Antithrombogenic hollow fiber membranes and filters

1. A method of performing a procedure selected from hemodialysis, hemofiltration, hemoconcentration, or hemodiafiltration on a subject using a dialysis filter, wherein said filter comprises

(a) a hollow fiber membrane comprising a base polymer admixed with from 0.005% to 10% (w/w) of a surface modifying macromolecule, wherein said base polymer is a polysulfone or a polyacrylonitrile, wherein said hollow fiber membrane is antithrombogenic when contacted with blood, wherein said surface modifying macromolecule has a structure according to:

(a1) formula (VII):

F T [B-(Oligo)] n - B -F T   (VII),

wherein Oligo is an oligomeric segment including polypropylene oxide or polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate; F T is a polyfluoroorgano group; and n is an integer from 1 to 10;

(a2) formula (VIII):

wherein A is an oligomeric segment including polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate biuret trimer; F T is a polyfluoroorgano group; and n is an integer from 0 to 10;

(a3) formula (IX):

F T -[B-(Oligo)] n -B-F T   (IX),

wherein Oligo is an oligomeric segment including poly (2,2 dimethyl-1,3-propylcarbonate and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from 4,4′-methylene bis(cyclohexyl isocyanate); F T is a polyfluoroorgano group; and n is an integer from 1 to 10; or

(a4) formula (XI):

wherein A is a block copolymer comprising polypropylene oxide and polydimethylsiloxane and having a theoretical molecular weight of from 1,000 to 5,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate biuret trimer; F T is a polyfluoroorgano group; and n is an integer from 1to 10;

(a5) formula (IV),

F T -[B-A] n -B-F T   (IV),

wherein A is a soft segment including 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 ethoxvlate; B is a hard segment including a urethane; F T is a polvfluoroorgano group, and n is an integer from 1to 10; and/or

(b) a potted bundle of hollow fiber membranes within an encasement comprising:

(i) 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;

(ii) 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

(iii) 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, and

wherein said potting resin comprises from 0.005% to 10% (w/w) of a surface modifying macromolecule having a structure according to:

(b 1) formula (III),

F T -[B-(oligo)] n -B-F T   (III),

wherein B includes a urethane; oligo includes polypropylene oxide, polyethylene oxide, or polytetramethylene oxide; F T is a polyfluoroorgano group; and n is an integer from 1 to 10;

(b2) formula (VII),

F T -[B-(Oligo)] n -B-F T   (VII),

wherein Oligo is an oligomeric segment including polypropylene oxide, polyethylene oxide, or polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from an isocyanate dimer; F T is a polvfluoroorgano group; and n is an integer from 1to 10; or

(b3) formula (IV),

F T -[B-A] n -B-F T   (IV),

wherein A is a soft segment including 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; B is a hard segment including a urethane; F T is a polyfluoroorgano group, and n is an integer from 1 to 10.

2. The method of claim 1 , wherein during said procedure said subject receives less than a standard dose of anticoagulant or receives no anticoagulant.

3. The method of claim 1 , wherein said filter has a prolonged working life, wherein said filter has an increased average functional working life of at least 125%, wherein the thrombi deposition on said filter is reduced by at least 10% when contacted with blood, wherein said filter has an operating pressure after 4 hours of use that is reduced by at least 10 %, or wherein the adverse events experienced by said subject are reduced.

4. The method of claim 1 , wherein said filter comprises said hollow fiber membrane, said hollow fiber membrane comprising a surface modifying macromolecule having a structure according to formula VII-a, VIII-a, IX-a, and XI-a.

5. The method of claim 1 , wherein said filter comprises said potted bundle, said potted bundle comprising a potting resin that comprises a surface modifying macromolecule selected from VII-a, VIII-a, IX-a, XI-a, VIII-b, VIII-d, and XI-b.

6. The method of claim 1 , wherein said filter comprises said hollow fiber membrane comprising said surface modifying macromolecule,

wherein the thrombi deposition on said surface said hollow fiber membrane is reduced by at least 10% when contacted with blood,

wherein said hollow fiber membrane has an operating pressure after 4 hours of use that is reduced by at least 10%, or

wherein said hollow fiber membrane reduces adverse advents in a subject receiving blood passing through said hollow fiber membrane.

