exterior surface to the formed polymer beads. In some embodiments, the beads are made porous by the macroreticular synthesis with an appropriately selected porogen (pore forming agent) and an appropriate time-temperature profile for the polymerization in order to develop the proper pore structure.

[0058] In another embodiment, polymers made by suspension polymerization can be made biocompatible and hemocompatible by further grafting of biocompatible and hemocompatible monomers or low molecular weight oligomers. It has been shown that the radical polymerization procedure does not consume all the vinyl groups of DVB introduced into copolymerization. On average, about 30% of DVB species fail to serve as crosslinking bridges and remain involved in the network by only one of two vinyl groups. The presence of a relatively high amount of pendant vinyl groups is therefore a characteristic feature of the adsorbents. It can be expected that these pendant vinyl groups are preferably exposed to the surface of the polymer beads and their macropores, if present, should be readily available to chemical modification. The chemical modification of the surface of DVB-copolymers relies on chemical reactions of the surface-exposed pendant vinyl groups and aims at converting these groups into more hydrophilic functional groups. This conversion via free radical grafting of monomers and/or cross-linkers or low molecular weight oligomers provides the initial hydrophobic adsorbing material with the property of hemocompatibility.

[0059] In yet another embodiment, the radical polymerization initiator is initially added to the dispersed organic phase, not the aqueous dispersion medium as is typical in suspension polymerization. During polymerization, many growing polymer chains with their chain-end radicals show up at the phase interface and can initiate the polymerization in the dispersion medium. Moreover, the radical initiator, like benzoyl peroxide, generates radicals relatively slowly. This initiator is only partially consumed during the formation of beads even after several hours of polymerization. This initiator easily moves toward the surface of the bead and activates the surface exposed pendant vinyl groups of the divinylbenzene moiety of the bead, thus initiating the graft polymerization of other monomers added after the reaction has proceeded for a period of time. Therefore, free-radical grafting can occur during the transformation of the monomer droplets into polymer beads thereby incorporating monomers and/or cross-linkers or low molecular weight oligomers that impart biocompatibility or hemocompatibility as a surface coating.

[0060] The hemoperfusion and perfusion devices consist of a packed bead bed of the polymer beads in a flow-through container fitted with either a retainer screen at both the exit end and the entrance end to maintain the bead bed inside the container, or with a subsequent retainer screen to collect the beads after mixing. The hemoperfusion and perfusion operations are performed by passing the whole blood, blood plasma or physiologic fluid through the packed bead bed. During the perfusion through the bead bed, the toxic molecules are retained by sorption, torturous path, and/or pore capture, while the remainder of the fluid and intact cell components pass through essentially unchanged in concentration.

[0061] In some other embodiments, an in-line filter is comprised of a packed bead bed of the polymer beads in a flow-through container, fitted with a retainer screen at both the exit end and the entrance end to maintain the bead bed inside the container. Biological fluids are passed from a storage bag once-through the packed bead bed via gravity, during which the toxic molecules are retained by sorption, torturous path, and/or pore capture, while the remainder of the fluid and intact cell components pass through essentially unchanged in concentration.

[0062] Certain polymers useful in the invention (as is or after further modification) are macroporous polymers prepared from the polymerizable monomers of styrene, divinylbenzene, ethylvinylbenzene, and the acrylate and methacrylate monomers such as those listed below by manufacturer. Rohm and Haas Company, (now part of Dow Chemical Company): macroporous polymeric sorbents such as Amberlite™ XAD-1, Amberlite™ XAD-2, Amberlite™ XAD-4, Amberlite™ XAD-7, Amberlite™ XAD-7HP, Amberlite™ XAD-8, Amberlite™ XAD-16, Amberlite™ XAD-16 HP, Amberlite™ XAD-18, Amberlite™ XAD-200, Amberlite™ XAD-1180, Amberlite™ XAD-2000, Amberlite™ XAD-2005, Amberlite™ XAD-2010, Amberlite™ XAD-761, and Amberlite™ XE-305, and chromatographic grade sorbents such as Amberchrom™ CG 71,s,m,c, Amberchrom™ CG 161,s,m,c, Amberchrom™ CG 300,s,m,c, and Amberchrom™ CG 1000,s,m,c. Dow Chemical Company: Dowex™ Optipore™ L-493, Dowex™ Optipore™ V-493, Dowex™ Optipore™ V-502, Dowex™ Optipore™ L-285, Dowex™ Optipore™ L-323, and Dowex™ Optipore™ V-503. Lanxess (formerly Bayer and Sybron): Lewatit™ VPOC 1064 MD PH, Lewatit™ VPOC 1163, Lewatit™ OC EP 63, Lewatit™ S 6328 A, Lewatit™ OC 1066, and Lewatit™ 60/150 MIBK. Mitsubishi Chemical Corporation: Diaion™ HP 10, Diaion™ HP 20, Diaion™ HP 21, Diaion™ HP 30, Diaion™ HP Diaion™ HP 50, Diaion™ SP70, Diaion™ SP 205, Diaion™ SP 206, Diaion™ SP 207, Diaion™ SP 700, Diaion™ SP 800, Diaion™ SP 825, Diaion™ SP 850, Diaion™ SP 875, Diaion™ HP 1MG, Diaion™ HP 2MG, Diaion™ CHP 55A, Diaion™ CHP 55Y, Diaion™ CHP Diaion™ CHP 20Y, Diaion™ CHP 2MGY, Diaion™ CHP 20P, Diaion™ HP 20SS, Diaion™ SP 20SS, Diaion™ SP 207SS. Purolite Company: Purosorb™ AP 250 and Purosorb™ AP 400, and Kaneka Corp. Lixelle and CTR beads.and BioSKY™ MG Blood Perfusion Column and polymers within, BioSKY™ DX Bilirubin Perfusion Column and polymers within, Jafron Columns/Cartridges and polymers within such as BS330, DNA230, HA130, HA230, HA280, HA330, and HA330-II.

