ANTITHROMBOGENIC HOLLOW FIBER MEMBRANES AND FILTERS

Abstract

The invention relates to extracorporeal blood circuits, and components thereof (e.g., hollow fiber membranes, potted bundles, and blood tubing), including 0.005% to 10% (w/w) surface modifying macromolecule. The extracorporeal blood circuits have an antithrombogenic surface and can be used in hemofiltration, hemodialysis, hemodiafiltration, hemoconcentration, blood oxygenation, and related uses.

Claims

1. (canceled)

2. An extracorporeal blood circuit comprising a blood tubing and an array of hollow fiber membranes, wherein the blood tubing, the hollow fiber membrane, or both comprise a base polymer admixed with from 0.005% to 10% (w/w) of a surface modifying macromolecule described by formula (VII):
F.sub.T—[B—(Oligo)].sub.n—B—F.sub.T,  (VII), wherein (i) Oligo is polypropylene oxide having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is a hard segment formed from hexamethylene diisocyanate; (iii) FT is a polyfluoroorgano group; and (iv) n is an integer from 1 to 10.

3. The extracorporeal blood circuit of claim 2, wherein the base polymer associated with said hollow fiber membrane comprises a polysulfone or a polyacrylonitrile.

4. The extracorporeal blood circuit of claim 2, wherein the base polymer associated with said blood tubing comprises polyvinyl chloride.

5. The extracorporeal blood circuit of claim 2, wherein the blood tubing, the hollow fiber membrane, or both are antithrombogenic when contacted with blood, as measured by γ-count.

6. The extracorporeal blood circuit of claim 2, wherein thrombi deposition at the blood contacting surface is reduced by at least 10% compared to an extracorporeal blood circuit not having said surface modifying macromolecule when contacted with blood, or wherein said hollow fiber membrane reduces adverse advents in a subject receiving blood passing through said extracorporeal blood circuit.

7. The extracorporeal blood circuit of claim 2, wherein the extracorporeal blood circuit has an increased average functional working life of at least 125% when contacted with blood compared to an extracorporeal blood circuit not having said surface modifying macromolecule.

8. The extracorporeal blood circuit of claim 2, wherein the extracorporeal blood circuit contains less than a standard dose of anticoagulant during dialysis therapy.

9. The extracorporeal blood circuit of claim 8, wherein the extracorporeal blood circuit contains no anticoagulant during dialysis therapy.

10. The extracorporeal blood circuit of claim 2, further comprising a citrate-containing anticoagulant.

11. The extracorporeal blood circuit of claim 2, further comprising a drip chamber.

12. The extracorporeal blood circuit of claim 8, wherein the drip chamber comprises a base polymer admixed with from 0.005% to 10% (w/w) of the surface modifying macromolecule of formula (VII).

13. A dialysis kit comprising a hollow fiber membrane, a potted bundle, a dialysis filter, and/or blood tubing, wherein one or more of the hollow fiber membrane, potted bundle, dialysis filter, and/or blood tubing comprises a base polymer admixed with from 0.005% to 10% (w/w) of a surface modifying macromolecule described by formula (VII):
F.sub.T—[B—(Oligo)].sub.n—B—F.sub.T,  (VII), wherein (i) Oligo is polypropylene oxide having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is a hard segment formed from hexamethylene diisocyanate; (iii) FT is a polyfluoroorgano group; and (iv) n is an integer from 1 to 10.

14. A potted bundle of hollow fiber membranes within an encasement comprising: (a) an array of hollow fiber membranes, said array of hollow fiber membranes having lumens, a first set of fiber ends, and a second set of fiber ends; (b) said first set of fiber ends being potted in a potting resin which defines a first internal wall near a first end of the encasement; and (c) said second set of fiber ends being potted in a potting resin which defines a second internal wall near a second end of the encasement, wherein said lumens of said hollow fiber membranes provide a path for the flow of blood from said first internal wall to said second internal wall, wherein said potting resin comprises from 0.005% to 10% (w/w) surface modifying macromolecule, and wherein said surface modifying macromolecule is described by:
(1)
F.sub.T—(oligo)—F.sub.T  (I) wherein F.sub.T is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da and oligo is an oligomeric segment; or ##STR00010## wherein (i) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da covalently attached to LinkB; (ii) C is a chain terminating group; (iii) Oligo is an oligomeric segment; (iv) LinkB is a coupling segment; and (v) a is an integer greater than 0; or
(3)
F.sub.T—[B—(oligo)].sub.n—B—F.sub.T  (III) wherein (i) B comprises a urethane; (ii) oligo comprises polypropylene oxide, polyethylene oxide, or polytetramethylene oxide; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 1 to 10; or
(4)
F.sub.T—[B—A].sub.n—B—F.sub.T  (IV) wherein (i) A comprises hydrogenated polybutadiene, poly (2,2 dimethyl-1,3-propylcarbonate), polybutadiene, poly (diethylene glycol)adipate, poly (hexamethylene carbonate), poly (ethylene-co-butylene), neopentyl glycol-ortho phthalic anhydride polyester, diethylene glycol-ortho phthalic anhydride polyester, 1,6-hexanediol-ortho phthalic anhydride polyester, or bisphenol A ethoxylate; (ii) B comprises a urethane; (iii) F.sub.T is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da, and (iv) n is an integer from 1 to 10; or ##STR00011## wherein (i) A comprises hydrogenated polybutadiene (HLBH), poly (2,2 dimethyl-1,3-propylcarbonate) (PCN), polybutadiene (LBHP), polytetramethylene oxide (PTMO), polypropylene oxide (PPO), diethyleneglycol-orthophthalic anhydride polyester (PDP), hydrogenated polyisoprene (HHTPI), poly(hexamethylene carbonate), poly(2-butyl-2-ethyl-1,3-propyl carbonate), or hydroxylterminated polydimethylsiloxane (C22); (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) each FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer between 0 to 10; or
(6)
F.sub.T-[B-(Oligo)].sub.n—B—F.sub.T  (VII) wherein (i) Oligo is an oligomeric segment comprising polypropylene oxide, polyethylene oxide, or polytetramethyleneoxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is formed from 3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylene bis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl) isocyanate; toluene-2,4 diisocyanate; m-tetramethylxylene diisocyanate; or hexamethylene diisocyanate; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 1 to 10; or ##STR00012## wherein (i) A is an oligomeric segment comprising polypropylene oxide, polyethylene oxide, polytetramethyleneoxide, or mixtures thereof, and having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10; or
(8)
F.sub.T-[B-(Oligo)].sub.n—B—F.sub.T  (IX) wherein (i) Oligo comprises a polycarbonate polyol having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is formed from 3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylene bis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl) isocyanate; toluene-2,4 diisocyanate; m-tetramethylxylene diisocyanate; or hexamethylene diisocyanate; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 1 to 10; or ##STR00013## wherein (i) A is an oligomeric segment comprising a polycarbonate polyol having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10; or ##STR00014## wherein (i) A comprises a first block segment selected from the group consisting of polypropylene oxide, polyethylene oxide, polytetramethyleneoxide, and mixtures thereof, and a second block segment comprising a polysiloxane or polydimethylsiloxane, wherein A has a theoretical molecular weight of from 1,000 to 5,000 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10; or
(11)
F.sub.T-[B—A].sub.n—B—F.sub.T  (XII) wherein (i) A comprises hydrogenated polybutadiene (HLBH), polybutadiene (LBHP), hydrogenated polyisoprene (HHTPI), or polystyrene and has a theoretical molecular weight of from 750 to 3,500 Daltons; (ii) B is formed from 3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylene bis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl) isocyanate; toluene-2,4 diisocyanate; m-tetramethylxylene diisocyanate; or hexamethylene diisocyanate; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 1 to 10; or ##STR00015## wherein (i) A comprises hydrogenated polybutadiene (HLBH), polybutadiene (LBHP), hydrogenated polyisoprene (HHTPI), or polystyrene and has a theoretical molecular weight of from 750 to 3,500 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) F.sub.T is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10; or ##STR00016## wherein (i) A is a polyester having a theoretical molecular weight of from 500 to 3,500 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10.

