HollowFiberMembranes US8877062

US008877O62B2
(12) United States Patent (10) Patent No.: US 8,877,062 B2

Mullick et al. (45) Date of Patent: Nov. 4, 2014
(54) ANTITHROMBOGENIC HOLLOW FIBER B01D 71/82; B01D 2313/04; B01D 2323/10;
MEMBRANES AND FILTERS B01D 2323/28: B01D 2323/36; A61M 1/16;
A61M 1/34: A61M 1/3672: A61M 2001/1623;
(75) Inventors: Sanjoy Mullick, Brampton (CA); A61M 2001/34
Weilun Chang, Toronto (CA); Hanje USPC ............. 210/500.23,500.24,500.27,500.36,
Chen, Toronto SA), Mark steedman, 210/500.41, 500.42, 321.61, 321.78,
S. (A) Reita Esfand, 210/321.79, 321.8, 321.87, 321.88, 321.89,
ississauga (CA) 210/500.43; 604/5.01, 6.01, 6.09, 19
(73) Assignee: Interface Biologics, Inc., Toronto (CA) See application file for complete search history.
(*) Notice: Subject to any disclaimer, the term of this (56) References Cited
patent is extended or adjusted under 35 U.S. PATENT DOCUMENTS
U.S.C. 154(b) by 480 days.
3,392, 183 A 7, 1968 Windemuth et al.
(21) Appl. No.: 12/834,730 3.427.366 A 2/1969 Ryan et al.
(22) Filed: Jul. 12, 2010 (Continued)
(65) Prior Publication Data FOREIGN PATENT DOCUMENTS
CN 1711127 A 12/2005
US 2011 FOOO9799 A1 Jan. 13, 2011 CN 18943O2 A 1, 2007
Related U.S. Application Data (Continued)
(63) Continuation-in-part of application No. 12/780,200, OTHER PUBLICATIONS
filed on May 14, 2010, now abandoned.
U.S. Appl. No. 12/780,200, filed May 14, 2010, Mullicket al.
(60) Provisional application No. 61/178,861, filed on May
15, 2009. (Continued)
(51) Int. Cl. Primary Examiner — Joseph Drodge
A6M I/6 (2006.01) (74) Attorney, Agent, or Firm — Clark & Elbing LLP:
A6M I/34 (2006.01) Kristina Bieker-Brady
(Continued) (57) ABSTRACT
(52) U.S. Cl.
CPC ........... BOID 63/023 (2013.01); A61M 1/3672 The invention relates to extracorporeal blood circuits, and
(2013.01); B01D 63/022 (2013.01); B0ID components thereof (e.g., hollow fiber membranes, potted
bundles, and blood tubing), including 0.005% to 10% (w/w)
(Continued) Surface modifying macromolecule. The extracorporeal blood
(58) Field of Classification Search circuits have an antithrombogenic Surface and can be used in
CPC ...... B01D 61/20; B01D 61/28; B01D 61/246; hemofiltration, hemodialysis, hemodiafiltration, hemocon
B01D 63/04; B01D 69/08; B01D 71/06; centration, blood oxygenation, and related uses.
B01D 71/26: B01D 71/44; B01D 71/54;
B01D 71/68; B01D 71/76; B01D 71/80; 41 Claims, 31 Drawing Sheets
Biti Fly &r Cartridge

Potted arei
seated
Fier area
ce -1
a. -1
3. 1
iber part
Bad Fox
US 8,877,062 B2
Page 2
(51) Int. Cl. 2008/0228253 A1 9, 2008 Mullicket al.

BOID 6/20 (2006.01) 2008/0237127 A1* 10/2008 Okafuji et al. ................ 210,646
2009, 0211968 A1 8, 2009 Ho et al.
BOID 6/28 (2006.01) 2011/OOO9799 A1 1/2011 Mullicket al.
BOLD 7L/06 (2006.01) 2011/0207893 A1 8, 2011 Mullicket al.
BOLD 7L/26 (2006.01) 2012fO148774 A1 6, 2012 Mullicket al.
2012fO220724 A1 8, 2012 Mullicket al.
BOLD 7L/44 (2006.01)
BOLD 7L/68 (2006.01) FOREIGN PATENT DOCUMENTS
BOID 71/76 (2006.01)
BOLD 63/02 (2006.01) EP O 068509 1, 1983
A6M I/36 (2006.01) EP O O73 978 3, 1983
BOLD 67/00 (2006.01) EP O 231927 2, 1987
EP O 332261 9, 1989
BOLD 69/02 (2006.01) EP O 335 664 10, 1989
BOLD 69/08 (2006.01) EP O 615 778 9, 1994
B29C 47/00 (2006.01) EP O 894 823 2, 1999
B29L 23/00 (2006.01) JP S612868 A 1, 1986
B29L 3 I/OO JP 2000-317275 A 11, 2000
(2006.01) JP 2004-248904. A 9, 2004
(52) U.S. C. RU 2215O12 10, 2003
CPC ..... 67/0093 (2013.01); B0ID 69/02 (2013.01); WO WO95/26993 10, 1995
BOID 69/08 (2013.01); B0ID 69/087 WO
WO
WO97,06195
WO98,34718
2, 1997
8, 1998
(2013.01); B0ID 71/44 (2013.01); B0ID 71/68 WO WO2004/056459 T 2004
(2013.01); B29C47/00 (2013.01); B29C WO WO2007/084514 7/2007
47/0014 (2013.01); B29C 47/0026 (2013.01); WO WO2008.076345 6, 2008
B29L 2023/00 (2013.01); B29L 2031/731 WO 2010/OOO746 1, 2010
(2013.01); B01D 2323/30 (2013.01) WO WO2010/O25398 3, 2010
USPC ................. 210/645; 210/321.61; 210/321.89: WO WO2O11,072398 6, 2011
210/500.23; 210/500.27: 210/500.41; 210/500.43; OTHER PUBLICATIONS
210/646; 604/5.01: 604/6.01: 604/6.09: 604/19
U.S. Appl. No. 12/834,730, filed Jul. 12, 2010, Mullicket al.
(56) References Cited BioInterface 2011 Conference Agenda (available at sib.affiniscape.
U.S. PATENT DOCUMENTS
com/cde.cfm?event=331217& addEventId=331217), with text of
abstracts from presentations by Cai, “Carboxyl-Ebselen-Based
3,872,058 3, 1975 Gresham Layer-by-Layer Film: A Potential Antithrombotic and Antimicrobial
4,312,907 1, 1982 Hiraoka et al. Coating” (Oct. 25, 2011); Cook, "Surface Modifications with
4.424,311 * 1?1984 Nagaoka et al. .............. 525/303 Improved Long-Term Hemocompatability” (Oct. 25, 2011); Dirks,
4.584,362 4, 1986 Leckart et al. “Non-Adhesive and Antimicrobial Coatings for Medical Implants'
4,661,530 4, 1987 Gogolewski et al. (Oct. 26, 2011); and Strokowski. “Adsorption and Hemocompat
4,742,090 5, 1988 Hunter et al. ibility Properties of Elastin-like Polypeptide Surfaces” (Oct. 25.
4,743,629 * 5, 1988 Karakelle et al. ............. 521, 175 2011).
4,788,083 11, 1988 Dammann et al. Engelberg et al., “Physico-Mechanical Properties of Degradable
4,792,354 12, 1988 Matsuo et al.
4,861,830 8, 1989 Ward Polymers Used in Medical Applications: A Comparative Study.”
4,879,032 11, 1989 Zemlin Biomaterials, 12:292-304 (1991).
4,966,699 * 10, 1990 Sasaki et al. ............... 210,321.8 Fang, “Separation of Liquid Mixtures by Membranes.” Department
4,994,503 2, 1991 Harris et al. of Chemical Engineering, University of Ottawa, Canada, ON, 1996.
5,064,871 11, 1991 Sciangola Goldberg, “Elastomeric Polycarbonate Block Copolymers,” Journal
5,145,727 9, 1992 Potts et al. of Polymer Science. Part C. 4: 707-730 (1963).
5,149,576 9, 1992 Potts et al.
5,242,995 9, 1993 Kim et al. Ho et al., “The Effect of Fluorinated Surface Modifying Macromol
5,395,525 3, 1995 Takano et al. ecules on the Surface Morphology of Polyethersulfone Membranes.”
5,428,123 * 6, 1995 Ward et al. ...................... 528/28 J. Biomater. Sci. 11(10): 1085-1104, 2004.
5,486,570 1, 1996 St. Clair Ho, “The Effects of Surface Modifying Macromolecules on the
5,542,200 8, 1996 Matsuoka Blood Compatibility of Polyethersulfone Membranes Intended for
5,543,200 8, 1996 Hargis et al. Biomedical Applications.” Graduate Department of Chemical Engi
5,589,563 12, 1996 Ward et al. neering and Applied Chemistry, University of Toronto, 1997.
5,779,897 7, 1998 Kalthod et al.
5,908,701 6, 1999 Jennings et al. Jinet al., “Thermotropic Liquid Crystalline Polyesters With Rigid or
5,929,201 7, 1999 Gibbons et al. Flexible Spacer Groups.” The British Polymer Journal. 132-146
5,954,966 * 9, 1999 Matsuura et al. ............. 210,640 (1980).
6,111,049 8, 2000 Sendijarevic et al. Kakimoto et al., “Preparation and Properties of Fluorine-Containing
6,127,485 10, 2000 Klun et al. Polyarylates From Tetrafluoroisophthaloyl Chloride and
6,127,507 10, 2000 Santerre Bisphenols,” Journal of Polymer Science. Part A. Polymer Chemis
6,254,645 B1 T/2001 Kellis, Jr. et al. try, 25: 2747-2753 (1987).
6,348, 152 2, 2002 Kawahara et al. ....... 210,500.24 Khayet et al., “Application of Surface Modifying Macromolecules
6,353,057 B1 3, 2002 He et al.
6,448,364 B1 9, 2002 Clatty et al. for the Preparation of Membranes for Membrane Distillation.”
6,685,832 2, 2004 Mahendran et al. 210,321.8 Desalination 158: 51-56, 2003.
B2
8,071,683 12, 2011 Mullick et al. Khayet et al., “Design of Novel Direct Contact Membrane Distilla
B2
8, 178,620 5, 2012 Mullick et al. tion Membranes.” Desalination 192: 105-111, 2006.
2004/O1211.75 A1 6, 2004 Flexman et al. Kim et al., “Application of Surface Modifying Macromolecules in
2004/O234575 11, 2004 Horres et al. ................. 424/426 Poly(Ether Suflone) Ultrafiltration Membranes: Influence on Surface
2005/0176893 8, 2005 Rana et al. .. 525/242 Morphology.” Research Study, University of Ottawa and Myongji
2007/0O37891 2, 2007 Esfand et al. .............. 514,772.1 University, Korea (6 pages).
US 8,877,062 B2
Page 3
(56) References Cited Tang et al., “Synthesis of Surface-Modifying Macromolecules for

use in Segmented Polyurethanes,” Journal of Applied Polymer Sci
OTHER PUBLICATIONS ence, 62: 1133-1145 (1996).
Tang et al., “Use of Surface-Modifying Macromolecules to Enhance
Kulesza et al., “Thermal Decomposition of Bisphenol A-Based the Biostability of Segmented Polyurethanes,” Journal of Biomedical
Polyetherurethanes Blown With Pentane Part I-Thermal and Materials Research Part A, 35:371-381 (1997).
Pyrolytical Studies,” J. Anal. Appl. Pyrolysis, 76: 243-248 (2006).
La Mantia et al., “Thermo-Mechanical Degradation of Polymer Office Action pertaining to U.S. Appl. No. 08/690,108 mailed Oct.
Blends.” Die Angewandte Makromolekulare Chemie, 216: 45-65 31, 1997.
(1994). Office Action pertaining to U.S. Appl. No. 08/690,108 mailed Apr.