7. The method of claim 1 , wherein said filter comprises said hollow fiber membrane comprising said surface modifying macromolecule admixed with said base polymer, wherein said base polymer is a polysulfone.

8. The method of claim 7 , wherein said polysulfone is poly(oxy-1,4-phenylene sulfonyl-1,4-phenyleneoxy-1,4-phenyleneisopropylidene-1,4-phenylene) or polyether sulfone.

9. The method of claim 1 , wherein said filter comprises said hollow fiber membrane, said hollow fiber membrane further comprising a hydrophilic pore forming agent

10. The method of claim 9 , wherein said hydrophilic pore forming agent is selected from polyvinylpyrrolidone, ethylene glycol, alcohols, polypropylene glycol, and polyethylene glycol, or mixtures thereof.

11. The method of claim 9 , wherein said hollow fiber membrane comprises from 80% to 96.5% (w/w) of said base polymer, from 3% to 20% (w/w) of said hydrophilic pore forming agent, and 0.005% to 10% (w/w) of said surface modifying macromolecule.

12. The method of claim 1 , wherein said filter comprises said potted bundle,

wherein said potted bundle has a prolonged working life,

wherein said bundle has an increased average functional working life of at least 125%,

wherein the thrombi deposition on said potted bundle is reduced by at least 10% when contacted with blood,

wherein said bundle has an operating pressure after 4 hours of use that is reduced by at least 10%,

wherein said potting resin is antithrombogenic when contacted with blood, or

wherein said potted bundle reduces adverse advents in a subject receiving blood passing through said potted bundle.

13. The method of claim 1 , wherein said filter comprises said bundle of potted hollow fiber membranes, wherein said bundle of potted hollow fiber membranes within an encasement is part of a blood purification device.

14. The method of claim 13 , wherein said blood purification device is a hemodialysis, hemodiafiltration, hemofiltration or hemoconcentration device.

15. The method of claim 1 , wherein said filter comprises said potted bundle, wherein said potting resin comprises a cross-linked polyurethane.

16. The method of claim 1 , wherein said filter comprises said hollow fiber membrame, said hollow fiber membrane comprising a surface modifying macromolecule having a structure according to formula (VII),

F T -[B-(Oligo)]-B-F T   (VII),

wherein

(i) Oligo is an oligomeric segment including polypropylene oxide or polytetramethylene oxide having a theoretical molecular weight of from 500 to 3,000 Daltons;

(ii) B is a hard segment formed from hexamethylene diisocyanate;

(iii) F T is a polyfluoroorgano group; and

(iv) n is an integer from 1 to 10.

17. The method of claim 16 , wherein n is an integer from 1 to 3.

18. The method of claim 17 , wherein F T is selected from the group consisting of CH m F (3-m) (CF 2 ) r CH 2 CH 2 - and CH m F (3-m) (CF 2 ) s (CH 2 CH 2 O) x —,

wherein m is 0, 1, 2, or 3; r is an integer from 2 to 20; s is an integer from 1 to 20; and x is an integer from 1 to 10.

19. The method of claim 16 , wherein said surface modifying macromolecule of formula (VII) is VII-a.

20. The method of claim 1 , wherein said filter comprises said potted bundle, said potted bundle comprising a surface modifying macromolecule having a structure according to formula (III),

F T -[B-(oligo)]-B-F T   (III)

wherein

(i) B includes a urethane;

(ii) oligo includes polypropylene oxide, polyethylene oxide, or polytetramethylene oxide;

(iii) F T is a polyfluoroorgano group; and

(iv) n is an integer from 1 to 10.

21. The method of claim 1 , wherein said filter comprises said potted bundle, said potted bundle comprising a surface modifying macromolecule having a structure according to formula (VII),

F T -[B-(Oligo)] n -B-F T   (VII),

wherein

(i) Oligo is an oligomeric segment including polypropylene oxide, polyethylene oxide, or polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons;

(ii) B is a hard segment formed from an isocyanate dimer;

(iii) F T is a polyfluoroorgano group; and

(iv) n is an integer from 1 to 10.