15. The potted bundle of claim 14, wherein said surface modifying macromolecule has a structure described by formula (VII), and wherein n is an integer from 1 to 3.

16. The potted bundle of claim 14, wherein said potting resin comprises a cross-linked polyurethane formed from 4,4′-methylene bis(cyclohexyl isocyanate), 2,2′-methylene bis(phenyl) isocyanate, 2,4′-methylene bis(phenyl) isocyanate, or 4,4′-methylene bis(phenyl) isocyanate.

17. The potted bundle of claim 14, wherein said surface modifying macromolecule is selected from the group consisting of VII-a as shown in FIG. 2, VIII-a as shown in FIG. 3, IX-a as shown in FIG. 7, XI-a as shown in FIG. 10, VIII-d as shown in FIG. 6, XI-b as shown in FIG. 11, XIV-a as shown in FIG. 18, and XIV-b as shown in FIG. 19.

18. The potted bundle of claim 14, wherein the encasement is part of a blood purification device, a hemodialysis device, a hemodiafiltration device, a hemofiltration device, a hemoconcentration device, or an oxygenator device.

19. A dialyzer comprising the potted bundle of claim 14.

20. An extracorporeal blood circuit comprising the potted bundle of claim 14.

21. A spinning solution for preparing a hollow fiber membrane, said spinning solution comprising (i) from 57% to 87% (w/w) of an aprotic solvent; (ii) from 10% to 25% (w/w) of base polymer; (iii) from 0.005% to 8% (w/w) of surface modifying macromolecule; and (iv) from 3% to 10% (w/w) of hydrophilic pore forming agent, wherein said aprotic solvent is selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone, and mixtures thereof, and comprises less than 25% (v/v) of a low boiling solvent selected from tetrahydrofuran, diethylether, methylethyl ketone, acetone, and mixtures thereof; and wherein said surface modifying macromolecule has a structure described by:
(1)
F.sub.T-(oligo)—F.sub.T  (I) wherein F.sub.T is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da and oligo is an oligomeric segment; or ##STR00017## wherein (i) F.sub.T is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da covalently attached to LinkB; (ii) C is a chain terminating group; (iii) Oligo is an oligomeric segment; (iv) LinkB is a coupling segment; and (v) a is an integer greater than 0; or
(3)
F.sub.T-[B-(oligo)].sub.n—B—F.sub.T  (III) wherein (i) B comprises a urethane; (ii) oligo comprises polypropylene oxide, polyethylene oxide, or polytetramethylene oxide; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 1 to 10; or
(4)
F.sub.T-[B—A].sub.n—B—F.sub.T  (IV) wherein (i) A comprises hydrogenated polybutadiene, poly (2,2 dimethyl-1,3-propylcarbonate), polybutadiene, poly (diethylene glycol)adipate, poly (hexamethylene carbonate), poly (ethylene-co-butylene), neopentyl glycol-ortho phthalic anhydride polyester, diethylene glycol-ortho phthalic anhydride polyester, 1,6-hexanediol-ortho phthalic anhydride polyester, or bisphenol A ethoxylate; (ii) B comprises a urethane; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da, and (iv) n is an integer from 1 to 10; or ##STR00018## wherein (i) A comprises hydrogenated polybutadiene (HLBH), poly (2,2 dimethyl-1,3-propylcarbonate) (PCN), polybutadiene (LBHP), polytetramethylene oxide (PTMO), polypropylene oxide (PPO), diethyleneglycol-orthophthalic anhydride polyester (PDP), hydrogenated polyisoprene (HHTPI), poly(hexamethylene carbonate), poly(2-butyl-2-ethyl-1,3-propyl carbonate), or hydroxylterminated polydimethylsiloxane (C22); (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) each FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer between 0 to 10; or
(6)
F.sub.T-[B-(Oligo)].sub.n—B—F.sub.T  (VII) wherein (i) Oligo is an oligomeric segment comprising polypropylene oxide, polyethylene oxide, or polytetramethyleneoxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is formed from 3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylene bis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl) isocyanate; toluene-2,4 diisocyanate; m-tetramethylxylene diisocyanate; or hexamethylene diisocyanate; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 1 to 10; or ##STR00019## wherein (i) A is an oligomeric segment comprising polypropylene oxide, polyethylene oxide, polytetramethyleneoxide, or mixtures thereof, and having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10; or
(8)
F.sub.T-[B-(Oligo)].sub.n—B—F.sub.T  (IX) wherein (i) Oligo comprises a polycarbonate polyol having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is formed from 3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylene bis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl) isocyanate; toluene-2,4 diisocyanate; m-tetramethylxylene diisocyanate; or hexamethylene diisocyanate; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 1 to 10; or ##STR00020## wherein (i) A is an oligomeric segment comprising a polycarbonate polyol having a theoretical molecular weight of from 500 to 3,000 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10; or ##STR00021## wherein (i) A comprises a first block segment selected from the group consisting of polypropylene oxide, polyethylene oxide, polytetramethyleneoxide, and mixtures thereof, and a second block segment comprising a polysiloxane or polydimethylsiloxane, wherein A has a theoretical molecular weight of from 1,000 to 5,000 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10; or
(11)
F.sub.T-[B—A].sub.n—B—F.sub.T  (XII) wherein (i) A comprises hydrogenated polybutadiene (HLBH), polybutadiene (LBHP), hydrogenated polyisoprene (HHTPI), or polystyrene and has a theoretical molecular weight of from 750 to 3,500 Daltons; (ii) B is formed from 3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylene bis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl) isocyanate; toluene-2,4 diisocyanate; m-tetramethylxylene diisocyanate; or hexamethylene diisocyanate; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 1 to 10; or ##STR00022## wherein (i) A comprises hydrogenated polybutadiene (HLBH), polybutadiene (LBHP), hydrogenated polyisoprene (HHTPI), or polystyrene and has a theoretical molecular weight of from 750 to 3,500 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10; or ##STR00023## wherein (i) A is a polyester having a theoretical molecular weight of from 500 to 3,500 Daltons; (ii) B is formed by reacting a triisocyanate with a diol of A, wherein the triisocyanate is selected from the group consisting of hexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; (iii) FT is a polyfluoroalkyl having a theoretical molecular weight of between 100-1,500 Da; and (iv) n is an integer from 0 to 10.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0127] FIG. 1 is a schematic of an exemplary extracorporeal blood circuit.

[0128] FIG. 2 is an illustration depicting surface modifying macromolecule VII-a of the invention.

[0129] FIG. 3 is an illustration depicting surface modifying macromolecule VIII-a of the invention.

[0130] FIG. 4 is an illustration depicting surface modifying macromolecule VIII-b of the invention.

[0131] FIG. 5 is an illustration depicting surface modifying macromolecule VIII-c of the invention.

[0132] FIG. 6 is an illustration depicting surface modifying macromolecule VIII-d of the invention.