Liaw et al., “Curing Kinetics of Epoxy Resins Based on Bisphenol-S 24, 1998.
and its Derivatives.” Die Angewandte Makromolekulare Chemie, Examination Report issued for European Patent Application No. 96
200: 137-146 (1992). 925 626.2-2115, dated Dec. 15, 1998.
Liaw et al., “Synthesis of Epoxy Resins Based on Bisphenol-Sand its Examination Report issued for European Patent Application No. 96
Derivatives.” Die Angewandte Makromolekulare Chemie, 199: 171 925 626.2-2115, dated Apr. 30, 1999.
190 (1992). Office Action pertaining to U.S. Appl. No. 09/198,268, mailed May
Liaw et al., “Radical Polymerization of Mono- and Di-Methacrylic
Esters Containing Bisphenol-S.” Die Angewandte Makromolekulare 12, 1999.
Chemie, 207:43-52 (1993). Office Action pertaining to U.S. Appl. No. 09/198,268, mailed Jan.
Liaw et al., “Curing of Acrylated Epoxy Resin Based on Bisphenol 21, 2000.
S.” Polymer Engineering and Science, 34(16): 1297-1303 (1994). Examination Report issued for European Patent Application No. 96
Liaw, “The Relative Physical and Thermal Properties of 925 626.2-2115, dated Feb. 17, 2000.
Polyurethane Elastomers: Effect of Chain Extenders of Bisphenols, International Search Report and Written Opinion (PCT/US07/
Diisocyanate, and Polyol Structures,” Journal of Applied Polymer 25577) mailed Apr. 17, 2008.
Science, 66: 1251-1265 (1997). International Preliminary Report on Patentability for PCT/US07/
Marks, “Interfacial Synthesis and Characterization of Random and 25577 issued Jun. 16, 2009.
Segmented Block Bisphenol A-Tetrabromobisphenol A
Copolycarbonates,” Journal of Applied Polymer Science, 52: 467 International Search Report and Written Opinion for PCT/US2009/
481 (1994). 055418, dated Oct. 20, 2009.
Maruyama et al., “Synthesis and Properties of Polyarylates From Office Action pertaining to U.S. Appl. No. 12/002,226 mailed Jan. 26.
2.2-Bis(4-hydroxyphenyl)-1,1,1,3,3,3-Hexafluoropropane and Aro 2010.
matic Diacid Chlorides,” Journal of Polymer Science. Part A. Poly Extended European Search Report from European Patent Applica
mer Chemistry, 24: 3555-3558 (1986). tion No. 07862900.3, dated Jul. 27, 2010.
Maruyama et al., “Synthesis and Properties of Fluorine-Containing Office Action pertaining to U.S. Appl. No. 12/002.226 mailed Oct. 5,
Aromatic Polybenzoxazoles from Bis(O-aminophenols) and Aro 2010.
matic Diacid Chlorides by the Sillylation Method.” Macromolecules, European Search Report issued for European Patent Application No.
21(8): 2305-2309 (1988). 10014044, dated Jan. 26, 2011.
Mitsui NOTIOTM Nano-crystal Structure Controlled Elastomer International Preliminary Report on Patentability for PCT/US2009/
(available at www.mitsuichemicals.com otion.htm#). 055418, dated Mar. 1, 2011.
Mohd-Norddin et al., “Charged Surface Modifying Macromolecules European Search Report for European Patent No. 07862900.3, dated
in Polymer Electrolyte Membrane.” Jurnal Teknologi 49(F): 91-102,
2008. Jun. 20, 2011.
Nagata et al., “Synthesis and Properties of Polyamides Derived from European Search Report for European Patent No. 07862900.3, dated
Systematically Halogenated Terephthalic Acids with Fluorine, Chlo Mar. 28, 2012.
rine, or Bromine Atoms,” Journal of Polymer Science. Part A. Poly Office Action for U.S. Appl. No. 13/323.427 dated Apr. 9, 2012.
mer Chemistry, 26: 235-245 (1988). Office Action for Chinese Application No. 200980 142814.7, mailed
Shimizu et al., “Synthesis and Characterization of Fluorine Jul. 4, 2012.
Countaining Aromatic Polyethers From Tetrafluoroisophthalonitrile Office Action for U.S. Appl. No. 13/060,542 dated Jul. 5, 2012.
and Bisphenols,” Journal of Polymer Science. Part A. Polymer English Translation of the Second Office Action for Chinese Patent
Chemistry, 25: 2385-2393 (1987). Application No. 201080001316.2, mailed Apr. 17, 2014 (21 pages).
Suk et al., “Study on the Kinetics of Surface Migration of Surface English Translation of First Office Action for Chinese Patent Appli
Modifying Macromolecules in Membrane Preparation.” Macromol cation No. 201080001316.2, mailed Sep. 12, 2013 (17 pages).
ecules 35:30 17-3021, 2002. First Office Action for European Patent Application No. 10014044.1.
Suket al., “Effects of Surface Modifying Macromolecule (SMM) on mailed Nov. 8, 2013 (4 pages).
the Properties of polyethersulfone Membranes.” Desalination 149: Second Office Action for European Patent Application No.
303-307, 2002. 10014044.1, mailed Apr. 24, 2014 (5 pages).
Sukumar et al., “Synthesis and Thermal Studies of Block Copoly
mers from NR and MDI-Based Polyurethanes,” Journal of Applied Office Action for Canadian Patent Application No. 2,716,502, mailed
Polymer Science, 111: 19-28 (2009). Feb. 19, 2014 (2 pages).
Tang et al., "Surface Modifying Macromolecules for Improved Office Action for Australian Patent Application No. 2010224421,
Resistance of Polyurethanes to Biodegradation.” Canadian mailed May 23, 2014 (3 pages).
Biomaterials Society Meeting, Quebec City, QC, 1994. English Translation of Final Office Action for Japanese Patent Appli
Tang et al., “The Use of Surface Modifying Macromolecules to cation No. 2013-516412, mailed Jun. 17, 2014 (4 pages).
Inhibit Biodegradation of Segmented Polyurethanes.” Society for English Translation of First Office Action for Japanese Patent Appli
Biomaterials, Boston, MA, 1994. cation No. 2013-516412, mailed Dec. 17, 2014 (5 pages).
Tang, "Surface Modifying Macromolecules for Biomaterials.”
Department of Chemical Engineering, University of Ottawa, 1995. * cited by examiner
U.S. Patent Nov. 4, 2014 Sheet 1 of 31 US 8,877,062 B2
U.S. Patent US 8,877,062 B2
"IN
=
000!
O|
No.terw-ºf,^~ )—, ^,…)

O O ||Of
| Î |
“IN
=
I
000
99.InÃ¡I
p-I A
L0.InÃ¡H
NHO
OVH384-190
U.S. Patent Nov. 4, 2014 US 8,877,062 B2
OR
O
pg3ør40e tpagie3n.?
i
Figure 23
Average change in Pr: Control vs. V-a and X-a (n - 6)

Average Gamma Count/10: Control vs. Vill-a and X-a (n = 6)
s
e
Es 1200
C
E
s 1000 Pr change: Control vs. V -a and
X-a
S
Gamma Count: Control vs. VII-a
O
800 xx. -------------------------------------------------------------------------
s
SOC
E
5
is 400
3. 2CO
C
Control : Wi-a X-a
Figure 24A
Control
Figure 24B
U.S. Patent Nov. 4, 2014 Sheet 25 Of 31 US 8,877,062 B2
Figure 25A igur e 25B
Figure 25C
Figure 26A
Control
Figure 26B
Figure 26C Figure 26D

Figure 28A
Figure 288
U.S. Patent Nov. 4, 2014 Sheet 29 Of 31 US 8,877,062 B2
Figure 29A
Figure 29B
Figure 30A
via x-a
Figure 30B
Figure 3A
Figure 31B
US 8,877,062 B2
1. 2
ANTITHROMBOGENIC HOLLOW FIBER (2003)). When the filters clog, the dialysis procedure is inter
MEMBRANES AND FILTERS rupted, and the filters are flushed with saline solution to clear
the thrombus. In patients undergoing chronic hemodialysis
CROSS-REFERENCE TO RELATED (e.g., hemodialysis for extended hours at a time and with
APPLICATIONS multiple sessions during a week) it is common to use heparin
in bolus amounts to reduce the rate of filter clogging.
This application is a continuation-in-part of U.S. applica While advantageous, the use of heparin in some patients
tion Ser. No. 12/780.200, filed May 14, 2010, which claims can be complicated by allergic reactions and bleeding, and
benefit from U.S. Provisional Application No. 61/178,861, can be contraindicated for use in patients taking certain medi
filed May 15, 2009, hereby incorporated by reference. 10
cations.
BACKGROUND OF THE INVENTION Some medical procedures require the use of extracorporeal
oxygenating methods, where blood is taken out from the
The invention relates to antithrombogenic extracorporeal living body of the patient to be oxygenated and the oxygen
blood circuits and components thereof, such as hollow fiber 15 ated blood is then returned to the body. For example, oxygen
membranes, blood tubing, and filters, and their use in hemo ator devices implementing Such extracorporeal oxygenating
filtration, hemodialysis, hemodiafiltration, hemoconcentra methods include heart-lung bypass units or extracorporeal
tion, blood oxygenation, and related uses. membrane oxygenation (ECMO) machines used during open
For a treatment of a patient suffering from renal failure, heart Surgery, such as coronary artery bypass grafting
various blood purifying methods have been proposed in (CABG) and cardiac valve replacement, or used to treat res
which blood is taken out from the living body of the patient to piratory distress syndrome or respiratory insufficiencies.
be purified and the purified blood is then returned into the During open heart Surgery, devices for hemoconcentration
body. For example, the blood purification methods utilizing can also be used to increase various blood components within
extracorporeal circulation are classified into the following the patient, thus minimizing the risk of post-operative bleed
types: hemodialysis (HD) by diffusion, hemofiltration (HF) 25 ing. These hemoconcentrators can be used in-line with an
which performs body fluid removal/substitution by ultrafil extracorporeal circuit that includes an oxygenator device,
tration, and hemodiafiltration (HDF) in which HD and HF are Such as a heart-lung bypass unit.
combined. Based on these treatments that require the use of pumping
The above-mentioned methods are implemented using a blood out of and into a patient, there is a need for extracor
hemodialyzer. The dialyzer is the piece of equipment that 30
poreal blood circuits that have reduced thrombogenicity. In
actually filters the blood of waste solutes and fluids (e.g., urea, particular, there is a need for methods and compositions to
potassium, creatinine, and uric acid). Almost all dialyzers in provide a polymeric component of an extracorporeal blood
use today are of the hollow-fiber variety. A cylindrical bundle circuit with a surface that minimizes the rate of thrombosis
of hollow fibers, whose walls are composed of semi-perme upon exposure to blood.
able membrane, is anchored at each end into potting com 35
pound (a sort of glue). This assembly is then put into a clear SUMMARY OF THE INVENTION
plastic cylindrical shell with four openings. One opening or
blood port at each end of the cylinder communicates with
each end of the bundle of hollow fibers. This forms the “blood The methods and compositions of the invention features
compartment of the dialyzer. Two other ports are cut into the 40 extracorporeal blood circuits, and components thereof (e.g.,
side of the cylinder. These communicate with the space hollow fiber membranes, potted bundles, and blood tubing),
around the hollow fibers, the “dialysate compartment.” Blood including 0.005% to 10% (w/w) surface modifying macro
is pumped via the blood ports through this bundle of verythin molecule.