22. The method of claim 1 , wherein said filter comprises said potted bundle, said potted bundle comprising a surface modifying macromolecule having a structure according to formula (IV),

F T -[B-A] n -B-F T   (IV)

wherein

A is a soft segment including 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 is a hard segment including a urethane; and

(iii) F T is a polyfluoroorgano group, and

(iv) n is an integer from 1 to 10.

23. The method of claim 1 , wherein said filter comprises said hollow fiber membrane, said hollow fiber membrane comprising a surface modifying macromolecule having a structure according to formula (XI),

wherein

(i) A is a block copolymer comprising polypropylene oxide and polydimethylsiloxane having a theoretical molecular weight of from 1,000 to 5,000 Daltons;

(ii) B is a hard segment formed from hexamethylene diisocyanate biuret trimer;

(iii) F T is a polyfluoroorgano group; and

(iv) n is 0, 1, 2, or 3.

24. The method of claim 23 , wherein said hollow fiber membrane comprises a surface modifying macromolecule having a structure according to formula XI-a.

25. The method of claim 1 , wherein said filter comprises said hollow fiber membrane, said hollow fiber membrane comprising a surface modifying macromolecule having a structure according to formula (VIII),

wherein

(i) A is an oligomeric segment including polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons;

(ii) B is a hard segment formed from hexamethylene diisocyanate biuret trimer;

(iii) F T is a polyfluoroorgano group; and

(iv) n is 0, 1, 2, or 3.

26. The method of claim 1 , wherein said hollow fiber membrane comprises a surface modifying macromolecule having a structure according to formula VIII-a.

27. The method of claim 1 , wherein said filter comprises said hollow fiber membrane, said hollow fiber membrane comprising a surface modifying macromolecule having a structure according to formula (IX),

F T -[B-(Oligo)] n -B-F T   (IX),

wherein

(i) Oligo is an oligomeric segment including poly (2,2dimethyl-1,3propylcarbonate and having a theoretical molecular weight of from 500 to 3,000 Daltons;

(ii) B is a hard segment formed from 4,4′-methylene bis(cyclohexyl isocyanate);

(iii) F T is a polyfluoroorgano group; and

(iv) n is 0, 1, 2, or 3.

28. The method of claim 27 , wherein said hollow fiber membrane comprises a surface modifying macromolecule having a structure according to formula IX-a.

29. The method of claim 1 , wherein said filter comprises said hollow fiber membrane, wherein F T is selected from the group consisting of CH m F (3-m) (CF 2 ) r CH 2 CH 2 - and CH m F (3-m) (CF 2 ) s (CH 2 CH 2 O) x —,

wherein m is 0, 1, 2, or 3; r is an integer from 2 to 20; s is an integer from 1 to 20; and x is an integer from 1 to 10.

30. A method of performing a procedure selected from hemodialysis, hemofiltration, hemoconcentration, or hemodiafiltration on a subject using a dialysis filter, wherein said filter comprises a hollow fiber membrane comprising a base polymer admixed with from 0.005% to 10% (w/w) of a surface modifying macromolecule, wherein said hollow fiber membrane is antithrombogenic when contacted with blood, wherein said surface modifying macromolecule has a structure according to:

(a1) formula (VII):

F T -[B-(Oligo)] n -B-F T   (VII),

wherein Oligo is an oligomeric segment including polypropylene oxide or polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate; F T is a polyfluoroorgano group; and n is an integer from 1to 10;

(a2 )formula (VIII):

wherein A is an oligomeric segment including polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate biuret trimer; F T is a polyfluoroorgano group; and n is an integer from 0to 10;

(a3) formula (IX):

F T -[B-(Oligo)] n -B-F T   (IX),

wherein Oligo is an oligomeric segment including poly (2,2dimethyl-1,3-propylcarbonate and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from 4,4′-methylene bis(cyclohexyl isocyanate); F T is a polyfluoroorgano group; and n is an integer from 1 to 10; or

(a4) formula (XI):

wherein A is a block copolymer comprising polypropylene oxide and polydimethylsiloxane and having a theoretical molecular weight of from 1,000 to 5,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate biuret trimer F T is a polyfluoroorgano group; and n is an integer from 1 to 10;

wherein the blood and dialysate are separated from each other by said hollow fiber membrane at a semipermeable surface of said hollow fiber membrane during said procedure, said semipermeable surface comprising said surface modifying macromolecule.