[0133] FIG. 7 is an illustration depicting surface modifying macromolecule IX-a of the invention.

[0134] FIG. 8 is an illustration depicting surface modifying macromolecule X-a of the invention.

[0135] FIG. 9 is an illustration depicting surface modifying macromolecule X-b of the invention.

[0136] FIG. 10 is an illustration depicting surface modifying macromolecule XI-a of the invention.

[0137] FIG. 11 is an illustration depicting surface modifying macromolecule XI-b of the invention.

[0138] FIG. 12 is an illustration depicting surface modifying macromolecule XII-a of the invention.

[0139] FIG. 13 is an illustration depicting surface modifying macromolecule XII-b of the invention.

[0140] FIG. 14 is an illustration depicting surface modifying macromolecule XIII-a of the invention.

[0141] FIG. 15 is an illustration depicting surface modifying macromolecule XIII-b of the invention.

[0142] FIG. 16 is an illustration depicting surface modifying macromolecule XIII-c of the invention.

[0143] FIG. 17 is an illustration depicting surface modifying macromolecule XIII-d of the invention.

[0144] FIG. 18 is an illustration depicting surface modifying macromolecule XIV-a of the invention.

[0145] FIG. 19 is an illustration depicting surface modifying macromolecule XIV-b of the invention.

[0146] FIGS. 20A and 20B show an exemplary hollow fiber and an exemplary bundle of fibers. FIG. 20A is a scanning electron micrograph of a single hollow fiber depicting the outer surface, the inner surface, and the fiber thickness. FIG. 20B is an illustration of bundle of hollow fibers arranged in the header part of the dialyzer cartridge with the potting area (areas indicated by arrow labeled “Potted area untreated” in the inner lumen of the dialyzer cartridge, including the thick dotted line within the inner lumen of the dialyzer cartridge and the areas marked with an X) exposed.

[0147] FIG. 21 is a photograph of an exemplary configuration for in vitro blood loop analysis and gamma probe reading.

[0148] FIG. 22 is a photograph of hemofilters after a blood loop procedure.

[0149] FIG. 23 is a graph showing average header pressure (APr) and γ-count profiles for control versus VII-a and XI-a (n=6).

[0150] FIGS. 24A and 24B are photographs of hemofilters from Experiment 4 in Example 5, as described herein. FIG. 24A shows thrombi formed at the inlet of the hemofilters. FIG. 24B shows thrombi formed at the outlet of the hemofilters.

[0151] FIGS. 25A-25C are photographs from Experiment 4 in Example 5, as described herein, which show extensive coagulation. FIG. 25A shows thrombi formed at the inlet of the control hemofilter (no surface modification). FIG. 25B shows thrombi formed at the outlet of the control hemofilter (no surface modification). FIG. 25C shows residue on the sieve after draining blood.

[0152] FIGS. 26A-26D are photographs of hemofilters from Experiment 5 in Example 5, as described herein. FIG. 26A shows thrombi formed at the inlet of the hemofilters. FIG. 26B shows thrombi formed at the outlet of the hemofilters. A control hemofilter showed complete occlusion, where close-ups are provided for the inlet (FIG. 26C) and outlet (FIG. 26D) for control.

[0153] FIG. 27 shows photographs of the inlet of hemofilters from Experiment 1-6 in Example 5, as described herein. Photographs are shown for control (C, top row), VII-a (middle row), and XI-a (bottom row).

[0154] FIGS. 28A and 28B are photographs of hemofilters from Experiment 1 in Example 5, as described herein. FIG. 28A shows thrombi formed at the inlet of the hemofilters. FIG. 28B shows thrombi formed at the outlet of the hemofilters.

[0155] FIGS. 29A and 29B are photographs of hemofilters from Experiment 2 in Example 5, as described herein. FIG. 29A shows thrombi formed at the inlet of the hemofilters. FIG. 29B shows thrombi formed at the outlet of the hemofilters.

[0156] FIGS. 30A and 30B are photographs of hemofilters from Experiment 3 in Example 5, as described herein. FIG. 30A shows thrombi formed at the inlet of the hemofilters. FIG. 30B shows thrombi formed at the outlet of the hemofilters. FIGS. 31A and 31B are photographs of hemofilters from Experiment 6 in Example 5, as described herein. FIG. 31A shows thrombi formed at the inlet of the hemofilters. FIG. 31B shows thrombi formed at the outlet of the hemofilters.

DETAILED DESCRIPTION

[0157] The methods and compositions of the invention feature antithrombogenic, extracorporeal blood circuits and components thereof (hollow fiber membranes, potting materials, and blood tubing, etc.) including a synthetic base polymer admixed with from 0.005% to 10% (w/w) surface modifying macromolecule. The extracorporeal blood circuit components of the invention can be used in therapies such as hemodialysis, hemofiltration, hemoconcentration, hemodiafiltration, and oxygenation, for the treatment of patients with renal failure, fluid overload, toxemic conditions, cardiac failure, or cardiac distress. They can also be used for protein separation, plasma filtration, and blood separation.

[0158] The selection of the combination of a particular surface modifying macromolecule (SMM) and a particular base polymer can be determined by the methods and protocols described herein. First, the type and amount of SMM to be added to base polymer is determined in part by whether the admixture forms a single stable phase, where the SMM is soluble in the base polymer (e.g., separation of the admixture to form two or more distinct phases would indicate an unstable solution). Then, the compatibility of the admixture can be tested by various known analytical methods. The surface of the admixture as a film or as a fiber can be analyzed by any useful spectroscopic method, such as X-ray photoelectron spectroscopy (XPS) with an elemental analysis (EA). Data from XPS could indicate the extent of modification of the surface by migrating SMMs and data from EA can indicate the extent of modification of the bulk material. Stable admixtures can then be tested to determine the thrombogenicity of the surface under various conditions.

Extracorporeal Blood Circuits

[0159] The invention features compositions and methods for reducing the activation of blood components in contact with any of the parts of an extracorporeal blood circuit (e.g., the blood tubing, the hollow fiber membrane, the potted surface, or the ends of the filter into which the blood tubing attaches) by including a surface modifying macromolecule in one or more of the parts of an extracorporeal blood circuit. The hemodialysis machine pumps the dialysate as well as the patient's blood through a dialyzer. The blood and dialysate are separated from each other by a semipermeable hollow fiber membrane, the blood passing through the extracorporeal blood circuit of a hemodialysis machine and the dialysate passing through the dialysate circuit of a hemodialysis machine. Any one or more of the blood-contacting surfaces in the extracorporeal blood circuit of a dialysis machine may be treated with a surface modifying macromolecule as described herein to produce an antithrombogenic surface. The medical separatory device of the invention can be an artificial kidney of the hollow fiber type, or a related device, such as hemofilter, blood oxygenator, or other separator of impurities from a body.

[0160] The devices include a dialysate chamber, and a pair of spaced apart drip chambers attached to each end of the dialysate chamber. Each drip chamber terminates in a port leading to blood tubing, which ultimately exit and enter a subject undergoing hemodialysis. The dialysate chamber is provided with conventional inlet and outlet dialysate ports and surrounds a bundle of axially extending hollow semipermeable fibers.

[0161] The fiber bundle contains thousands (e.g., 3,000 to 30,000) individual fibers which may formed from cellulose (e.g., made by deacetylating cellulose acetate as taught in U.S. Pat. No. 3,546,209), cellulose acetate, cellulose ester, polyesters, polyamides, polysulfone, or any other hollow fiber membrane known in the art. Typically, the fibers are fine and of capillary size which typically ranges from about 150 to about 300 microns internal diameter with a wall thickness in the range of about 20 to about 50 microns.