[0063] Various DAMPs and PAMPs may be adsorbed by the composition of the instant disclosure Some of these proteins and their molecular weights are shown in the table below.

TABLE-US-00001 Molecular Protein Weight (Da) Gliotoxin 326 T-2 toxin 466 PAF (Platelet Activating Factor) 524 Bilirubin 549 Heme b 616 Lipopeptides 607-1,536 Formyl peptides 437-3,600 cathelicidin 4,500 β-Defensin 7,000 Ubiquitin 8000 Complement C5a 8,200 Complement C3a 9,089 Heat shock protein 10 10,000 S100B (monomer) 10,000 Histone H4 11,000 Procalcitonin 13,000 Serum amyloid A 13,000 Phospholipase A2, secretory PLA2 14,000 PLA2G2A 16,083 S100 proteins A8 (dimer) 20,000 Trypsin 23,300 Staph Enterotoxin B 24,500 HMGB1 24,894 Chymotrypsin 25,000 Elastase (neutrophil) 25,000 Staph ETA 26,900 HDGF 27,000 PF4 27,100 Staph ETB 27,300 PCNA, proliferating cell 29,000 nuclear antigen Panton-Valentine leukocidin 34,000 Arginse I 35,000 Carboxypeptidase A 35,000 Thrombin 36,700 Flagellin H4 37,000 Flagellin H17 39,000 Heat shock protein 40 40,000 Strep pyrogenic exotoxin B 42,000 alpha-1 antitrypsin 44,324 Soluble CD14 49,000 Rabies nucleocapsid N protein 50,600 Soluble TNF-α receptor 55,000 Activated Protein C 56,200 Amylase 57,000 Hemopexin 57,000 Lysteriolysin 58,000 Heat shock protein 60 60,000 Streptolysin O 60,500 Diptheria toxoid 62,000 Hemoglobin, oxy 64,000 Pseudomonas Exotoxin A 66,000 Flagellin H9 69,000 Heat shock protein 70 70,000 Calpain-1 (human erythrocytes) 112,00 C reactive Protein (5 × 25 kDa) 115,000 Myeloperoxidase (neutrophils) 150,000 NOS synthase 150,000

[0064] The following examples are intended to be exemplary and non-limiting.

Example 1: Base Sorbent Synthesis CY14175 & CY15077

[0065] Reactor Setup: a 4-neck glass lid was affixed to a 3 L jacketed cylindrical glass reaction vessel using a stainless steel flange clamp and PFTE gasket. The lid was fitted with a PFTE stirrer bearing, RTD adapter, and water-cooled reflux condenser. A stainless steel stirring shaft having five 60° agitators was fit through the stirrer bearing and inserted into a digital overhead stirrer. An RTD was fit through the corresponding adapter, and connected to a PolyStat circulating heating and chilling unit. Compatible tubing was used to connect the inlet and outlet of the reaction vessel jacket to the appropriate ports on the PolyStat. The unused port in the lid was used for charging the reactor and was plugged at all other times.