capillary-like tubes, and the dialysate is pumped through the In a first aspect, the invention features an extracorporeal
space Surrounding the fibers. Pressure gradients are applied 45 blood circuit including a polymeric component, where the
when necessary to move fluid from the blood to the dialysate polymeric component includes a base polymer admixed with
compartment. from 0.005% to 10% (w/w) of a surface modifying macro
Hemodialysis is an important procedure that plays the role molecule (e.g., from 0.005% to 0.1% (w/w), from 0.005% to
of an artificial kidney and replaces all vital functions due to 5% (w/w), from 0.1% to 0.3% (w/w), from 0.1% to 5% (w/w),
chronic or acute kidney failure. The dialyzer may be used for 50
from 0.1% to 10% (w/w), from 0.05% to 5% (w/w), 0.05% to
the treatment of patients with renal failure, fluid overload, or 8% (w/w), from 1% to 5% (w/w), from 1% to 8% (w/w), from
toxemic conditions, and can be configured to perform HD, 1% to 10% (w/w), and from 2% to 10% (w?w)), where the
HF, HDF, or hemoconcentration. polymeric component has a surface positioned to contact the
While the blood is being transported to and from the body blood when the extracorporeal blood circuit is in use, and
or cleaned in the dialyzer, an anticoagulant, Such as heparin, 55
where the surface is antithrombogenic when contacted with
may be added to prevent clotting or thrombosis. For patients the blood. In one embodiment, the thrombi deposition at the
receiving continuous renal replacement therapy (CRRT) (i.e.,
continuous dialysis 24 hours/7 days a week), heparin is typi surface is reduced by at least 10%, 20%, 40%, 60%, or 80%
cally given as a bolus systemically to prevent clogging of (e.g., from 10% to 95%, from 10% to 80%, from 20% to 95%,
filter membranes during dialysis due to coagulation of blood. 60 from 35% to 85%, or from 40% to 80%) when contacted with
In cases where no heparin is administered filters clog 27% of blood. In another embodiment, the extracorporeal blood cir
the time, while with heparin filters clog 17% of the time (see cuit has an increased average functional working life of at
Richardson et al., Kidney International 70:963-968 (2006)). least 110%, 125%, 150%,200%, or 400% (e.g., from 110% to
For patients receiving intermittent hemodialysis (IHD) (inter 1,000%, from 200% to 900%, or from 300% to 900%). In yet
mittent dialysis of about 4 hours twice daily), typically no 65 another embodiment, the extracorporeal blood circuit
heparin is administered. During IHD the filters clog 20-30% reduces adverse advents in a Subject receiving blood passing
of time (see Manns et al., Critical Care Medicine 31:449-455 through the extracorporeal blood circuit.
US 8,877,062 B2
3 4
Any of the extracorporeal blood circuits described herein ments, the bundle has an increased average functional work
can include one or more of a hollow fiber membrane of the ing life of at least 110%, 125%, 150%, 200%, or 400% (e.g.,
invention; a potted bundle of the invention; or a blood tubing from 110% to 1,000%, from 125% to 1,000%, from 200% to
of the invention. 900%, or from 300% to 900%). In other embodiments, the
In a second aspect, the invention features a hollow fiber 5 thrombi deposition on the potted bundle is reduced by at least
membrane, the hollow fiber membrane including a base poly 10%, 20%, 40%, 60%, or 80% (e.g., from 10% to 95%, from
mer admixed with from 0.005% to 10% (w/w) surface modi 10% to 80%, from 20% to 95%, from 35% to 85%, or from
fying macromolecule (e.g., from 0.005% to 0.1% (w/w), from 40% to 80%) when contacted with blood. In still other
0.005% to 5% (w/w), from 0.1% to 0.3% (w/w), from 0.1% to embodiments, the bundle has an operating pressure after 4
5% (w/w), from 0.1% to 10% (w/w), from 0.05% to 5% 10 hours of use that is reduced by at least 10%, 20%, 30%, 40%,
(w/w), 0.05% to 8% (w/w), from 1% to 5% (w/w), from 1% or 50% (e.g., from 10% to 95%, from 10% to 80%, from 20%
to 8% (w/w), from 1% to 10% (w/w), and from 2% to 10% to 75%, from 25% to 45%, or from 30% to 80%). In some
(w/w)), where the hollow fiber membrane is antithrombo embodiment, the potted bundle reduces adverse advents in a
genic when contacted with blood. In one embodiment, the Subject receiving blood passing through the potted bundle. In
thrombi deposition on the hollow fiber membrane is reduced 15 other embodiments, the potting resin is antithrombogenic
by at least 10%, 20%, 40%, 60%, or 80% (e.g., from 10% to when contacted with blood.
95%, from 10% to 80%, from 20% to 95%, from 35% to 85%, In one embodiment, the bundle of potted hollow fiber
or from 40% to 80%) when contacted with blood. In another membranes within an encasement is part of a blood purifica
embodiment, the hollow fiber membrane has an operating tion device (e.g., hemodialysis, hemodiafiltration, hemofil
pressure after 4 hours of use that is reduced by at least 10%, tration, hemoconcentration, or oxygenator device). In yet
20%, 30%, 40%, or 50% (e.g., from 10% to 95%, from 10% another embodiment, the potting resin is a cross-linked poly
to 80%, from 20% to 75%, from 25% to 45%, or from 30% to urethane (e.g., a cross-linked polyurethane formed from
80%). In yet another embodiment, the hollow fiber membrane 4'-methylene bis(cyclohexyl isocyanate; 2,2'-methylene bis
reduces adverse advents in a Subject receiving blood passing (phenyl) isocyanate; 2,4'-methylene bis(phenyl) isocyanate;
through the hollow fiber membrane. In certain embodiments, 25 or 4,4'-methylene bis(phenyl) isocyanate).
the base polymer is selected from the group consisting of a In another aspect, the invention features a dialysis filter
polysulfone (e.g., poly(oxy-1,4-phenylene Sulfonyl-1,4-phe including any hollow fiber membrane described herein or any
nyleneoxy-1,4-phenyleneisopropylidene-1,4-phenylene) or potted bundle described herein, where the filter has a pro
polyether Sulfone), a polyacrylonitrile, a cellulose acetate, a longed working life. In one embodiment, the dialysis filter
cellulose di- or tri-acetate, a polyimide, a poly(methyl meth 30 reduces adverse advents in a Subject receiving blood passing
acrylate), a polycarbonate, a polyamide, a polypropylene, and through the dialysis filter.
a polyethylene. In further embodiments, the hollow fiber In another aspect, the invention features a blood tubing
membrane further includes a hydrophilic pore forming agent including a base polymer (e.g., polyvinyl chloride) admixed
(e.g., polyvinylpyrrolidone, ethylene glycol, alcohols, with from 0.005% to 10% (w/w) (e.g., from 0.005% to 0.1%
polypropylene glycol, and polyethylene glycol, or mixtures 35 (w/w), from 0.005% to 5% (w/w), from 0.1% to 0.3% (w/w),
thereof). In one embodiment, the hollow fiber membrane from 0.1% to 5% (w/w), from 0.1% to 10% (w/w), from
includes from 80% to 96.5% (w/w) (e.g., from 80% to 95%, 0.05% to 5% (w/w), 0.05% to 8% (w/w), from 1% to 5%
from 80% to 90% (w/w), from 85% to 90% (w/w), and from (w/w), from 1% to 8% (w/w), from 1% to 10% (w/w), and
90% to 95% (w?w)) of the base polymer, from 3% to 20% from 2% to 10% (w/w)) surface modifying macromolecule,
(w/w) (e.g., from 3% to 15% (w/w), from 3% to 7% (w/w), 40 where the blood tubing is antithrombogenic when contacted
from 3% to 5% (w/w), and from 5% to 10% (w?w)) of the with blood. In a particular embodiment, the base polymer
hydrophilic pore forming agent, and 0.005% to 10% (w/w) includes polyvinyl chloride. In one embodiment, the blood
(e.g., from 0.005% to 0.1% (w/w), from 0.005% to 5% (w/w), tubing reduces adverse advents in a subject receiving blood
from 0.1% to 0.3% (w/w), from 0.1% to 5% (w/w), from 0.1% passing through the blood tubing. In one embodiment, the
to 10% (w/w), from 0.05% to 5% (w/w), 0.05% to 8% (w/w), 45 thrombi deposition at the surface of the blood tubing is
from 1% to 5% (w/w), from 1% to 8% (w/w), from 1% to 10% reduced by at least 10%, 20%, 40%, 60%, or 80% (e.g., from
(w/w), and from 2% to 10% (w/w)) of the surface modifying 10% to 95%, from 10% to 80%, from 20% to 95%, from 35%
macromolecule. to 85%, or from 40% to 80%) when contacted with blood. In
In a third aspect, the invention features a potted bundle of another embodiment, the blood tubing has an increased aver
hollow fiber membranes within an encasement including: (a) 50 age functional working life of at least 110%, 125%. 150%,
an array of hollow fiber membranes, the array of hollow fiber 200%, or 400% (e.g., from 110% to 1,000%, from 125% to
membranes having lumens, a first set of fiber ends, and a 1,000%, from 200% to 900%, or from 300% to 900%).
second set of fiber ends; (b) the first set of fiber ends being The invention further features method for treating a subject
potted in a potting resin which defines a first internal wall near Suffering from impaired kidney function, the method includ
a first end of the encasement; and (c) the second set of fiber 55 ing performing a procedure selected from hemodialysis,
ends being potted in a potting resin which defines a second hemofiltration, hemoconcentration, or hemodiafiltration on
internal wall near a second end of the encasement, where the the subject using a dialysis filter, where the filter includes any
lumens of the hollow fiber membranes provide a path for the hollow fiber membrane described herein or any potted bundle
flow of blood from the first internal wall to the second internal described herein. In one embodiment, during the procedure
wall, and where the potting resin includes from 0.005% to 60 the Subject receives less than a standard dose of anticoagulant
10% (w/w) Surface modifying macromolecule (e.g., from (e.g., where during the procedure the Subject receives no
0.005% to 0.1% (w/w), from 0.005% to 5% (w/w), from 0.1% anticoagulant). In another embodiment, the filter has a pro
to 0.3% (w/w), from 0.1% to 5% (w/w), from 0.1% to 10% longed working life. In yet another embodiment, the filter has
(w/w), from 0.05% to 5% (w/w), 0.05% to 8% (w/w), from an increased average functional working life of at least 110%,
1% to 5% (w/w), from 1% to 8% (w/w), from 1% to 10% 65 125%, 150%, 200%, or 400% (e.g., from 110% to 1,000%,
(w/w), and from 2% to 10% (w/w)). In certain embodiments, from 125% to 1,000%, from 200% to 900%, or from 300% to
the bundle has a prolonged working life. In some embodi 900%). In one embodiment, the thrombi deposition on the
US 8,877,062 B2
5 6
filter is reduced by at least 10%, 20%, 40%, 60%, or 80% The invention also features a method of potting hollow
(e.g., from 10% to 95%, from 10% to 80%, from 20% to 95%, fiber membranes including the steps of: (a) forming abundle
from 35% to 85%, or from 40% to 80%) when contacted with of hollow fiber membranes, the bundle of hollow fiber mem
blood. In another embodiment, the filter has an operating branes having lumens, a first set offiber ends, and a second set
pressure after 4 hours of use that is reduced by at least 10%, 5 of fiber ends; (b) placing the first set of fiber ends and the
20%, 30%, 40%, or 50% (e.g., from 10% to 95%, from 10% second set of fiber ends in an uncured potting liquid; (c)
to 80%, from 20% to 75%, from 25% to 45%, or from 30% to curing the potting liquid to form a potting resin in which the
80%). In yet another embodiment, the adverse events expe hollow fiber membranes are potted; (d) cutting the potting
rienced by the subject are reduced. resin and fiber ends to form a first wall in which the first set of
The invention features a method for treating a subject suf 10 fiber ends is potted and a second wall in which the second set
fering from impaired cardiac function, the method including of fiber ends is potted; and (e) heating the first wall and the
performing a Surgery selected from a coronary artery bypass second wall (i.e., heating to facilitate the migration of Surface
grafting and a cardiac valve replacement using an oxygenator modifying macromolecule to the surface of the wall), where
device, where the oxygenator device includes any hollow the potting liquid includes from 0.005% to 10% (w/w) (e.g.,
fiber membrane described herein or any potted bundle 15 from 0.005% to 0.1% (w/w), from 0.005% to 5% (w/w), from
described herein. In one embodiment, during the procedure 0.1% to 0.3% (w/w), from 0.1% to 5% (w/w), from 0.1% to
the Subject receives less than a standard dose of anticoagulant 10% (w/w), from 0.05% to 5% (w/w), 0.05% to 8% (w/w),
(e.g., where during the procedure the Subject receives no from 1% to 5% (w/w), from 1% to 8% (w/w), from 1% to 10%
anticoagulant). In another embodiment, the adverse events (w/w), and from 2% to 10% (w/w)) surface modifying mac
experienced by the subject are reduced. romolecule.