[0162] Referring to FIG. 1, a typical extracorporeal blood circuit 100 includes tubing through which the blood flows and components for filtering and performing dialysis on the blood.

[0163] Blood flows from a patient 105 through arterial tubing 110. Blood drips into a drip chamber 115 where a connecting tube from the drip chamber 115 attaches to a sensor 125 on a hemodialysis machine that determines the pressure of the blood on the arterial side of the extracorporeal blood circuit. A pump 120 forces the blood to continue along the path through the extracorporeal blood circuit. A dialyzer 130 separates waste products from the blood. After passing through the dialyzer 130, the blood flows through venous tubing 140 into a second drip chamber 150. The drip chamber 150 can function as an air trap. Free gases in the blood may be able to escape into the drip chamber 150 before the blood continues to the patient. A sensor 170 is in communication with air in the drip chamber through tube 165. The sensor 170 can determine the pressure on the venous side of the extracorporeal blood circuit.

[0164] Heparin 160 can be added to the blood in the drip chamber 115. When blood is exposed to oxygen, the blood begins to clot. The drip chamber 150 may include a filter for preventing any clots from exiting the drip chamber 150 and entering the patient 105. The blood continues from the drip chamber through venous tubing 180 and through a bubble detector 175 before returning to the patient 105.

[0165] Any of the blood contacting components of the extracorporeal blood circuit can be modified with a surface modifying macromolecule as described herein to produce an antithrombogenic surface. The extracorporeal blood circuit can be useful for hemodialysis, as explained above, and can also be applied for other therapies involving hemoconcentration, oxygenation, protein separation, plasma filtration, and blood separation.

Surface Modifying Macromolecule

[0166] Illustrations of VII-a to XI-b are shown in FIGS. 2-19. For all of the SMMs, the number of soft segments can be any integer or non-integer to provide the approximate theoretical molecule weight of the soft segment. For compounds of formulas (XII) and (XIII), the number of hydrogenated alkyl moieties can be any integer or non-integer to provide the approximate theoretical molecule weight of the soft segment. Examples of XII-a, XII-b, XIII-a, XIII-b, and XIII-c include SMM's, where x=0.225, y=0.65, and z=0.125. For compounds of formula (XI), the number of first block segments and second block segments can be any integer or non-integer to provide the approximate theoretical molecule weight of the soft segment. Examples of XI-a and XI-b include SMM's, where m=12 to 16 and n=12 to 18.

[0167] Table 1 shows the SMM distribution of hard segments, soft segments, and fluorinated end-groups (F end groups). Table 1 also shows the ratio of hard segment to soft segment, which range from 0.16 to 1.49.

TABLE-US-00001 TABLE 1 Ratio: MW % Soft Seg % Hard Seg % F End Hard/Soft SMM's Theo (Diol) (Isocyanate) Groups segment VII-a 2016 47.21 16.68 36.11 0.35 VIII-a 3814 25.78 30.59 43.63 1.19 VIII-b 3545 27.73 31.18 41.09 1.12 VIII-c 3870 25.64 37.01 37.35 1.44 VIII-d 4800 39.59 30.07 30.34 0.76 IX-a 3515 56.89 22.39 20.72 0.39 X-a 4075 23.74 35.42 40.84 1.49 X-b 4861 40.35 29.69 29.96 0.74 XI-a 5562 53.94 19.87 26.19 0.37 XI-b 5900 50.85 24.46 24.69 0.48 XII-a 3785 64.60 13.90 22.00 0.22 XII-b 6372 76.20 12.40 11.40 0.16 XIII-a 5259 46.18 22.18 31.64 0.48 XIII-b 5536 43.87 26.07 30.06 0.59 XIII-c 5198 46.72 21.26 32.01 0.46 XIII-d 5227 40.55 27.61 25.38 0.68 XIV-a 5097 38.76 28.59 32.65 0.74 XIV-b 5450 46.79 26.48 26.72 0.57

Hollow Fiber Membranes

[0168] Hydrophobic polymers have been a popular choice as polymeric materials in hollow fiber spinning e.g. polysulfones, aromatic polyimides, and amides. Any base polymers described herein can be used as a hydrophobic polymer for hollow fiber spinning. For hemodialysis, hollow fiber membranes are often made from natural cellulose, cellulose derivatives (e.g. cellulose di- or tri-acetate), or synthetic polymers (e.g., polysulfones, polyacrylonitrile, or polyamides, among others), which are selected for their biocompatibility. However, none of these materials have proven to provide the desired antithrombogenicity that is needed to reduce the reliance upon anticoagulants.

[0169] In particular, polysulfones (PS) are synthetic hydrophobic polymers that are widely used in hollow fiber membranes due to their excellent fiber spinning properties and biocompatibility. However, pure hydrophobic PS cannot be used directly for some applications, e.g., dialysis membranes, as this will decrease the wetting characteristics of the membrane in an aqueous environment and affect the wetting properties essential for the clearance of toxins. To address this problem, polyvinylpyrrolidone (PVP) is typically added to the PS as a pore forming hydrophilic polymer, most of which dissolves and is lost during the hollow fiber spinning process and hydrophilically modify the PS to make it suitable as a semipermeable membrane. Although some of the PVP remains in the fiber this is not sufficient as clotting still occurs during dialysis requiring heparin anticoagulants or saline flushes of the dialyzer to clear the blockage.

[0170] The methods and compositions of the invention address these issues by including a surface modifying macromolecule in the hollow fiber membrane. The surface modifying macromolecule migrates to the surface of the hollow fiber membrane (both inner lumen and outer surface during the spinning process) to occupy the top 10 microns of the hollow fiber.

Manufacture of Hollow Fiber Membranes

[0171] A porous hollow fiber membrane adapted for use in the methods of the invention, e.g., kidney dialysis, should be capable of removing low molecular weight uremic substances while retaining useful substances such as albumin. Such porous hollow fiber membranes are produced using processes adapted to accurately control the pore diameter in the porous hollow fiber membrane. The pore diameter of the hollow fiber membrane can depend upon the composition of the spinning solution, composition of the core solution, draft ratio, liquid composition for membrane coagulation, temperature, humidity, among other factors. The composition of the core solution is an important factor as the combination and the mixing ratio of the solvent and the nonsolvent in relation to the membrane-constituting polymer determine the coagulation rate, and hence, the morphology of the interior surface of the hollow fiber membrane.

[0172] Various processes are known in the art for the production of hollow fiber membranes (see, for example, U.S. Pat. Nos. 6,001,288; 5,232,601; 4,906,375; and 4,874,522, each of which is incorporated herein by reference) including (i) processes wherein a tube-in-tube type orifice is used and the spinning solution is extruded from the outer tube (i.e., from the annular space defined between the inner and outer tubes) and the core solution is ejected from the inner tube; (ii) by extruding the spinning solution into air, allowing the filament to fall down by gravity, passing the filament through a coagulant bath for coagulation, and washing and drying the filament (dry-wet spinning); (iii) by using a bath including an upper layer of a non-coagulating solution and a lower layer of a coagulating solution, and extruding the spinning solution directly into the non-coagulating solution and passing the filament through the coagulating solution; (iv) by using a bath including an upper layer of a coagulating solution and a lower layer of a non-coagulating solution, and extruding the spinning solution directly into the non-coagulating solution and passing the filament through the coagulating solution; (v) by extruding the spinning solution directly into a non-coagulating solution and passing the filament along the boundary between the coagulating solution and the non-coagulating solution; and (vi) by extruding the spinning solution from the orifice surrounding a non-coagulating solution and passing the filament through a coagulating solution.