[0066] Polymerization: Aqueous phase and organic phase compositions are shown below, in Table I and Table II, respectively. Ultrapure water was split into approximately equal parts in two separate Erlenmeyer flasks, each containing a PFTE coated magnetic stir bar. Poly(vinyl alcohol) (PVA), having a degree of hydrolysis of 85.0 to 89.0 mol percent and a viscosity of 23.0 to 27.0 cP in a 4% aqueous solution at 20° C., was dispersed into the water in the first flask and heated to 80° C. on a hot plate with agitation. Salts (see Table 1, MSP, DSP, TSP and Sodium nitrite) were dispersed into the water in the second flask and heated to 80° C. on a hot plate with agitation. Circulation of heat transfer fluid from the PolyStat through the reaction vessel jacket was started, and fluid temperature heated to 60° C. Once PVA and salts dissolved, both solutions were charged to the reactor, one at a time, using a glass funnel. The digital overhead stirrer was powered on and the rpm set to a value to form appropriate droplet sizes upon organic phase addition. Temperature of the aqueous phase in the kettle was set to 70° C. The organic phase was prepared by adding benzoyl peroxide (BPO) to the divinylbenzene (DVB) in a 2 L Erlenmeyer flask and swirling until completely dissolved. 2,2,4-trimethylpentane and toluene were added to the flask, which was swirled to mix well. Once the temperature of the aqueous phase in the reactor reached 70° C., the organic phase was charged into the reactor using a narrow-necked glass funnel. Temperature of the reaction volume dropped upon the organic addition. A temperature program for the PolyStat was started, heating the reaction volume from to 77° C. over 30 minutes, 77 to 80° C. over 30 minutes, holding the temperature at 80° C. for 960 minutes, and cooling to 20° C. over 60 minutes.

TABLE-US-00002 TABLE I Aqueous Phase Composition Reagent Mass (g) Ultrapure water 1500.000 Poly(vinyl alcohol) (PVA) 4.448 Monosodium phosphate (MSP) 4.602 Disodium phosphate (DSP) 15.339 Trisodium phosphate (TSP) 9.510 Sodium nitrite 0.046 Total 1533.899

TABLE-US-00003 TABLE II Organic Phase Compositions CY14175 CY15077 Reagent Mass (g) Mass (g) Divinylbenzene, 63% (DVB) 508.751 498.383 2,2,4-trimethylpentane (Isooctane) 384.815 482.745 Toluene 335.004 222.404 Benzoyl peroxide, 98% (BPO) 3.816 3.738 Total (excluding BPO) 1228.571 1203.532

[0067] Work-up: reaction volume level in the reactor was marked. Overhead stirrer agitation was stopped, residual liquid siphoned out of the reactor, and the reactor filled to the mark with ultrapure water at room temperature. Overhead stirrer agitation was restarted and the slurry heated to 70° C. as quickly as possible. After 30 minutes, agitation was stopped and residual liquid siphoned out. Polymer beads were washed five times in this manner. During the final wash, the slurry temperature was cooled to room temperature. After the final water wash, polymer beads were washed with 99% isopropyl alcohol (IPA) in the same manner. 99% IPA was siphoned out and replaced with 70% IPA before transferring the slurry into a clean 4 L glass container. Unless noted otherwise, on an as-needed basis the polymer was steam stripped in a stainless steel tube for 8 hours, rewet in 70% IPA, transferred into DI water, sieved to obtain only the portion of beads having diameters between 300 and 60011m, and dried at 100° C. until no further weight loss on drying was observed.

[0068] Cumulative pore volume data for polymers CY14175 and CY15077, measured by nitrogen desorption isotherm and mercury intrusion porosimetry, respectively, are shown below in Tables III and IV, respectively.

TABLE-US-00004 TABLE III Nitrogen Desorption Isotherm Data for CY14175 Pore Diameter Pore size Cumulative Pore Range (Å) Diameter (Å) Volume (cm.sup.3/g) 1411.9-1126.5 1236.809577 0.018062878 1126.5-981.7 1043.979923 0.038442381  981.7-752.9 836.7828769 0.141559621  752.9-659.9 700.1024343 0.24336622  659.9-572.0 609.4657394 0.416511969  572.0-483.1 519.8089977 0.646318614  483.1-449.8 465.2234212 0.730406771  449.8-401.4 422.7246485 0.849167577  401.4-354.1 374.6289335 0.956165766  354.1-337.9 345.6019761 0.997336398  337.9-313.5 324.758962 1.0547802  313.5-290.8 301.2432086 1.09667858  290.8-262.8 275.299967 1.164042391  262.8-247.2 254.510376 1.199751164  247.2-233.6 240.0176376 1.228796957  233.6-220.1 226.435352 1.256631669  220.1-208.6 213.9982044 1.283063762  208.6-130.5 151.2300725 1.464027373  130.5-105.7 115.2567614 1.527062065  105.7-82.8 91.14860242 1.592486039  82.8-67.6 73.42901881 1.641003444  67.6-57.5 61.59836256 1.6763711  57.5-51.6 54.15491457 1.699539142  51.6-45.0 47.72291376 1.728282889  45.0-39.8 42.01726183 1.752728216  39.8-35.8 37.55877213 1.779016164  35.8-31.8 33.51596841 1.8086605  31.8-28.7 30.02327371 1.82963357  28.7-26.0 27.18773181 1.850084632  26.0-23.3 24.46989555 1.87529426  23.3-20.9 21.92055755 1.902736527  20.9-18.5 19.52461159 1.935789448  18.5-16.2 17.16324429 1.97779901