The invention features a method for treating a subject, said The invention features a dialysis kit including (i) a hollow
method including withdrawing blood from, and returning fiber membrane of the invention, a potted bundle of the inven
blood to, said subject via any extracorporeal blood circuit tion, a dialysis filter of the invention, and/or blood tubing of
described herein. In one embodiment, during the procedure the invention; and (ii) instructions for performing dialysis on
the Subject receives less than a standard dose of anticoagulant 25 a Subject receiving less than a standard dose of anticoagulant
(e.g., where during the procedure the Subject receives no (e.g., receiving no anticoagulant).
anticoagulant). In another embodiment, the adverse events In any of the hollow fiber membranes described herein, the
experienced by the subject are reduced. Surface modifying macromolecule is selected from VII-a,
The invention also features a method for purifying a pro VIII-a, VIII-b, VIII-c, VIII-d, IX-a, X-a, X-b, XI-a, XI-b,
tein in blood, a blood product (e.g., plasma or fractionated 30 XII-a, XII-b, XIII-a, XIII-b, XIII-c, XIII-d, XIV-a, and XIV
blood component), or a combination thereof, the method b.
including dialyzing the blood, the blood product, or the com In one embodiment, the potting resin includes a surface
bination thereof across any hollow fiber membrane described modifying macromolecule selected from VII-a, VIII-a, IX-a,
herein or any potted bundle described herein. XI-a, VIII-d, and XI-b.
The invention features a hollow fiber plasma purification 35 In another embodiment, the blood tubing includes a surface
membrane, including any bundle of potted hollow fiber mem modifying macromolecule selected from VII-a, XIV-a, and
branes described herein. XIV-b.
The invention also features a spinning Solution for prepar In any of the extracorporeal blood circuits, hollow fiber
ing a hollow fiber membrane, the spinning solution including membranes (or potted bundles thereof or plasma purification
(i) from 57% to 87% (w/w) (e.g., from 57% to 85% (w/w), 40 membranes thereof), potting materials (e.g., potting resin or
from 70% to 87% (w/w), and from 70% to 85% (w?w)) of an potting liquid), blood tubings, dialysis filters, spinning solu
aprotic solvent; (ii) from 10% to 25% (w/w) (e.g., from 10% tions, methods, systems, and kits, the Surface modifying mac
to 20% (w/w), from 12% to 25% (w/w), and from 12% to 20% romolecule is described by any of the formulas(I)-CXIV)
(w/w)) of base polymer; (iii) from 0.005% to 8% (w/w) (e.g., below.
from 0.005% to 5% (w/w), from 0.005% to 3% (w/w), 45 (1)
0.005% to 2% (w/w), from 0.01% to 3% (w/w), and from
0.01% to 2% (w/w)) of surface modifying macromolecule: F-(oligo)-F (I)
and (iv) from 3% to 10% (w/w) (e.g., from 3% to 7% (w/w), wherein F is a polyfluoroorgano group and oligo is an
from 3% to 5% (w/w), and from 5% to 10% (w?w)) of hydro oligomeric segment.
philic pore forming agent. In certain embodiments, the apro 50
(2)
tic solvent is selected from dimethylformamide, dimethylsul
foxide, dimethylacetamide, N-methylpyrrolidone, and
mixtures thereof. In other embodiments, the aprotic solvent (II)
further includes less than 25% (v/v) (i.e., from 1% to 25% FT
(v/v), 1% to 15% (v/v), or 5% to 20% (v/v)) of a low boiling 55
C-(Oligo)-(LinkB)-(Oligo)-C
solvent selected from tetrahydrofuran, diethylether, methyl
ethyl ketone, acetone, and mixtures thereof. In still other
embodiments, the hydrophilic pore forming agent is polyvi wherein
nylpyrrolidone. The spinning Solution can be processed as (i) F is a polyfluoroorgano group covalently attached to
described herein to produce a hollow fiber membrane of the 60 LinkB;
invention. (ii) C is a chain terminating group;
The invention features a method for making a hollow fiber (iii) Oligo is an oligomeric segment;
membrane including the steps of: (a) preparing a homoge (iv) LinkB is a coupling segment; and
neous spinning Solution of the invention; and (b) extruding (v) a is an integer greater than 0.
the homogeneous spinning Solution from an outer annular 65 (3)
orifice of a tube-in-orifice spinneret into an aqueous solution
to form the hollow fiber membrane. F-B-(oligo)-B-F (III)
US 8,877,062 B2
8
wherein (ii) B is a hard segment including an isocyanurate trimer or
(i) B includes a urethane; biuret trimer;
(ii) oligo includes polypropylene oxide, polyethylene (iii) F is a polyfluoroorgano group; and
oxide, or (iv) n is an integer from 0 to 10.
polytetramethylene oxide; (8)
(iii) F is a polyfluoroorgano group; and
(iv) n is an integer from 1 to 10.
(4) wherein
F-B-A-B-F (IV) (i) Oligo is a polycarbonate polyol having a theoretical
wherein
10 molecular weight of from 500 to 3,000 Daltons (e.g., from
500 to 2,000 Daltons, from 1,000 to 2,000 Daltons, or from
(i) A is a soft segment including hydrogenated polybutadi 1,000 to 3,000 Daltons):
ene, poly(2.2 dimethyl-1-3-propylcarbonate), polybutadiene, (ii) B is a hard segment formed from an isocyanate dimer;
poly(diethylene glycol)adipate, poly(hexamethylene carbon (iii) F is a polyfluoroorgano group; and
ate), poly(ethylene-co-butylene), neopentyl glycol-ortho 15 (iv) n is an integer from 1 to 10.
phthalic anhydride polyester, diethylene glycol-ortho (9)
phthalic anhydride polyester, 1.6-hexanediol-orthophthalic
anhydride polyester, or bisphenol A ethoxylate:
(ii) B is a hard segment including a urethane; and F (X)
(iii) F is a polyfluoroorgano group, and F T F
(iv) n is an integer from 1 to 10. ----Y T
(5) M * \
FT FT
F (V) 25 wherein
F T F
(i) A is an oligomeric segment including a polycarbonate
M
----Y
* \
T polyol having a theoretical molecular weight of from 500 to
FT FT, 3,000 Daltons (e.g., from 500 to 2,000 Daltons, from 1,000 to
F F (VI) 30 2,000 Daltons, or from 1,000 to 3,000 Daltons):
(ii) B is a hard segment including an isocyanurate trimer or
'----
? * \
T biuret trimer;
(iii) F is a polyfluoroorgano group; and
FT FT, (iv) n is an integer from 0 to 10.
(10)
wherein 35
(i) A is a Soft segment;
(ii) B is a hard segment including a isocyanurate trimer or (XI)
FT FT
biuret trimer;
(iii) each Fis a polyfluoroorgano group; and
(iv) n is an integer between 0 to 10. 40 M
'a-A-B-A-Y
* \
FT FT
(6)
F-B-(Oligo)-B-F (VII)
wherein
wherein
(i) Oligo is an oligomeric segment including polypropy (i) A includes a first block segment selected from polypro
45 pylene oxide, polyethylene oxide, polytetramethyleneoxide,
lene oxide, polyethylene oxide, or polytetramethyleneoxide or mixtures thereof, and a second block segment including a
and having a theoretical molecular weight of from 500 to polysiloxane or polydimethylsiloxane, wherein A has a theo
3,000 Daltons (e.g., from 500 to 2,000 Daltons, from 1,000 to retical molecular weight of from 1,000 to 5,000 Daltons (e.g.,
2,000 Daltons, or from 1,000 to 3,000 Daltons): from 1,000 to 3,000 Daltons, from 2,000 to 5,000 Daltons, or
(ii) B is a hard segment formed from an isocyanate dimer; 50
from 2,500 to 5,000 Daltons);
(iii) F is a polyfluoroorgano group; and (ii) B is a hard segment including an isocyanurate trimer or
(iv) n is an integer from 1 to 10. biuret trimer;
(7) (iii) F is a polyfluoroorgano group; and
(iv) n is an integer from 0 to 10.
55
(11)
F (VIII)
F T F F-B-A-B-F (XII)
M
----
* \
T wherein
FT FT
(i) A is a soft segment selected from hydrogenated polyb
60 utadiene
(HLBH) diol (e.g., HLBH diol), polybutadiene (LBHP)
wherein diol (e.g., LBHP diol), hydrogenated polyisoprene (HHTPI)
(i) A is an oligomeric segment including polypropylene diol (e.g., HHTPIdiol), and polystyrene and has a theoretical
oxide, polyethylene oxide, polytetramethyleneoxide, or mix molecular weight of from 750 to 3,500 Daltons (e.g., from
tures thereof, and having a theoretical molecular weight of 65 750 to 2,000 Daltons, from 1,000 to 2,500 Daltons, or from
from 500 to 3,000 Daltons (e.g., from 500 to 2,000 Daltons, 1,000 to 3,500 Daltons):
from 1,000 to 2,000 Daltons, or from 1,000 to 3,000 Daltons): (ii) B is a hard segment formed from an isocyanate dimer;
US 8,877,062 B2
10
(iii) F is a polyfluoroorgano group; and hydrogenated polybutadiene (HLBH), poly(2.2 dimethyl-1-
(iv) n is an integer from 1 to 10. 3-propylcarbonate) (PCN), polybutadiene (LBHP), polytet
(12) ramethylene oxide (PTMO), (propylene)oxide (PPO), dieth
yleneglycol-orthophthalic anhydride polyester (PDP),
hydrogenated polyisoprene (HHTPI), poly(hexamethylene
(XIII) carbonate), poly(2-butyl-2-ethyl-1,3-propyl carbonate), or
FT FT hydroxyl terminated polydimethylsiloxane (C22). In other
M
'a-a-b-a *-\ embodiments of the Surface modifying macromolecule of
formulas (V) and (VI), the hard segment is formed by reacting
FT FT 10 atriisocyanate with a diol including the soft segment, wherein
the triisocyanate is selected from hexamethylene diisocyan
wherein ate (HDI) biuret trimer, isophorone diisocyanate (IPDI) tri
(i) A is a Soft segment selected from hydrogenated polyb mer, or hexamethylene diisocyanate (HDI) trimer.
utadiene (HLBH) diol (e.g., HLBH diol), polybutadiene In Some embodiments of the Surface modifying macromol
(LBHP) diol (e.g., LBHP diol), hydrogenated polyisoprene 15 ecule of formula (VII), B is a hard segment formed from
3-isocyanatomethyl, 3.5.5-trimethyl cyclohexylisocyanate;
(HHTPI) diol (e.g., HHTPI diol), and polystyrene and has a 4,4'-methylene bis(cyclohexyl isocyanate); 4,4'-methylene
theoretical molecular weight of from 750 to 3,500 Daltons bis(phenyl) isocyanate; toluene-2.4 diisocyanate); m-tetram
(e.g., from 750 to 2,000 Daltons, from 1,000 to 2,500 Daltons, ethylxylene diisocyanate; and hexamethylene diisocyanate;
or from 1,000 to 3,500 Daltons): and n is an integer from 1 to 3. In one particular embodiment,
(ii) B is a hard segment including an isocyanurate trimer or the surface modifying macromolecule of formula (VII) is
biuret trimer; VII-a. The surface modifying macromolecules of formula
(iii) F is a polyfluoroorgano group; and (VII) can be used in an extracorporeal blood circuit of the
(iv) n is an integer from 0 to 10. invention, or a component thereof. Such as a hollow fiber
(13) 25 membrane, potted bundle, blood tubing, or dialysis filter, and
in conjunction with any methods, systems, and kits of the
invention described herein. For example, the surface modify
F
F
T F
(XIV) ing macromolecules of formula (VII) can be added to poly
vinyl chloride to make an antithrombogenic blood tubing;
M
----
* \
T 30 added to a potting material to make an antithrombogenic
FT FT potted bundle; and/or added to the base polymer of a hollow
fiber membrane (e.g., a polysulfone, a polyacrylonitrile, a
cellulose acetate, a cellulose di- or tri-acetate, a polyimide, a
wherein poly(methyl methacrylate), a polycarbonate, a polyamide, a
(i) A is a polyester having a theoretical molecular weight of 35 polypropylene, or a polyethylene) to form a hollow fiber
from 500 to 3,500 Daltons (e.g., from 500 to 2,000 Daltons, membrane that is antithrombogenic when contacted with
from 1,000 to 2,000 Daltons, or from 1,000 to 3,000 Daltons): blood.