31. The method of claim 30 , wherein said surface modifying macromolecule has a structure according to formula (VII):

F T -[B-(Oligo)] n -B-F T   (VII),

wherein Oligo is an oligomeric segment including polypropylene oxide, polyethylene oxide, or polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate; F T is a polyfluoroorgano group; and n is an integer from 1 to 10.

32. The method of claim 31 , wherein n is an integer from 1 to 3.

33. The method of claim 32 , wherein Oligo is an oligomeric segment including polypropylene oxide.

34. The method of claim 32 , wherein Oligo is an oligomeric segment including polytetramethylene oxide.

35. The method of claim 32 , wherein F T is selected from the group consisting of CH m F (3-m) CF 2 ) r CH 2 CH 2 - and CH m F (3-m) (CF 2 ) s (CH 2 CH 2 O) x —,

wherein m is 0, 1, 2, or 3; r is an integer from 2 to 20; s is an integer from 1 to 20; and X is an integer from 1 to 10.

36. A method of performing a procedure selected from hemodialysis, hemofiltration, hemoconcentration, or hemodiafiltration on a subject using a dialysis filter, wherein said filter comprises a hollow fiber membrane comprising a base polymer admixed with from 0.005% to 10% (w/w) of a surface modifying macromolecule, wherein said hollow fiber membrane is antithrombogenic when contacted with blood, wherein said surface modifying macromolecule has a structure according to:

(a1) formula (VII):

F T -[B-(Oligo)] n -B-F T   (VII),

wherein Oligo is an oligomeric segment including polypropylene oxide or polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate; F T is a polyfluoroorgano group; and n is an integer from 1 to 10;

(a2) formula (VIII):

wherein A is an oligomeric segment including polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate biuret trimer; F T is a polyfluoroorgano group; and n is an integer from 0 to 10;

(a3) formula (IX):

F T -[B-(Oligo)] n -B-F T   (IX),

wherein Oligo is an oligomeric segment including poly (2,2dimethyl -1,3-propylcarbonate and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from 4,4′-methylene bis(cyclohexyl isocyanate); F T is a polyfluoroorgano group; and n is an integer from 1 to 10; or

(4) formula (XI):

wherein A is a block copolymer comprising polypropylene oxide and polydimethylsiloxane and having a theoretical molecular weight of from 1,000 to 5,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate biuret trimer; F T is a polyfluoroorgano group; and n is an integer from 1 to 10;

wherein said hollow fiber membrane is formed from a spinning solution by extruding said spinning solution through a tube-in-tube type orifice, wherein said spinning solution comprises said base polymer and said surface-modifying macromolecule.

37. The method of claim 36 , wherein said surface modifying macromolecule has a structure according to formula (VII):

F T -[B-(Oligo)] n -B-F T   (VII),

wherein Oligo is an oligomeric segment including polypropylene oxide or polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Daltons; B is a hard segment formed from hexamethylene diisocyanate; F T is a polyfluoroorgano group; and n is an integer from 1 to 10.

38. The method of claim 37 , wherein n is an integer from 1 to 3.

39. The method of claim 38 , wherein Oligo is an oligomeric segment including polypropylene oxide.

40. The method of claim 38 , wherein Oligo is an oligomeric segment including polytetramethylene oxide.

41. The method of claim 38 , wherein F T is selected from the group consisting of CH m F (3-m) (CF 2 ) r CH 2 CH 2 - and CH m F (3-m) (CF 2 ) s (CH 2 CH 2 O) x —,

wherein m is 0, 1, 2, or 3; r is an integer from 2 to 20; s is an integer from 1 to 20 ; and x is an integer from 1 to 10.