TABLE-US-00005 TABLE IV Mercury Intrusion Data for CY15077 Pore size Cumulative Diameter (Å) Intrusion (mL/g) 226299.0625 3.40136E−30 213166.0781 0.001678752 201295.1563 0.002518128 172635.8125 0.004364755 139538.0625 0.007554384 113120.7813 0.011919139 90542.36719 0.01645177 78733.25781 0.0203129 72446.375 0.022327403 60340.40234 0.027867284 48343.83984 0.035327822 39009.13672 0.040918175 32136.4082 0.04899035 25330.65625 0.063195683 20981.51563 0.079529688 16219.86426 0.108860672 13252.41211 0.141730919 10501.53613 0.193969816 8359.911133 0.262399256 6786.30127 0.345866203 5538.122559 0.438174427 4337.931152 0.563276172 3501.674805 0.681870878 2838.742188 0.804727197 2593.016846 0.865813017 2266.688965 0.938610673 1831.041748 1.056586146 1509.850708 1.163395643 1394.006104 1.21002543 1294.780151 1.257248282 1207.692627 1.293158531 1131.860962 1.326992273 1065.099976 1.35812819 953.1816406 1.405935764 884.0358887 1.445426106 823.5491333 1.478719592 770.9108276 1.510579824 722.4724731 1.537048101 684.6119995 1.564400196 672.187561 1.581117511 636.7885742 1.60271585 604.7248535 1.621845484 558.1287231 1.651492 518.2624512 1.678913713 483.5536499 1.708594561 453.5110779 1.735918999 426.9998474 1.755934 403.1251526 1.783603072 382.7776794 1.793849826 362.7162476 1.817784309 342.3734436 1.838774562 330.1105042 1.851493955 315.5238037 1.869742155 302.2973938 1.885128617 290.2946777 1.895119786 279.1246643 1.912378907 268.7442627 1.924305081 259.1106873 1.936048627 241.8737793 1.955100656 226.7678223 1.972970247 213.3626251 1.988123298 201.4908142 2.007521152 194.9888611 2.022114754 188.9506989 2.033871174 180.582901 2.035052776 172.8530121 2.050720692 164.9621735 2.062945843 157.8110657 2.071056128 151.1540375 2.082133055 143.9185333 2.096480608 138.4670563 2.106938839 132.8492737 2.119287968 129.5760345 2.126605988 126.5438614 2.126605988 124.2635574 2.132267475 120.8976135 2.141504765 117.3792267 2.150759459 114.791893 2.154810667 111.9475937 2.162935257 108.8830032 2.167646885 106.6480179 2.174062729 104.5217743 2.179908991 102.4295197 2.179908991 100.1580353 2.182951927 98.29322052 2.184018135 96.44822693 2.191127539 94.42159271 2.198545218 91.52587891 2.209161043 89.25807953 2.209312439 87.0777359 2.215425491 85.42358398 2.221472025 83.62612915 2.232139587 82.11174011 2.237514496 79.91614532 2.239231586 78.01462555 2.239560127 76.19993591 2.239560127 75.09249115 2.239560127 73.41201019 2.239560127 72.23709869 2.240245819 71.09960175 2.242422104 69.86301422 2.243849993 68.40761566 2.257676363 67.13697815 2.259181261 66.03359222 2.266284466 65.08189392 2.270181179 64.04368591 2.272682428 62.38490295 2.280714512 61.32764053 2.280714512 60.30379868 2.287917852 59.41370392 2.287917852 58.54679489 2.293802738 57.79866409 2.297607183 56.88977814 2.299046278 55.9213295 2.302111387 54.98665237 2.303381443