(ii) B is a hard segment including an isocyanurate trimer or In certain embodiments of the Surface modifying macro
biuret trimer; molecule of formula (VIII), B is a hard segment formed by
(iii) F is a polyfluoroorgano group; and 40 reacting a triisocyanate with a diol of A (e.g., the oligomeric
(iv) n is an integer from 0 to 10. segment), wherein the triisocyanate is selected from hexam
In certain embodiments, the Surface modifying macromol ethylene diisocyanate (HDI) biuret trimer, isophorone diiso
ecule of formulas (I) and (II) include an oligo segment that is cyanate (IPDI) trimer, and hexamethylene diisocyanate
a branched or non-branched oligomeric segment of fewer (HDI) trimer; and n is 0, 1, 2, or 3. In one particular embodi
than 20 repeating units (e.g., from 2 to 15 units, from 2 to 10 45 ment, the Surface modifying macromolecule of formula
units, from 3 to 15 units, and from 3 to 10 units). In another (VIII) is VIII-a, VIII-b, VIII-c, or VIII-d. The surface modi
embodiment, the Surface modifying macromolecule of for fying macromolecules of formula (VIII) can be used in an
mulas (I) and (II) include an oligomeric segment selected extracorporeal blood circuit of the invention, or a component
from polyurethane, polyurea, polyamide, polyalkylene thereof, such as a hollow fiber membrane, potted bundle,
oxide, polycarbonate, polyester, polylactone, polysilicone, 50 blood tubing, or dialysis filter, and in conjunction with any
polyetherSulfone, polyolefin, polyvinyl derivative, polypep methods, systems, and kits of the invention described herein.
tide, polysaccharide, polysiloxane, polydimethylsiloxane, For example, the Surface modifying macromolecules of for
polyethylene-butylene, polyisobutylene, polybutadiene, mula (VIII) can be added to polyvinyl chloride to make an
polypropylene oxide, polyethylene oxide, polytetramethyl antithrombogenic blood tubing; added to a potting material to
ene oxide, or polyethylenebutylene segments. 55 make an antithrombogenic potted bundle; and/or added to the
In certain embodiments, the Surface modifying macromol base polymer of a hollow fiber membrane (e.g., a polysulfone,
ecule of formulas (IV) include a hard segment formed from a a polyacrylonitrile, a cellulose acetate, a cellulose di- or tri
diisocyanate selected from 3-isocyanatomethyl, 3.5.5-trim acetate, a polyimide, a poly(methyl methacrylate), a polycar
ethyl cyclohexylisocyanate; 4,4'-methylene bis(cyclohexyl bonate, a polyamide, a polypropylene, or a polyethylene) to
isocyanate); 4,4'-methylene bis(phenyl)isocyanate; toluene 60 form a hollow fiber membrane that is antithrombogenic when
2.4 diisocyanate); m-tetramethylxylene diisocyanate; and contacted with blood.
hexamethylene diisocyanate; and n is 1 or 2. In certain embodiments of the Surface modifying macro
In certain embodiments, the Surface modifying macromol molecule of formula (IX), Oligo includes poly (2.2 dimethyl
ecule of formulas (V) and (VI) include a soft segment having 1-3-propylcarbonate) (PCN) polyol (e.g., PCN diol); B is a
a theoretical molecular weight of 500 to 3,500 Daltons (e.g., 65 hard segment formed from 3-isocyanatomethyl, 3.5.5-trim
from 500 to 2,000 Daltons, from 1,000 to 2,000 Daltons, or ethyl cyclohexylisocyanate; 4,4'-methylene bis(cyclohexyl
from 1,000 to 3,000 Daltons) and/or the soft segment includes isocyanate); 4,4'-methylene bis(phenyl) isocyanate; toluene
US 8,877,062 B2
11 12
2.4 diisocyanate); m-tetramethylxylene diisocyanate; and bonate, a polyamide, a polypropylene, or a polyethylene) to
hexamethylene diisocyanate; and n is 1, 2, or 3. In one par form a hollow fiber membrane that is antithrombogenic when
ticular embodiment, the Surface modifying macromolecule of contacted with blood.
formula (IX) is IX-a. The surface modifying macromolecules In certain embodiments of the Surface modifying macro
of formula (IX) can be used in an extracorporeal blood circuit 5 molecule of formula (XII), A includes hydrogenated polyb
of the invention, or a component thereof. Such as a hollow utadiene diol; B is a hard segment formed from 3-isocy
fiber membrane, potted bundle, blood tubing, or dialysis fil anatomethyl, 3.5.5-trimethyl cyclohexylisocyanate; 4,4'-
ter, and in conjunction with any methods, systems, and kits of methylene bis(cyclohexyl isocyanate); 4,4'-methylene bis
the invention described herein. For example, the surface (phenyl) isocyanate; toluene-2.4 diisocyanate);
modifying macromolecules of formula (IX) can be added to 10 m-tetramethylxylene diisocyanate; and hexamethylene diiso
polyvinyl chloride to make an antithrombogenic blood tub cyanate; and n is 1, 2, or 3. In one particular embodiment, the
ing; added to a potting material to make an antithrombogenic surface modifying macromolecule of formula (XII) is XII-a
potted bundle; and/or added to the base polymer of a hollow or XII-b. The surface modifying macromolecules of formula
fiber membrane (e.g., a polysulfone, a polyacrylonitrile, a (XII) can be used in an extracorporeal blood circuit of the
15 invention, or a component thereof. Such as a hollow fiber
cellulose acetate, a cellulose di- or tri-acetate, a polyimide, a membrane, potted bundle, blood tubing, or dialysis filter, and
poly(methyl methacrylate), a polycarbonate, a polyamide, a in conjunction with any methods, systems, and kits of the
polypropylene, or a polyethylene) to form a hollow fiber invention described herein. For example, the surface modify
membrane that is antithrombogenic when contacted with ing macromolecules of formula (XII) can be added to poly
blood. vinyl chloride to make an antithrombogenic blood tubing;
In certain embodiments of the Surface modifying macro added to a potting material to make an antithrombogenic
molecule of formula (X), A includes poly (2.2 dimethyl-1-3- potted bundle; and/or added to the base polymer of a hollow
propylcarbonate) (PCN) polyol (e.g., PCN diol) or poly(hex fiber membrane (e.g., a polysulfone, a polyacrylonitrile, a
amethylene carbonate) (PHCN) polyol; B is a hard segment cellulose acetate, a cellulose di- or tri-acetate, a polyimide, a
formed by reacting a triisocyanate with a diol of A (e.g., the 25 poly(methyl methacrylate), a polycarbonate, a polyamide, a
oligomeric segment), wherein the triisocyanate is selected polypropylene, or a polyethylene) to form a hollow fiber
from hexamethylene diisocyanate (HDI) biuret trimer, iso membrane that is antithrombogenic when contacted with
phorone diisocyanate (IPDI) trimer, and hexamethylene blood.
diisocyanate (HDI) trimer; and n is 0, 1, 2, or 3. In one In certain embodiments of the Surface modifying macro
particular embodiment, the Surface modifying macromol 30 molecule of formula (XIII), A is selected from hydrogenated
ecule of formula (X) is X-a or X-b. The surface modifying polybutadiene (HLBH) diol (e.g., HLBH diol), and hydroge
macromolecules of formula (X) can be used in an extracor nated polyisoprene (HHTPI) diol (e.g., HHTPI diol); B is a
poreal blood circuit of the invention, or a component thereof, hard segment formed by reacting a triisocyanate with a diol of
such as a hollow fiber membrane, potted bundle, blood tub A (e.g., the oligomeric segment), wherein the triisocyanate is
ing, or dialysis filter, and in conjunction with any methods, 35 selected from hexamethylene diisocyanate (HDI) biuret tri
systems, and kits of the invention described herein. For mer, isophorone diisocyanate (IPDI) trimer, and hexameth
example, the Surface modifying macromolecules of formula ylene diisocyanate (HDI) trimer; and n is 0, 1, 2, or 3. In one
(X) can be added to polyvinyl chloride to make an antithrom particular embodiment, the Surface modifying macromol
bogenic blood tubing; added to a potting material to make an ecule of formula (XIII) is XIII-a, XIII-b, XIII-c, or XIII-d.
antithrombogenic potted bundle; and/or added to the base 40 The surface modifying macromolecules of formula (XIII) can
polymer of a hollow fiber membrane (e.g., a polysulfone, a be used in an extracorporeal blood circuit of the invention, or
polyacrylonitrile, a cellulose acetate, a cellulose di- or tri a component thereof. Such as a hollow fiber membrane, potted
acetate, a polyimide, a poly(methyl methacrylate), a polycar bundle, blood tubing, or dialysis filter, and in conjunction
bonate, a polyamide, a polypropylene, or a polyethylene) to with any methods, systems, and kits of the invention
form a hollow fiber membrane that is antithrombogenic when 45 described herein. For example, the Surface modifying mac
contacted with blood. romolecules of formula (XIII) can be added to polyvinyl
In certain embodiments of the Surface modifying macro chloride to make an antithrombogenic blood tubing; added to
molecule of formula (XI), A is a includes polypropylene a potting material to make an antithrombogenic potted
oxide and polydimethylsiloxane; B is a hard segment formed bundle; and/or added to the base polymer of a hollow fiber
by reacting a triisocyanate with a diol of A, wherein the 50 membrane (e.g., a polysulfone, a polyacrylonitrile, a cellu
triisocyanate is selected from hexamethylene diisocyanate lose acetate, a cellulose di- or tri-acetate, a polyimide, a
(HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, poly(methyl methacrylate), a polycarbonate, a polyamide, a
and hexamethylene diisocyanate (HDI) trimer; and n is 0,1,2, polypropylene, or a polyethylene) to form a hollow fiber
or 3. In one particular embodiment, the Surface modifying membrane that is antithrombogenic when contacted with
macromolecule of formula (XI) is XI-a or XI-b. The surface 55 blood.
modifying macromolecules of formula (XI) can be used in an In certain embodiments of the Surface modifying macro
extracorporeal blood circuit of the invention, or a component molecule of formula (XIV), A is selected from poly (diethyl
thereof, such as a hollow fiber membrane, potted bundle, ene glycol)adipate, neopentyl glycol-orthophthalic anhy
blood tubing, or dialysis filter, and in conjunction with any dride polyester, diethylene glycol-orthophthalic anhydride
methods, systems, and kits of the invention described herein. 60 polyester, and 1.6-hexanediol-orthophthalic anhydride poly
For example, the Surface modifying macromolecules of for ester; B is a hard segment formed by reacting a triisocyanate
mula (XI) can be added to polyvinyl chloride to make an with a diol of A (e.g., the polyester segment), wherein the
antithrombogenic blood tubing; added to a potting material to triisocyanate is selected from hexamethylene diisocyanate
make an antithrombogenic potted bundle; and/or added to the (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer,
base polymer of a hollow fiber membrane (e.g., a polysulfone, 65 and hexamethylene diisocyanate (HDI) trimer; and n is 0,1,2,
a polyacrylonitrile, a cellulose acetate, a cellulose di- or tri or 3. In one particular embodiment, the Surface modifying
acetate, a polyimide, a poly(methyl methacrylate), a polycar macromolecule of formula (XIV) is XIV-a or XIV-b. The
US 8,877,062 B2
13 14
surface modifying macromolecules of formula (XIV) can be anates described herein; modified isocyanates derived from
used in an extracorporeal blood circuit of the invention, or a the above diisocyanates; and Substituted and isomeric mix
component thereof. Such as a hollow fiber membrane, potted tures thereof.