[0173] In such processes, pore diameter of the hollow fiber membrane is controlled by adjusting the rate and the extent of the coagulation of the extruded spinning solution through the use of a coagulation solution which promotes the coagulation of the spinning solution (a non solvent for the spinning solution) and a non-coagulation solution which inhibits the coagulation of the spinning solution (a solvent for the spinning solution) either separately or in a mixture.

[0174] For use in the compositions and methods of the invention, a typical spinning solution will include a base polymer (e.g., a polysulfone), a hydrophilic pore forming agent (e.g., polyvinylpyrrolidone, ethylene glycol, alcohols, polypropylene glycol, or polyethylene glycol), a solvent for the polymer (i.e., dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone, or mixtures thereof), and a surface modifying macromolecule.

[0175] The hollow fiber membranes of the invention can be produced, for example, by extruding the spinning solution from a tube-in-tube type orifice of the spinner in a coagulation solution to form the hollow fiber membrane. The polymer-containing spinning solution is extruded from the outer tube (i.e., annular space defined between the inner and outer tubes) to form a cylindrical filament having an inner bore and the core solution for coagulation of the spinning solution is extruded from the inner tube of the orifice into the inner bore of the filament. In this process, the filament may be directly extruded into the coagulation solution, or extruded into air and then drawn to the coagulation solution. As noted above, the spinning solution is supplemented with a hydrophilic pore forming agent and a surface modifying macromolecule and the resulting hollow fiber membrane contains the surface modifying macromolecule on its surface.

[0176] The viscosity of the spinning solution can be modified as needed. For example, by adding a thickener (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or polypropylene glycol) to increase viscosity, or by adding an aprotic low boiling solvent (i.e., tetrahydrofuran, diethylether, methylethyl ketone, acetone, or mixtures thereof) to the spinning solution to reduce viscosity. An aprotic low boiling solvent may also be included to increase the solubility of the surface modifying macromolecule in the spinning solution.

[0177] The spinning solution is extruded to form the shape of a filament which is precipitated using a coagulating solution, resulting in formation of the desired porous hollow fiber. The coagulating solution may include a nonsolvent or a mixture of a nonsolvent and a solvent for the base polymer of the spinning solution. Typically the nonsolvent used for the coagulating solution is an aqueous solution.

[0178] After the porous hollow fiber is formed, it may be passed through a second rinsing bath. The porous hollow fiber may then be processed further, e.g., cutting, bundling, and drying, and made into a porous hollow fiber membrane suitable, e.g., for use in a dialyzer.

Potted Bundles of Hollow Fiber Membranes

[0179] The invention features compositions and methods for reducing the activation of blood components in contact with the potting material of a filter (e.g., as part of a blood purification device, such as a hemodialysis, hemodiafiltration, hemofiltration, hemoconcentration, or oxygenator device) by including a surface modifying macromolecule in the potting material at the time that the hollow fiber membranes are potted.

[0180] In order to filter or permeate with hollow fiber membranes, a large number of thin hollow fibers must be potted (i.e., fixed) to a header of an encasement such that their inner surfaces are each completely sealed to the inside of the encasement but their lumens are open to pass blood from a first potted end to a second potted end of a filter. Potting materials are an important integral part of blood purification filter as these are cured polymer materials (usually a polyurethane) that act as a glue to hold the hollow membrane fiber bundles (e.g., numbering up to 20,000) firmly at the ends inside the cartridge of the dialyzer, while at the same time leaving the ends of the hollow fibers open to allow for passage of blood into the fibers for filtration purposes. Holding these numerous fiber bundles inside an encasement and ensuring that each and every hollow fiber is properly aligned along the axis of the cartridge is a necessary step in a filter assembly.

[0181] The potted walls formed at either end of a blood purification filter is an area prone to turbulent blood flow under shear conditions which causes activation of the blood components and first initiate thrombus formation which can adversely affect blood flow and filter function. This problem is not ameliorated by the use of antithrombogenic hollow fiber membranes as the ends of the hollow fiber membranes are only a very small portion of a typical wall surface (e.g., ca. 18% of the wall surface), followed by hollow lumen (e.g., ca. 16% of the wall surface), and a large amount of potting material (e.g., ca. 66% of the wall surface). There is a need to address this larger area where dynamic blood flow takes place and where most of thrombus starts that may lead to occlusion of the filters. There is a need for hollow fiber membranes and blood filtration devices that have reduced thrombogenicity.

[0182] Potting materials can be thermoset polymers formed by mixing two or more components to form a cured resin (i.e., typically a polyurethane). To produce an antithrombogenic potting material of the invention a surface modifying macromolecule is added to at least one of the components of the potting material prior to mixing to form the cured resin.

[0183] The surface modifying macromolecules can be incorporated into any potting material known in the art. For example, surface modifying macromolecules can be incorporated into polyurethane potting materials formed from an isocyanate-terminated prepolymer, the reaction product of a polyol and a polyisocyanate, and cured with one or more polyfunctional crosslinking agents have been described in the art. Potting materials that can be used in the methods, compositions, and dialysis systems of the invention include those described in U.S. Pat. Nos. 3,362,921; 3,483,150; 3,362,921; 3,962,094; 2,972,349; 3,228,876; 3,228,877; 3,339,341; 3,442,088; 3,423,491; 3,503,515; 3,551,331; 3,362,921; 3,708,071; 3,722,695; 3,962,094; 4,031,012; 4,256,617; 4,284,506; and 4,332,927, each of which is incorporated herein by reference.

[0184] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

EXAMPLE 1

Illustration and Calculation of Potting Area

[0185] FIG. 20A is a scanning electron micrograph of a single hollow fiber. FIG. 20B is an illustration of a hollow fiber bundle. FIGS. 20A-20B highlight the ability of the fiber bundle to provide an antithrombogenic surface area when in contact with blood. Based upon the dimensions of the potted area and the fiber, it can be estimated that if only the hollow fiber membranes are modified as described herein, then only ˜18% of the header area occupied by the fibers (depicted by circles with thick lines within the dialyzer cartridge) is modified with the surface modifying macromolecules (SMM) for providing the antithrombogenic effect. This leaves ˜66% of the area including the potted part unmodified and prone to thrombus formation when in contact with blood during hemodialysis. Accordingly, this invention features a method of treating this ˜66% of the potted part (an integral part of the fiber) also with surface modifying macromolecules to obtain a header surface that is antithrombogenic, minimizes blood activation, reduces blood coagulation, and reduces the incidence of hemofilter occlusion.

EXAMPLE 2

Surface Modifying Macromolecule in Films of PS/PVP Polymer Blends

[0186] Films were prepared to demonstrate the surface composition in the mixtures from which the hollow fiber membranes of the invention can be made. A surface modifying macromolecule (SMM, 5 wt %), polysulfone (PS, 10 wt %) and polyvinylpyrrolidone (PVP, 5 wt %) were dissolved in a mixture of dimethylacetamide and tetrahydrofuran (ca. 80 wt %). Films having a thickness of 254 μm were cast on Teflon substrates and were then dried and analyzed for surface Fluorine and Nitrogen content. The results are provided in Table 2 for the four solution cast formulation films that were analyzed, each utilizing a different surface modifying macromolecule.