Example 2: Polymer Modification CY15065

[0069] 250 mL base polymer CY14175, wetted in DI water, was added to a 500 mL jacketed glass reactor which was equipped with a Teflon coated agitator and RTD probe. 90 mL excess DI water was added to the reactor, and the slurry mixed at 90 RPM. Reaction temperature was set to 20° C. Three separate additions were prepared; 1.4 g ammonium persulfate in 14 mL DI water, 0.7 g N-vinylpyrrolidinone in 21 mL DI water, and 1.5 g N,N,N,N-tetramethylethylenediamine in 7 mL DI water. Reaction temperature setpoint was increased to and monitored closely. Ammonium persulfate solution was added once reaction temperature reached 30° C. N,N,N,N-tetramethylethylenediamine solution was added once reaction temperature reached 35° C. N-vinylpyrrolidinone solution was added once reaction temperature reached 39° C. Reaction was then maintained at 40° C. for 2 hours, before decreasing temperature to 25° C.

[0070] Work-up: reaction volume level in the reactor was marked. Overhead stirrer agitation was stopped, residual liquid siphoned out of the reactor, and the reactor filled to the mark with ultrapure water at room temperature. Overhead stirrer agitation was restarted. After minutes, agitation was stopped and residual liquid siphoned out. Polymer beads were washed three times in this manner. The polymer was steam stripped in a stainless steel tube for 8 hours, rewet in 70% IPA, then transferred into DI water.

[0071] Cumulative pore volume data for polymers CY15065, measured by nitrogen desorption isotherm, is shown below in Table V.

TABLE-US-00006 TABLE V Nitrogen Desorption Isotherm Data for CY15065 Pore Diameter Pore size Cumulative Pore Range (Å) Diameter (Å) Volume (cm.sup.3/g) 3735.2-1226.3 1462.700326 0.005546248 1226.3-724.9 851.9599269 0.012549654  724.9-656.2 686.9797148 0.01499268  656.2-595.3 622.6438437 0.020898533  595.3-566.7 580.2249215 0.033282221  566.7-511.2 535.9524733 0.111667343  511.2-459.4 482.4242892 0.244617735  459.4-410.9 432.3534717 0.366033907  410.9-376.5 392.140848 0.468167046  376.5-334.5 352.8905481 0.63111569  334.5-298.7 314.4631626 0.753980937  298.7-291.1 294.7961544 0.786627632  291.1-273.8 281.8886994 0.844237668  273.8-256.6 264.6128479 0.91291745  256.6-228.9 241.1063341 0.990966112  228.9-224.9 226.9020278 1.007532081  224.9-209.7 216.7455697 1.046516069  209.7-141.7 162.0655488 1.225860688  141.7-103.9 116.5968304 1.329424083  103.9-82.9 90.79492123 1.388864147  82.9-69.3 74.73718587 1.431186463  69.3-59.3 63.39311832 1.465462484  59.3-50.9 54.36935206 1.495795233  50.9-44.8 47.39226606 1.521105084  44.8-39.5 41.71847385 1.544891234  39.5-35.3 37.12325172 1.568519104  35.3-31.4 33.1071979 1.594220982  31.4-28.2 29.60557504 1.614149255  28.2-25.6 26.73665706 1.633426358  25.6-22.8 24.01512381 1.656221583  22.8-20.5 21.49286805 1.680044553  20.5-18.2 19.15056378 1.707534945

Example 3: Removal from Whole Bovine Blood in a Recirculation Model

[0072] Purified proteins were added to 300 mL 3.8% citrated whole bovine blood (Lampire Biologicals) at expected clinical concentrations and recirculated through a 20 mL polymer-filled device or control (no bead) device at a flow rate of 140 mL/min for five hours. Proteins and initial concentrations were: S100A8 at 50 ng/mL, complement C5a at 25 ng/mL, procalcitonin at 16 ng/mL, HMGB-1 at 100 ng/mL, and SPE B at 100 ng/mL. Plasma was analyzed by enzyme-linked immunosorbent assay (ELISA) following manufacturer instructions (S100, and C5a, duosets (R&D Systems); procalcitonin (Sigma), HMGB-1 (Chondrex ELISA); and toxins (Toxin Technologies). Removal data from experiments using polymer CY15065 are shown below in FIG. 1 and FIG. 2 for DAMPs and PAMPs, respectively. For brevity, CY15065 is denoted ‘CS’ in the figure legends. Removal data from experiments using polymer CY15077 are shown below in FIG. 3 and FIG. 4 for DAMPs and PAMPs, respectively.