bundle, blood tubing, or dialysis filter, and in conjunction In any of formulas (I)-CXIV), the above surface modifying
with any methods, systems, and kits of the invention macromolecule includes the group F that is a polyfluoroalkyl
described herein. For example, the Surface modifying mac having a theoretical molecular weight of between 100-1,500
Da. For example, F may be selected from the group consist
romolecules of formula (XIV) can be added to polyvinyl ing of radicals of the general formula CF (CF), CHCH
chloride to make an antithrombogenic blood tubing; added to wherein r is 2-20, and CF (CF).(CH2CH2O) wherein X is
a potting material to make an antithrombogenic potted 10 1-10 and s is 1-20. Alternatively, F may be selected from the
bundle; and/or added to the base polymer of a hollow fiber group consisting of radicals of the general formula
membrane (e.g., a polysulfone, a polyacrylonitrile, a cellu CHF (CF), CHCH- and CHF.s. (CF2),
lose acetate, a cellulose di- or tri-acetate, a polyimide, a (CH2CH2O) , wherein m is 0, 1, 2, or 3: X is an integer
poly(methyl methacrylate), a polycarbonate, a polyamide, a between 1-10;r is an integer between 2-20; and s is an integer
polypropylene, or a polyethylene) to form a hollow fiber between 1-20. In certain embodiments, F is selected from
membrane that is antithrombogenic when contacted with
15 1H, 1H,2H2H-perfluoro-1-decanol: 1H, 1H,2H2H-per
blood. fluoro-1-octanol; 1H, 1H,5H-perfluoro-1-pentanol; and
1H, 1H, perfluoro-1-butanol, and mixtures thereof. In still
For any of the Surface modifying macromolecules of the other embodiments, F is selected from (CF)
invention formed from an isocyanate dimer, the isocyanate (CF). CHCHO , (CF)(CF). CHCHO ,
dimers can be selected from 3-isocyanatomethyl, 3.5.5-trim (CF)(CF). CHCHO CHF (CF)-CHO , and (CF)
ethyl cyclohexylisocyanate; 4,4'-methylene bis(cyclohexyl (CF),CHO-.
isocyanate) (HMDI); 2.2-, 2,4'-, and 4,4'-methylene bis(phe In another embodiment, the above Surface modifying mac
nyl) isocyanate (MDI); toluene-2.4 diisocyanate; aromatic romolecule has a theoretical molecular weight of less than
aliphatic isocyanate. Such 1.2-, 1.3-, and 1,4-Xylene diisocy 10,000 Daltons (e.g., from 500 to 10,000 Daltons, from 500 to
anate; meta-tetramethylxylene diisocyanate (m-TMXDI): 25 9,000 Daltons, from 500 to 5,000 Daltons, from 1,000 to
para-tetramethylxylene diisocyanate (p-TMXDI); hexameth 10,000 Daltons, from 1,000 to 6,000 Daltons, or from 1,500 to
ylene diisocyanate (HDI): ethylene diisocyanate; propylene 8,000 Daltons).
1.2-diisocyanate; tetramethylene diisocyanate; tetramethyl In still another embodiment, the above surface modifying
ene-1,4-diisocyanate; octamethylene diisocyanate; macromolecule includes from 5% to 40% (w/w) of the hard
decamethylene diisocyanate; 2.2,4-trimethylhexamethylene 30 segment (e.g., from 5% to 35% (w/w), from 5% to 30%
diisocyanate; 2,4,4-trimethylhexamethylene diisocyanate; (w/w), and from 10% to 40% (w?w)), from 20% to 90% (w/w)
dodecane-1,12-diisocyanate; dicyclohexylmethane diisocy of the soft segment (e.g., from 20% to 80% (w/w), from 30%
anate; cyclobutane-1,3-diisocyanate; cyclohexane-1,2-diiso to 90% (w/w), and from 40% to 90% (w?w)), and from 5% to
cyanate; cyclohexane-1,3-diisocyanate; cyclohexane-1,4-di 50% (w/w) of the polyfluoroorgano group (e.g., from 5% to
isocyanate; methyl-cyclohexylene diisocyanate (HTDI); 2.4- 35 40% (w/w), from 5% to 30% (w/w), and from 10% to 40%
methylcyclohexane diisocyanate; 2.6-methylcyclohexane (w/w)).
diisocyanate; 4,4'-dicyclohexyl diisocyanate; 2,4'-dicyclo In one embodiment, the above Surface modifying macro
hexyl diisocyanate; 1,3,5-cyclohexane triisocyanate; isocy molecule has a ratio of hard segment to soft segment of from
anatomethylcyclohexane isocyanate, 1-isocyanato-3.3-5-tri 0.15 to 2.0 (e.g., from 0.15 to 1.8, from 0.15 to 1.5, and from
methyl-5-isocyanatomethylcyclohexane; 40 0.2 to 2.0).
isocyanatoethylcyclohexane isocyanate; bis(isocyanatom As used herein, the term “antithrombogenic’ refers to an
ethyl)-cyclohexane diisocyanate; 4,4'-bis(isocyanatomethyl) extracorporeal blood circuit, or component thereof (e.g., a
dicyclohexane; 2,4'-bis(isocyanatomethyl)dicyclohexane: hollow fiber membrane, blood tubing, dialysis filter, and/or a
isophoronediisocyanate (IPDI); 2.4-hexahydrotoluene diiso potted bundle of hollow fiber membranes) for which the rate
cyanate; 2,6-hexahydrotoluene diisocyanate:3,3'-dimethyl-4, 45 at which thrombosis occurs upon exposure to whole blood
4'-biphenylene diisocyanate (TODI); polymeric MDI; carbo under is reduced in comparison to an otherwise identical
diimide-modified liquid 4,4'-diphenylmethane diisocyanate; extracorporeal blood circuit, or component thereof, that dif
para-phenylene diisocyanate (PPDI); meta-phenylene diiso fers only by the absence of a Surface modifying macromol
cyanate (MPDI); triphenyl methane-4,4'-, and triphenyl ecule tested under the same blood-contacting conditions. A
methane-4.4"-triisocyanate; naphthylene-1,5-diisocyanate; 50 reduced rate of thrombosis can be determined by any of the
2,4'-, 4,4'-, and 2.2-biphenyl diisocyanate; polyphenyl poly assays and methods described herein. For example, anti
methylene polyisocyanate (PMDI); mixtures of MDI and thrombogenicity can be determined by radiolabeling blood
PMDI; mixtures of PMDI and TDI; dimerized uredione of components and measuring the formation of thrombi using,
any isocyanate described herein, Such as uredione of toluene for example, a Y-count to assess the amount of thrombosis
diisocyanate, uredione of hexamethylene diisocyanate, and 55 occurring at a Surface. For the extracorporeal blood circuits,
mixtures thereof, and Substituted and isomeric mixtures or components thereof, of the invention an average decrease
thereof. in thrombosis based upon the y-count can be 70%, 60%, 50%,
For any of the Surface modifying macromolecules of the 40%, 30%. 20%, or 10% of the average thrombosis as deter
invention formed from an isocyanate trimer, the isocyanate mined by Y-count of a reference hollow fiber membrane lack
trimer can be selected from hexamethylene diisocyanate 60 ing the Surface modifying macromolecule). Alternatively,
(HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, antithrombogenicity in a filter or hollow fiber membrane can
hexamethylene diisocyanate (HDI) trimer; triisocyanate of be determined by a reduced operating pressure (e.g., an aver
2,2,4-trimethyl-1,6-hexane diisocyanate (TMDI); a trimer age decrease in operating pressure at the header of a hollow
ized isocyanurate of any isocyanates described herein, Such fiber membrane being reduced by at least 10%, 20%, 30%,
as isocyanurate of toluene diisocyanate, trimer of diphenyl 65 40%, 50%, or 60% in comparison to the average pressure at
methane diisocyanate, trimer of tetramethylxylene diisocy the header of a reference filter or hollow fiber membrane
anate, and mixtures thereof a trimerized biuret of any isocy lacking the Surface modifying macromolecule.
US 8,877,062 B2
15 16
By “base polymer is meant a polymer having a theoretical oligo-amides; react with diacid chlorides to form oligo-es
molecular weight of greater than 50,000 Daltons (e.g., greater ters, oligo-amides; and react with dialdehydes to form oligo
than 50,000, 75,000, 100,000, 150,000, 200,000 Daltons). acetal, oligo-imines.
As used herein, “C” refers to a chain terminating group. By "oligo' is meant a relatively short length of a repeating
Exemplary chain terminating groups include monofunctional unit or units, generally less than about 50 monomeric units
groups containing an amine, alcohol, or carboxylic acid func and theoretical molecular weights less than 10,000 Daltons,
tionality. but preferably <7,000 Daltons and in some examples, <5,000
By “dialysis filter is meant a filter configured for use in a Daltons. In certain embodiments, oligo is selected from the
dialysis machine which can be used by patients Suffering 10
group consisting of polyurethane, polyurea, polyimide, poly
from impaired kidney function. alkylene oxide, polycarbonate, polyester, polylactone, poly
By “hard segment” is meant a portion of the surface modi silicone, polyetherSulfone, polyolefin, polyvinyl, polypep
fying macromolecule or a portion of an oligo segment, where tide, polysaccharide, and ether and amine linked segments
the portion includes a urethane group —NH-C(O)C)—(e.g., thereof.
a urethane group formed by reacting an isocyanate with a 15 By “polyethersulfone' is meant a polymer of the formula:
hydroxyl group of a soft segment diol or a hydroxyl group of
a polyfluoroorgano group).