TABLE-US-00002 TABLE 2 XPS in PS/PVP/SMM Films EA of SMM (Surface) (Bulk) SMM # % F % N % F % N VIII-a 42.77 4.23 33.2 5.07 VIII-b 43.82 4.39 23.29 6.66 XI-a 37.34 4.93 15.94 3.9 XIII-a 42.75 4.05 20.63 3.49

[0187] The surface fluorine content is provided by the X-ray photoelectron spectroscopy (XPS) results for the four films, while the elemental analysis (EA) of the bulk (neat) SMM is provided for comparison. The difference in XPS and EA data for percent fluorine content results from the migration of the oligofluoro groups of the surface modifying macromolecule to the surface of the film. The percent nitrogen content at the surface reflects the presence of the hydrophilic urethane portion of the surface modifying macromolecule at the surface of the film in addition to the presence of the polyvinylpyrrolidone.

EXAMPLE 3

Surface Modifying Macromolecule in Fibers of PS/PVP Polymer Blends

[0188] Fibers were also analyzed for Fluorine and Nitrogen content. The results are provided in Table 3 for the four solution spun fibers that were analyzed, each utilizing a different surface modifying macromolecule (VII-a, VIII-a, IX-a, and XI-a).

TABLE-US-00003 TABLE 3 SMM XPS (OS) XPS (IS) EA (Fibers) Fibers % F % N % F % N % F (x) % N VII-a 12.06 4.02 10.79 2.33 0.83 (4).sup.a  0.50 VIII-a 5.14 4.15 8.68 2.90 0.74 ((3).sup.b 0.52 IX-a 0.78 2.9 2.76 1.51 0.17 (2).sup.b  <0.50 XI-a 1.35 3.11 1.71 1.39 .sup. 0.27 (1.6).sup.c <0.50 Si = 1.51% Si = 2.38% Control 0.00 4.12 0.00 1.47  0 (0) <0.5 Polysulfone/PVP Fibers .sup.aTarget incorporation of VII-a = 6% .sup.bTarget incorporation of VIII-a & IX-a = 4% .sup.cTarget incorporation of XI-a = 3%

[0189] The X-ray photoelectron spectroscopy (XPS) data indicated that all of the SMM modified fibers have surface fluorine to various degrees both in the inner surface (IS) that actually comes in contact with blood during hemodialysis and the outer surface (OS).

[0190] Table 3 also provides the elemental analysis (EA) of the SMM's and the % F in the bulk, which indicates the amount of the additive incorporated into the fibers as compared to the targeted incorporation amount. For VII-a, the EA of the % F shows that of the 6 wt % additive incorporation only 4 wt % was actually present. This loss of ˜33% can be attributed to the harsh conditions of the fiber spinning process, which involves spinning solvent mixtures that dissolves some of the SMM at the same time that it dissolves the pore forming polyvinylpyrrolidone (PVP). This is true for VIII-a, IX-a, and XI-a and is reflected in the difference between the target incorporation and the actual incorporation that is calculated from the elemental analysis. However, all the SMM's no matter their final concentration are robust enough to remain in sufficient quantities to provide significant impact on the surface properties, which can be reflected in the antithrombogenic properties evidenced in the blood loop studies in Example 5.

[0191] Table 3 shows that for the commercial control PS/PVP fibers (not modified with SMM) the XPS results show an absence of Fluorine. The nitrogen content in the commercial fiber comes from the PVP that remains after most of it is washed away during the spinning process. The amount of PVP remaining in the unmodified and SMM modified fibers will also vary.

[0192] Considering the XPS results of the inner surface of the fibers (IS) which comes in contact with the blood, Table 3 shows that for VII-a, VIII-a, IX-a, and XI-a the % F (hydrophobic groups) range from 1.71%-10.79% and the % N (hydrophilic groups) are in the range 1.39%-2.90%. As determined from the data from Table 3, the ratio of % F to % N includes from 1.23-4.63 and possible ranges for the ratio of % F to % N include from 1.20 to 10.0. As provided in Table 1, the ratio of hard segments to soft segments includes from 0.16-1.49 and possible ranges for this ratio of hard segments to soft segments include from 0.15 to 2.0.

[0193] While VII-a and XI-a performed the best in this series as shown in Example 5, VIII-a and IX-a did not have any major failures, compared to the control nor did the failures result in major occlusion of the filters. Unlike the control, filters modified with VII-a, VIII-a, IX-a, or XI-a did not show such large variation in the header pressures and γ-count (as compared to the standard error in Table 6.).

EXAMPLE 4

Surface Modifying Macromolecule in Potting Materials

[0194] Sample disks were prepared to demonstrate the surface composition in the polymer material including the potted area.

[0195] A commercially available potting compound GSP-1555 from GS polymers Inc. was used as the potting material. It is a two part system consisting of Part A (HMDI based diisocyanate) and Part B (a polyol). Four SMM's designated as VII-a, VIII-a, IX-a, and XI-a (structure depicted in FIGS. 2-5) were admixed with the GSP 1555 potting material as shown in Table 4. VII-a was used in two concentrations of 1% and 2%, respectively. All other SMM's, i.e., VIII-a, IX-a, and XI-a, were prepared in only 2% (w/w) concentration according to the following method.

[0196] To the GSP 1555 precursor polyol was added the SMM in a 40 ml plastic falcon tube with thorough mixing. The mixture was dissolved in a volume of THF. The GSP 1555 precursor diisocyanate was then added, and the reaction mixture was stirred. The resulting GSP 1555 potting compound containing SMM was allowed to cure at room temperature for 24-48 hours. The cured mixture was then dried under vacuum for 48 hours to remove any residual solvent from the samples.

TABLE-US-00004 TABLE 4 GSP 1555 2A:1B Part A Part B Conc of Conc of SMM # (HMDI) (Polyol) A:B in Sol. SMM SMM in Form (g) (g) (%) (g) (A:B) % VII-a 6.7 3.3 20 0.1 1 VII-a 6.7 3.3 20 0.2 2 VIII-a 6.7 3.3 20 0.2 2 IX-a 6.7 3.3 20 0.2 2 XI-a 6.7 3.3 20 0 2 2

[0197] The samples were cut into appropriate sizes and submitted for XPS. The XPS results are provided in Table 5. Values of the atomic % F demonstrate that all parts of the potted materials (i.e., the top surface and new surfaces generated after cutting) have been modified with the additive. That the cut portions of the potted materials have been modified with the additive is important, because production of a filter from a bundle of potted hollow fiber membranes typically includes generating a new surface as the potted portion of the bundle is cut to produce a smooth finish to expose the hollow fiber openings. Values of the atomic % F also demonstrate that migration of the SMM to a surface is a dynamic process and occurs at all surfaces, including those surfaces newly generated. For example, VII-a was incorporated at 1% (w/w) to produce a top portion which displays a surface that is 30% fluorine. After heating at 60° C. for 24 hours to increase the amount of surface modifying macromolecule near the surface of the wall, the % F content at the surface was reduced to ˜13%. After cutting the sample the XPS showed that the cut surface displays a surface that is ˜7% fluorine, which upon heating at 60° C. for 24 hours is increased to ˜26% fluorine. Thus, the potting material surface of the invention can be heated if there is insufficient fluorine at a freshly cut surface. Similar observations were made for the other SMM's. This also demonstrates that SMM's can migrate through cured or thermoset polymers.

TABLE-US-00005 TABLE 5 Samples % F % N % Si Control 1-T.sup.1  .sup. 3.51 .sup.5 4.42 0.49 GSP1555 1-T60.sup.2  0.36 4.40 0.80 polyurethane 1-C.sup.3  0.60 4.68 1.03 # .sub.1 1-C60.sup.4 — — — VII-a 2 -T 30.23 3.45 0.31 1% 2-T60 13.24 3.18 0.37 # 2 2-C  6.77 3.96 0.41 2-C60 26.10 3.32 0.24 VII-a 3-T 18.00 3.80 0.09 2% 3-T60 27.00 3.31 0.19 # 3 3-C 12.60 3.16 0.16 3-C60 41.93 3.62 0.01 4-T 28.90 6.31 1.79 VIII-a 4-T60 31.40 6.66 0.78 2% 4-C 23.88 5.54 1.50 # 4 4-C60 22.75 5.93 1.04 5-T  3.00 3.29 0.26 IX-a 5-T60  9.10 2.69 0.75 2% 5-C  7.47 3.93 1.42 # 5 5-C60 11.08 2.99 0.47 6-T 36.71 5.72 0.00 XI-a 6-T60 42.31 5.25 0.02 2% 6-C 26.19 6.07 0.17 # 6 6-C60 33.35 5.81 0.01 .sup.1T = Top portion of sample at ambient temperature. .sup.2T60 = Top portion of sample at 60° C., 24 hours. .sup.3C = Cut portion of sample at ambient temperature. .sup.4C60 = Cut portion of sample at 60° C., 24 hours. .sup.5Control should be devoid of fluorine. Here a 3% F content indicates contamination.

EXAMPLE 5

In Vitro Assessment of Hemofilter Thrombosis

[0198] Thrombotic surface activity of hemofilters was assessed using commercially available hemofilters in response to heparinized bovine blood. Hemofilters were surface modified with VII-a, VIII-a, IX-a, or XI-a and compared with control (hemofilter that was not surface modified).

[0199] Materials

[0200] Commercially available hemofilters containing PS/PVP were used as the control. Four surface modifying macromolecules (SMM's) of VII-a, VIII-a, IX-a, and XI-a (as shown in the Figures) having various chemical constituents were used to modify the commercial hemofilters, which were used as the test samples together with the control filters. Commercial filters modified with VII-a had 4% additive incorporation. Commercial filters modified with VIII-a had 3% additive incorporation. Commercial filters modified with IX-a had 2% additive incorporation. Commercial filters modified with XI-a had 1.6% additive incorporation. A total of 30 filters were analyzed in the study. Heparinized bovine blood (2 units/ml) was used for each experiment, where the study included 3 or 6 cows. QC release tests were performed on the modified filters for dialyzer function and assessment of fiber dimensions. These were compared to the control filters.

Methods

[0201] An in vitro assessment of hemofilter thrombosis was made using a standard blood loop system and protocol (see Sukavaneshvar et al., Annals of Biomedical Engineering 28:182-193 (2000), Sukavaneshvar et al., Thrombosis and Haemostasis 83:322-326 (2000), and Sukavaneshvar et al., ASAIO Journal 44:M388-M392 (1998)).

[0202] Briefly, the following protocol was used. The blood loop system included a reservoir, a pump, a hemofilter, and tubing to form a closed flow loop. The loop system was primed with phosphate buffered saline (PBS) at 37° C. and circulated for 1 hour before starting an experiment, and pressure was measured at the pressure port between the pump and the hemofilter.

[0203] Approximately 10 liters of fresh bovine blood was obtained from a single animal for each experiment and heparinized (typical concentration=2 U/ml). The experiments were conducted within 8 h of blood collection. Radiolabeled, autologous platelets (with .sup.111Indium) were added to the blood prior to the commencement of the study. The PBS in the reservoir was replaced with blood, and pressure was monitored. Blood circulation in the loop system was typically maintained for 1-2 hours (unless terminated due to significant pressure build-up, as monitored by a pressure gauge). At the end of the experiment, hemofilters were photographed, and γ-count was measured at the inlet, outlet, and middle of the hemofilter using a γ-probe.

[0204] FIG. 21 shows the experimental set-up for the in vitro blood loop analysis and the configuration of the hemofilters for the study. The figure also shows the arrangement of the γ-probe reading for the hemofilters, where measurements were determined end-on and in the middle of the hemofilters. The γ-probe readings for the radiolabeled platelets were determined after the filters were exposed to the blood flow and rinsed with PBS solution to remove any residual blood. FIG. 22 shows an arrangement of the hemofilters after the blood loop procedure, just before the header caps (top and bottom caps) are unscrewed to visually examine for thrombus.

[0205] Results & Discussion

[0206] Table 6 shows the results of the in vitro study of hemodialysis filters thrombus for control (Cl) versus VII-a, VIII-a, IX-a, and XI-a. Table 6 also shows the header pressure change (AP) at the inlet (top cap in FIG. 22) and the γ-probe readings of the radiolabeled activated platelets at the inlet (top cap in FIG. 22), middle, and outlet (bottom cap in FIG. 22) regions of the hemofilters after blood contacting for Experiments 1-6. In Experiment 1, the first filter to fail after 25 minutes was IX-a, where the header pressure was 180 mm Hg. This is called the failure or occlusion time. Failure here means when the header pressure reached ≥175 mm Hg over the base pressure. At this point, the γ-count of the activated platelets was 3582, while it was 3250 in the middle and 2223 at the outlet. VII-a performed the best in this experiment not only amongst the SMM's but also compared to the control with the lowest header pressure of 20 vs. 53 mm Hg (control). The γ-count at this point was 2631. However, the γ-count in the middle was higher (at 4534) and lower in the outlet (at 2454). The higher γ-count in the middle may be indicative of loosely bound micro-thrombi that slips through into the fiber (due to the additive nature of the SMM), which does not allow the thrombi to accumulate. The higher concentration of activated platelets in the middle of the filters is generally true for most of the SMM modified filters, as is evident in Experiments 1, 2, 3, 5, and 6. In this experiment (Experiment 1), XI-a modified filters also performed well with a header pressure of 35 mm Hg, as compared to the control.

TABLE-US-00006 TABLE 6 Header pr γ-probe read. (cpm) Expt Δ Pr R M B Total Radiation Flow = 200 ml/min Filters # Inlet (red) Inlet Middle Outlet cpm Expt 1 C1 53 2231 2165 1410 4396 Occlusion time VII-a 20 2631 4534 2454 7165 t = 25 mins VIII-a 53 2667 3683 2049 6350 IX-a.sup.a 180 3582 3250 2223 6832 XI-a 35 2701 4631 2527 7332 Expt 2 C1 86 1905 1536 1078 3441 Occlusion time VII-a 158 3293 3557 2085 6850 t = 57 mins VIII-a.sup.a 185 2623 2806 1512 5429 IX-a 155 2413 2510 1821 4923 XI-a 176 2791 2942 1770 5733 3 C1 154 20339 4624 2619 24963 Occlusion time VII-a 21 6554 4608 2662 11162 t = 30 mins VIII-a.sup.a 227 19816 5799 2692 25615 IX-a 217 19982 6876 3930 26858 XI-a 36 7660 2962 1867 10622 4 C1.sup.a 926 17982 4342 5707 22324 Occlusion time VII-a 9 1915 2547 1479 4462 t = 8 mins VIII-a 12 1941 2106 1311 4047 IX-a 133 6433 3893 2554 10326 XI-a 51 1404 1993 1196 3397 5 C1.sup.a 362 4836 2747 1984 7583 Occlusion time VII-a −3 2255 3442 2301 5697 t = 10 mins VIII-a 8 5577 8065 4835 13642 IX-a 8 905 917 913 1822 XI-a −5 1012 1098 435 2110 6 C1 33 2465 1717 1082 4182 Occlusion time VII-a 41 5091 5762 2967 10853 t = 40 mins VIII-a.sup.a 222 5019 3664 1850 8683 IX-a 35 2280 2348 1519 4628 XI-a 63 3644 3186 1673 6830 .sup.aFilters that failed in each experiment