As used herein, the term “increased average functional O
working life” refers to an average increase in functional
working life for an extracorporeal blood circuit, or compo
nent thereof, of the invention in comparison to the average
working life of an extracorporeal blood circuit, or component
o–O)- O
Polyether Sulfone (PES)
thereof, used under the same conditions and differing only by
the absence of Surface modifying macromolecule, where the
working life is determined by the length of time the extracor 25 This polymer is commercially available under the trade name
poreal circuit, or a component thereof, can be used without RadelTM from Amoco Corp.
having to flush thrombi deposits from the extracorporeal cir By "polymeric component' is meant any component
cuit, or a component thereof (e.g., working life without a within an extracorporeal blood circuit, wherein the compo
saline flush, or flush with an anticoagulant). The increased nent includes a base polymer, as described herein. For
average functional working life for an extracorporeal blood 30 example, polymeric components include a hollow fiber mem
circuit, or component thereof, of the invention can be at least brane, a potted bundle of hollow fiber membranes, a dialysis
110%, 125%, 150%, 200%, 250%, 300%, or 400% longer filter, an oxygenator device, and a blood tubing.
than the working life of the reference extracorporeal blood By "poly(oxy-1,4-phenylene Sulfonyl-1,4-phenyleneoxy
circuit, or component thereof, lacking the Surface modifying 1,4-phenyleneisopropylidene-1,4-phenylene) is meant a
macromolecule. 35 polymer of the formula:
By "less than a standard dose of anticoagulant' is meant a
reduction in the anticoagulant administered to a Subject dur
ing hemodialysis when using the dialysis filters of the inven
tion in comparison to the amount used for a dialysis filter that
differs only by the absence of a Surface modifying macromol
ecule. A standard dose is generally identified by each institu
tion in a standard operating procedure for a clinical setting,
40
--------K)
Such as for use of an extracorporeal blood circuit, and com This polymer is commercially available under the trade name
ponents thereof. The standard dose of anticoagulant refers to UdelTM P-3500 from Solvay Advanced Polymers. For use in
a dose or a range of doses determined by reference to a 45 the hollow fiber membranes of the invention, a particular size
standard operating procedure of an institution, and a reduced for this polymer may be preferred (i.e., in the range of 30-90
dose is determined as compared to that standard dose. The kDa; 45-80 kDa; or 60-80 kDa.).
reduced dose of anticoagulant can be 80%, 70%, 60%, 50%, As used herein, the term “polysulfone' refers to a class of
40%, 30%, 20%, or 10% of the standard dose of anticoagulant polymers that include as a repeating Subunit the moiety -aryl
(e.g., heparin or citrate). 50 SO-aryl-. Polysulfones include, without limitation, poly
As used herein, "LinkB” refers to a coupling segment etherSulfones and poly(oxy-1,4-phenylene Sulfonyl-1,4-phe
capable of covalently linking two oligo moieties and a Surface nyleneoxy-1,4-phenyleneisopropylidene-1,4-phenylene).
active group. Typically, LinkB molecules have molecular By “prolonged working life' is meant a dialysis filter for
weights ranging from 40 to 700. Preferably the LinkB mol which the rate at which the filter becomes clogged during a
ecules are selected from the group of functionalized 55 hemodialysis procedure (e.g., and then requiring a saline
diamines, diisocyanates, disulfonic acids, dicarboxylic acids, flush to unclog the filter), is reduced in comparison to a
diacid chlorides and dialdehydes, wherein the functionalized dialysis filter that differs only by the absence of a surface
component has secondary functional chemistry that is modifying macromolecule used under the same conditions.
accessed for chemical attachment of a surface active group. The prolonged working life for a dialysis filter can be at least
Such secondary groups include, for example, esters, carboxy 60 110%, 125%, 150%, 200%, 250%, 300%, or 400% longer
lic acid salts, Sulfonic acid salts, phosphonic acid salts, thiols, than the working life of the reference dialysis filter lacking the
vinyls and secondary amines. Terminal hydroxyls, amines or Surface modifying macromolecule.
carboxylic acids on the oligo intermediates can react with As used herein, the term “reduced thrombi deposition'
diamines to form oligo-amides; react with diisocyanates to refers to an average decrease in Y-count following a period of
form oligo-urethanes, oligo-ureas, oligo-amides; react with 65 use (e.g., 60.90, 120, 360, or 720 minutes), for an extracor
disulfonic acids to form oligo-Sulfonates, oligo-Sulfona poreal blood circuit, or component thereof, of the invention in
mides; react with dicarboxylic acids to form oligo-esters, comparison to the average y-count observed for an extracor
US 8,877,062 B2
17 18
poreal blood circuit used under the same conditions and dif method, including the use of animal models (see Livignietal.
fering only by the absence of Surface modifying macromol Critical Care 10:R151 (2006); Walker et al., Artificial Organs
ecule. The y-count is obtained by incorporating Surface 8:329-333 (1984); Cheung, Blood Purification 5:155-161
modifying macromolecule into the extracorporeal blood cir (1987); Kamler et al., Journal of Thoracic and Cardiovascular
cuit to provide an antithrombogenic interface between the 5 Surgery 49:157-161 (2001); and Kamler et al., European
membrane and the flow of blood passing through the mem Journal of Cardio-Thoracic Surgery 11:973-980 (1997)).
brane, where y-count is measured at any treated Surface of the Adverse events include bleeding (e.g., measured by the acti
circuit and is measured under conditions in which the amount vated clotting time), hemolysis, reduced blood cell counts,
of anticoagulant included in the blood is insufficient to pre severe hemodynamic instability, embolism, thromboembo
vent the formation of thrombi in the absence of surface modi 10 lism, a thrombi-related event, and any other event requiring
fying macromolecule. A y-count can be determined by any of that the Subject take an erythropoiesis-stimulating agent (e.g.,
the assays and methods described herein. For example, erythropoietin and/or intravenous iron). The presence of one
Y-count can be determined by flowing blood or plasma con or more adverse events can be indicative of the presence of
taining radiolabeled platelets (or other blood components, thrombi or the activation of blood complements in the coagul
such as red blood cells) into an extracorporeal blood circuit 15 lation cascade.
and measuring the radiation from the radiolabel within the By “soft segment' is meant a portion of the surface modi
extracorporeal blood circuit. These assays and methods can fying macromolecule or a portion of an oligo segment, where
be performed multiple times to obtain an average y-count or the portion includes an ether group, an ester group (e.g., a
an average decrease in Y-count. The thrombi deposition for an polyester), an alkyl group, a carbonate group, a siloxane
extracorporeal blood circuit, or component thereof, of the group, or a mixture thereof. For example, the Soft segment can
invention can be on average reduced by 10%, 20%, 30, 40%, have a theoretical molecular weight or average molecular
50%. 60%, 70%, 80%, 90%, or 95% in comparison to the weight from 500 to 3,000 Daltons (e.g., from 500 to 2,000
average thrombi deposition of the extracorporeal blood cir Daltons, from 1,000 to 2,000 Daltons, or from 1,000 to 3,000
cuit, or component thereof, lacking the Surface modifying Daltons).
macromolecule. 25 As used herein, “surface modifying macromolecule' refers
By “reduced operating pressure' is meant an average to the macromolecules containing polyfluoroorgano groups
decrease in operating pressure following a period ofuse (e.g., and described herein by formulas (I)-CXIV) and in U.S. Pat.
2 hrs, 4 hrs, 8 hrs, 12 hrs, or 16 hrs), for a hollow fiber No. 6,127,507; in U.S. Patent Publication No. 20080228253;
membrane, or filters or potted bundles thereof, of the inven and in U.S. Provisional Ser. No. 61/092,667, filed Aug. 28,
tion in comparison to the average pressure observed for a 30 2008, each of which is incorporated herein by reference.
hollow fiber membrane used under the same conditions and Surface modifying macromolecules can be prepared as
differing only by the absence of surface modifying macro described in U.S. Pat. No. 6,127,507; U.S. Patent Publication
molecule. The reduced operating pressure is obtained by No. 20080228253; and PCT Publication No. WO/2010/
incorporating Surface modifying macromolecule into the hol 025398, filed Aug. 28, 2009. Briefly, surface modifying mac
low fiber membrane to provide an antithrombogenic interface 35 romolecules, such as XI-a and X-a, may be synthesized from
between the membrane and the flow of blood passing through a polyisocyanate (e.g., Desmodur N3200 or Desmodur
the membrane, where pressure is measured at the header of Z4470) reacted dropwise with a fluoroalkyl alcohol in an
the membrane. For an array of hollow fiber membranes hav organic solvent (e.g., anhydrous THF or DMAC) in the pres
ing a potting resin at an end of the array, a reduced operating ence of a catalyst at 25°C. for 2 hours. After addition of the
pressure can be obtained by using a surface modifying mac 40 fluorinated alcohol, stirring is continued for 1 hour at 50° C.
romolecule to provide an antithrombogenic interface and for a further 1 hour at 70° C. These steps lead to the
between the membrane and/or the potting resin and the flow formation of apartially fluorinated intermediate which is then
of blood passing through the potted bundle. Operating pres coupled with a polyol soft segment (e.g., polydimethylsilox
Sure can be determined by any of the assays and methods ane diol or poly(2.2 dimethyl-1-3-propyl carbonate)diol) at
described herein. For example, operating pressure can be 45 70° C. over a period of 14 hours to provide the surface modi
determined by flowing blood into a hollow fiber membrane fying macromolecule. Because the reactions are moisture
and measuring the change in pressure within the hollow fiber sensitive, they are typically carried out under an inert N.
membrane over a period of time. These assays and methods atmosphere and under anhydrous conditions. The reaction
can be performed multiple times to obtain an average oper product is precipitated in 1% MeOH/water mixture and then
ating pressure or an average decrease in operating pressure. 50 washed several times with water, and the Surface modifying
The reduced operating pressure for a hollow fiber membrane macromolecule is dried prior to use. The Soft segment of the
(or filters or potted bundles thereof) of the invention can be Surface modifying macromolecule can function as an anchor
less than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% after for the surface modifying macromolecule within the base
2, 4, 8, 12, or 16 hours of use in comparison to the average polymer Substrate upon admixture. The Surface active groups
pressure observed for a reference hollow fiber membrane, 55 are responsible, in part, for carrying the Surface modifying
filter, or potted bundle lacking the Surface modifying macro macromolecule to the surface of the admixture, where the
molecule. Surface active groups are exposed on the Surface. The migra
As used herein, the terms “reduces adverse events’ and tion of the Surface modifying macromolecules to the Surface
“adverse events experienced by a subject” refer to a number is a dynamic process and is dependent on the Surface envi
or extent of adverse events experienced by a subject con 60 ronment. The process of migration is driven by the tendency
nected to an extracorporeal blood circuit, or component towards establishing a low Surface energy at the mixture's
thereof, of the invention, where such adverse events are surface. When the balance between anchoring and surface
reduced or decreased during or after a period of use, in com migration is achieved, the Surface modifying macromolecule
parison to an extracorporeal blood circuit, or component, remains stable at the surface of the polymer, while simulta
used under the same conditions and differing only by the 65 neously altering Surface properties.
absence of surface modifying macromolecule. The number or This invention features blood circuits which can be useful
extent of adverse events can be determined by any useful for reducing platelet adhesion, reducing occlusion, reducing
US 8,877,062 B2
19 20
the need for heparin and/or otheranticoagulants, reducing the shows thrombi formed at the inlet of the hemofilters. FIG.
costs associated with certain medical procedures, such as 24B shows thrombi formed at the outlet of the hemofilters.
dialysis, prolonging the working life of the blood circuit, FIGS. 25A-25C are photographs from Experiment 4 in
improving patient safety, and reducing waste. Example 5, as described herein, which show extensive coagu
Other features and advantages of the invention will be lation. FIG. 25A shows thrombi formed at the inlet of the
apparent from the Drawings, Detailed Description, and the control hemofilter (no surface modification). FIG.25B shows
claims. thrombi formed at the outlet of the control hemofilter (no
surface modification). FIG. 25C shows residue on the sieve
BRIEF DESCRIPTION OF THE DRAWINGS after draining blood.
10 FIGS. 26A-26D are photographs of hemofilters from
FIG. 1 is a schematic of an exemplary extracorporeal blood Experiment 5 in Example 5, as described herein. FIG. 26A
circuit. shows thrombi formed at the inlet of the hemofilters. FIG.
FIG. 2 is an illustration depicting Surface modifying mac 26B shows thrombi formed at the outlet of the hemofilters. A
romolecule VII-a of the invention. control hemofilter showed complete occlusion, where close
FIG. 3 is an illustration depicting Surface modifying mac
15 ups are provided for the inlet (FIG. 26C) and outlet (FIG.
romolecule VIII-a of the invention. 26D) for control.
FIG. 4 is an illustration depicting Surface modifying mac FIG. 27 shows photographs of the inlet of hemofilters from
romolecule VIII-b of the invention.
Experiment 1-6 in Example 5, as described herein. Photo
FIG. 5 is an illustration depicting Surface modifying mac graphs are shown for control (C, top row), VII-a (middle row),
romolecule VIII-c of the invention.
and XI-a (bottom row).
FIGS. 28A and 28B are photographs of hemofilters from
FIG. 6 is an illustration depicting Surface modifying mac Experiment 1 in Example 5, as described herein. FIG. 28A
romolecule VIII-d of the invention. shows thrombi formed at the inlet of the hemofilters. FIG.