[0207] In Experiment 2, VIII-a failed within 57 minutes with a header pressure of 185 mm Hg. In this experiment, the control performed the best with the lowest header pressure at 86 mm Hg compared to VII-a or IX-a. The corresponding γ-counts are also shown in the Table 6. However, in the next 4 experiments, VII-a performed the best among all the filters tested with the lowest header pressure, except in Experiment 6 where the header pressure for XI-a was slightly higher than the control. The γ-counts at the header inlet are also reflective of its performance. XI-a performed second best in this series. Experiments 4 and 5 showed some interesting results, where the control filters failed catastrophically within 8 and 10 minutes, respectively, with massive fibrin rich thrombus and complete occlusion of the filters. Table 6 shows how high the pressure was (926 and 362 mm Hg) of the control filters relative to the SMM modified filters and the corresponding high platelet count at this point. None of the SMM modified filters failed within 10 minutes in any of the experiments nor did they reach such high pressures at any point during the entire analysis.

[0208] Table 7 shows the average header pressure and the γ-count at the inlet for the control and VII-a, VIII-a, IX-a, and XI-a modified filters with the corresponding standard deviation and standard error for six experiments (n=6). The high value of the standard error (STE) for the control in comparison to any of the SMM's is also an indication of the large variability in the control filter performance. The table also indicates that the header pressures (inlet) of VII-a and XI-a had the least variability, evident from the STE values of 24 and 25 respectively. The γ-counts of the activated platelets at the header inlet (Table 7) also show a much lower STE for VII-a and XI-a compared to the control filters. Both these values are in conformity with the filter performance of VII-a and XI-a vs. control filters.

[0209] It should be noted that Experiment 5 in Table 7 shows that the header pressures of VII-a was −3 mm Hg and XI-a was −5 mm Hg. These are actual values in the in vitro analysis due to a pulsating blood flow under high shear stress through the fibers, which can result in a slight negative pressure and should actually be interpreted as ‘0’ for all intents and purposes.

TABLE-US-00007 TABLE 7 Occlusion T Expt. Control VII-a VIII-a IX-a XI-a min Header Pressure Change -Inlet (Red) 1 53 20 53 180 35 25 2 86 158 185 155 176 57 3 154 21 227 217 36 30 4 926 9 12 133 51 8 5 262 −3 8 8 −5 10 6 33 41 222 35 63 40 Av 269 41 118 121 59 STD 343 59 105 83 62 STE 140 24 43 34 25 Gamma Count - Inlet (Red) 1 2231 2631 2667 3582 2701 2 1905 3293 2623 2413 2791 3 20339 6554 19816 19982 7660 4 17982 1915 1941 6433 1404 5 4836 2255 5577 905 1012 6 2465 5091 5019 2280 3644 Av 8293 3623 6274 5933 3202 Av/10 829.3 362 627 593 320 STD 8514 1824 6791 7130 2388 STE 3476 744 2772 2911 975 STE/10 348 74 277 291 97

[0210] Table 8 illustrates the time to failure and the corresponding filters that failed first in each experiment. It can be seen that in Experiments 4 and 5 the control filters failed catastrophically, whereas in Experiment 1, IX-a failed in 25 minutes. In Experiments 2, 3, and 6, VIII-a failed (57, 30, and 40 minutes respectively), but none of these were major failures nor did they result in filters becoming fully occluded with thrombus. Table 8 also summarizes the header pressure of the two best SMM formulations (VII-a and XI-a) and how these compare relative to the control.

TABLE-US-00008 TABLE 8 Parameters Expt 1 Expt 2 Expt 3 Expt 4 Expt 5 Expt 6 Time to Failure 25 57 30 8 10 40 minutes.sup.1 First Filter IX-a VIII-a VIII-a Control Control VIII-a to Fail ΔP at Header (Inlet) for VII-a & XI-a Filters vs Control.sup.2 VII-a 20 158 21 9 −3 41 XI-a 35 176 36 51  −5 63 Control 53 86 154  926 .sup.3   362 .sup.3 33 .sup.1Each experiment was terminated if the pressure was ≥175 mm Hg, relative to the baseline pressure. This was deemed as filter failure. Control in Expt 4 and 5 failed within 10 minutes. .sup.2ΔP denote the change in header pressure relative to the baseline pressure. .sup.3 The filters in Expt 4 and 5 were fully occluded with thrombus

[0211] FIG. 23 illustrates graphically the average header pressure and γ-counts of VII-a and XI-a in comparison to the control filters. The error bars are an indication of variability in both the pressure and γ readings; both of which are higher in the control vs. VII-a and XI-a. On average, VII-a had 85% less header pressure and XI-a had 78% less header pressure than the control while the γ-counts were 56% and 61% lower in VII-a and XI-a, respectively, as compared to the commercial control.

[0212] FIGS. 24A-24B and FIGS. 25A-25C are thrombus photos of Experiment 4, and FIGS. 26A-26D are thrombus photos of Experiment 5. In these experiments, the control filters failed within 10 minutes or less with massive thrombus formation and filter occlusion. FIGS. 24A-24B and FIGS. 25A-25C especially shows that not only the headers had thrombus but there was thrombus residue on the sieve after the draining of the blood indicative of hypercoagulation.

[0213] FIG. 27 compares the thrombus photos of VII-a and XI-a with control filters for all the 6 experiments. From the degree of redness of the header inlet indicative of red thrombus build-up and platelet activation, it can be seen that VII-a and XI-a on an average, performed better than the control (besides the pressure values).

[0214] Thrombus photos were taken of the filter headers at the inlet and outlet positions after the blood loop analysis for all the 6 experiments. Experimental results are shown as thrombus photos for Experiment 1 (FIGS. 28A-28B), Experiment 2 (FIGS. 29A-29B), Experiment 3 (FIGS. 30A-30B), and Experiment 6 (FIGS. 31A-31B). In all these cases it was either VIII-a or IX-a failed, but the filters were never occluded unlike the control in experiment 4 and 5.

[0215] In addition, all the SMM modified filters (VII-a, VIII-a, IX-a, or XI-a) were able to be spun into fibers. When assembled into dialyzer filters, the hemofilters were tested, and all were able to function as a hemofilter, as compared to a control hemofilter. In general, all of the hemofilters functioned as a dialyzer.

[0216] Conclusions

[0217] The in vitro blood loop studies using heparinized bovine blood indicated that VII-a and XI-a performed the best among all the filters tested. These two formulations showed no filter failure with the lowest average header pressure (>75% less pressure), low average γ-count (>55% less), low thrombus and less thrombogenicity, than the control. Conversely, the control filters performed the worst, failing catastrophically in two experiments within 10 minutes. It also had the highest average header pressure, γ-count and variability of all the filters tested in the 6 experiments. VIII-a failed in 3 experiments and IX-a failed in 1 experiment, but all of these were within 25-57 minutes and none of the filters had any major occlusion. All of the hemofilters function as a dialyzer in various degrees and adjustments can be made easily to conform to the desired specifications.

Other Embodiments

[0218] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

[0219] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0220] Other embodiments are within the claims.