FIG. 7 is an illustration depicting Surface modifying mac 28B shows thrombi formed at the outlet of the hemofilters.
romolecule IX-a of the invention. 25 FIGS. 29A and 29B are photographs of hemofilters from
romolecule X-a of the invention. shows thrombi formed at the inlet of the hemofilters. FIG.
romolecule X-b of the invention. FIGS. 30A and 30B are photographs of hemofilters from
FIG. 10 is an illustration depicting Surface modifying mac 30 Experiment 3 in Example 5, as described herein. FIG. 30A
romolecule XI-a of the invention. shows thrombi formed at the inlet of the hemofilters. FIG.
FIG. 11 is an illustration depicting surface modifying mac 30B shows thrombi formed at the outlet of the hemofilters.
romolecule XI-b of the invention. FIGS. 31A and 31B are photographs of hemofilters from
romolecule XII-a of the invention. 35 shows thrombi formed at the inlet of the hemofilters. FIG.
romolecule XII-b of the invention.
FIG. 14 is an illustration depicting Surface modifying mac DETAILED DESCRIPTION
romolecule XIII-a of the invention.
FIG. 15 is an illustration depicting Surface modifying mac 40 The methods and compositions of the invention feature
romolecule XIII-b of the invention. antithrombogenic, extracorporeal blood circuits and compo
FIG.16 is an illustration depicting Surface modifying mac nents thereof (hollow fiber membranes, potting materials, and
romolecule XIII-c of the invention. blood tubing, etc.) including a synthetic base polymer
FIG. 17 is an illustration depicting Surface modifying mac admixed with from 0.005% to 10% (w/w) surface modifying
romolecule XIII-d of the invention. 45 macromolecule. The extracorporeal blood circuit compo
FIG. 18 is an illustration depicting Surface modifying mac nents of the invention can be used in therapies such as hemo
romolecule XIV-a of the invention. dialysis, hemofiltration, hemoconcentration, hemodiafiltra
FIG. 19 is an illustration depicting surface modifying mac tion, and oxygenation, for the treatment of patients with renal
romolecule XIV-b of the invention. failure, fluid overload, toxemic conditions, cardiac failure, or
FIGS. 20A and 20B show an exemplary hollow fiberand an 50 cardiac distress. They can also be used for protein separation,
exemplary bundle of fibers. FIG. 20A is a scanning electron plasma filtration, and blood separation.
micrograph of a single hollow fiber depicting the outer Sur The selection of the combination of a particular surface
face, the inner surface, and the fiberthickness. FIG.20B is an modifying macromolecule (SMM) and aparticular base poly
illustration of bundle of hollow fibers arranged in the header mer can be determined by the methods and protocols
part of the dialyzer cartridge with the potting area (areas 55 described herein. First, the type and amount of SMM to be
indicated by arrow labeled “Potted area untreated in the added to base polymer is determined in part by whether the
inner lumen of the dialyzer cartridge, including the thick admixture forms a single stable phase, where the SMM is
dotted line within the inner lumen of the dialyzer cartridge soluble in the base polymer (e.g., separation of the admixture
and the areas marked with an X) exposed. to form two or more distinct phases would indicate an
FIG. 21 is a photograph of an exemplary configuration for 60 unstable solution). Then, the compatibility of the admixture
in vitro blood loop analysis and gamma probe reading. can be tested by various known analytical methods. The sur
FIG. 22 is a photograph of hemofilters after a blood loop face of the admixture as a film or as a fiber can be analyzed by
procedure. any useful spectroscopic method, Such as X-ray photoelec
FIG. 23 is a graph showing average header pressure (APr) tron spectroscopy (XPS) with an elemental analysis (EA).
and Y-count profiles for control versus VII-a and XI-a (n=6). 65 Data from XPS could indicate the extent of modification of
FIGS. 24A and 24B are photographs of hemofilters from the surface by migrating SMMs and data from EA can indi
Experiment 4 in Example 5, as described herein. FIG. 24A cate the extent of modification of the bulk material. Stable
US 8,877,062 B2
21 22
admixtures can then be tested to determine the thromboge Any of the blood contacting components of the extracor
nicity of the Surface under various conditions. poreal blood circuit can be modified with a surface modifying
Extracorporeal Blood Circuits macromolecule as described herein to produce an antithrom
The invention features compositions and methods for bogenic Surface. The extracorporeal blood circuit can be use
reducing the activation of blood components in contact with ful for hemodialysis, as explained above, and can also be
any of the parts of an extracorporeal blood circuit (e.g., the applied for other therapies involving hemoconcentration,
blood tubing, the hollow fiber membrane, the potted surface, oxygenation, protein separation, plasma filtration, and blood
or the ends of the filter into which the blood tubing attaches) separation.
by including a Surface modifying macromolecule in one or Surface Modifying Macromolecule
more of the parts of an extracorporeal blood circuit. The 10 Illustrations of VII-a to XI-b are shown in FIGS. 2-19. For
hemodialysis machine pumps the dialysate as well as the all of the SMMs, the number of soft segments can be any
patient’s blood through a dialyzer. The blood and dialysate integer or non-integer to provide the approximate theoretical
are separated from each other by a semipermeable hollow molecule weight of the soft segment. For compounds of for
fiber membrane, the blood passing through the extracorporeal mulas (XII) and (XIII), the number of hydrogenated alkyl
blood circuit of a hemodialysis machine and the dialysate 15 moieties can be any integer or non-integer to provide the
passing through the dialysate circuit of a hemodialysis approximate theoretical molecule weight of the Soft segment.
machine. Any one or more of the blood-contacting Surfaces in Examples of XII-a, XII-b, XIII-a, XIII-b, and XIII-c include
the extracorporeal blood circuit of a dialysis machine may be SMMs, where x=0.225, y=0.65, and Z-0.125. For com
treated with a surface modifying macromolecule as described pounds of formula (XI), the number of first block segments
herein to produce an antithrombogenic Surface. The medical and second block segments can be any integer or non-integer
separatory device of the invention can be an artificial kidney to provide the approximate theoretical molecule weight of the
of the hollow fiber type, or a related device, such as hemofil soft segment. Examples of XI-a and XI-b include SMM’s,
ter, blood oxygenator, or other separator of impurities from a where m=12 to 16 and n=12 to 18.
body. Table 1 shows the SMM distribution of hard segments, soft
The devices include a dialysate chamber, and a pair of 25 segments, and fluorinated end-groups (F end groups). Table 1
spaced apart drip chambers attached to each end of the dialy also shows the ratio of hard segment to soft segment, which
sate chamber. Each drip chamber terminates in a port leading range from 0.16 to 1.49.
to blood tubing, which ultimately exit and enter a subject
undergoing hemodialysis. The dialysate chamber is provided TABLE 1
with conventional inlet and outlet dialysate ports and Sur 30
rounds a bundle of axially extending hollow semipermeable Ratio:
fibers. MW % Soft Seg % Hard Seg % F End Hard/Soft
SMM’s Theo (Diol) (Isocyanate) Groups segment
The fiberbundle contains thousands (e.g., 3,000 to 30,000)
individual fibers which may formed from cellulose (e.g., VII-a 2016 47.21 16.68 36.11 O.35
made by deacetylating cellulose acetate as taught in U.S. Pat. 35 VIII-a 3814 25.78 30.59 43.63 1.19
VIII-b 3545 27.73 31.18 41.09 1.12
No. 3.546,209), cellulose acetate, cellulose ester, polyesters, VIII-c 3870 25.64 37.01 37.35 1.44
polyamides, polysulfone, or any other hollow fiber mem VIII-d 4800 39.59 30.07 30.34 O.76
brane known in the art. Typically, the fibers are fine and of IX-a
X-a
3515
4075
56.89
23.74
22.39
35.42
20.72
40.84
O.39
1.49
capillary size which typically ranges from about 150 to about X-b 4861 40.35 29.69 29.96 O.74
300 microns internal diameter with a wall thickness in the 40
XI-a 5562 S3.94 19.87 26.19 0.37
range of about 20 to about 50 microns. XI-b S900 50.85 24.46 24.69 O.48
Referring to FIG. 1, a typical extracorporeal blood circuit XII-a 3785 64.60 13.90 22.OO O.22
100 includes tubing through which the blood flows and com XII-b 6372 76.2O 12.40 1140 O16
XIII-a 5259 46.18 22.18 31.64 O.48
ponents for filtering and performing dialysis on the blood. XIII-b 5536 43.87 26.07 30.06 O.S9
Blood flows from a patient 105 through arterial tubing 110. 45 XIII-c S198 46.72 21.26 32.01 O46
Blood drips into a drip chamber 115 where a connecting tube XIII-d 5227 4.O.S.S 27.61 25.38 O.68
XIV-a 5097 38.76 28.59 32.65 O.74
from the drip chamber 115 attaches to a sensor 125 on a XIVb 5450 46.79 26.48 26.72 0.57
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 50 Hollow Fiber Membranes
through the extracorporeal blood circuit. A dialyzer 130 sepa Hydrophobic polymers have been a popular choice as poly
rates waste products from the blood. meric materials in hollow fiber spinning e.g. polysulfones,
After passing through the dialyzer 130, the blood flows aromatic polyimides, and amides. Any base polymers
through venous tubing 140 into a second drip chamber 150. described herein can be used as a hydrophobic polymer for
The drip chamber 150 can function as an air trap. Free gases 55 hollow fiber spinning. For hemodialysis, hollow fiber mem
in the blood may be able to escape into the drip chamber 150 branes are often made from natural cellulose, cellulose
before the blood continues to the patient. A sensor 170 is in derivatives (e.g. cellulose di- or tri-acetate), or synthetic poly
communication with air in the drip chamber through tube mers (e.g., polysulfones, polyacrylonitrile, or polyamides,
165. The sensor 170 can determine the pressure on the venous among others), which are selected for their biocompatibility.
side of the extracorporeal blood circuit. 60 However, none of these materials have proven to provide the
Heparin 160 can be added to the blood in the drip chamber desired antithrombogenicity that is needed to reduce the reli
115. When blood is exposed to oxygen, the blood begins to ance upon anticoagulants.
clot. The drip chamber 150 may include a filter for preventing In particular, polysulfones (PS) are synthetic hydrophobic
any clots from exiting the drip chamber 150 and entering the polymers that are widely used in hollow fiber membranes due
patient 105. The blood continues from the drip chamber 65 to their excellent fiber spinning properties and biocompatibil
through venous tubing 180 and through a bubble detector 175 ity. However, pure hydrophobic PS cannot be used directly for
before returning to the patient 105. Some applications, e.g., dialysis membranes, as this will
US 8,877,062 B2
23 24
decrease the wetting characteristics of the membrane in an of the spinning Solution (a solvent for the spinning solution)
aqueous environment and affect the wetting properties essen either separately or in a mixture.
tial for the clearance of toxins. To address this problem, For use in the compositions and methods of the invention,
polyvinylpyrrolidone (PVP) is typically added to the PS as a a typical spinning solution will include a base polymer (e.g.,
pore forming hydrophilic polymer, most of which dissolves a polysulfone), a hydrophilic pore forming agent (e.g., poly
and is lost during the hollow fiber spinning process and vinylpyrrolidone, ethylene glycol, alcohols, polypropylene
hydrophilically modify the PS to make it suitable as a semi glycol, or polyethylene glycol), a solvent for the polymer
permeable membrane. Although some of the PVP remains in (i.e., dimethylformamide, dimethylsulfoxide, dimethylaceta
the fiber this is not sufficient as clotting still occurs during mide, N-methylpyrrolidone, or mixtures thereof), and a sur
dialysis requiring heparin anticoagulants or saline flushes of 10 face modifying macromolecule.
the dialyzer to clear the blockage. The hollow fiber membranes of the invention can be pro
The methods and compositions of the invention address duced, for example, by extruding the spinning Solution from
these issues by including a surface modifying macromolecule a tube-in-tube type orifice of the spinner in a coagulation
solution to form the hollow fiber membrane. The polymer
in the hollow fiber membrane. The surface modifying mac 15 containing spinning Solution is extruded from the outer tube
romolecule migrates to the surface of the hollow fiber mem (i.e., annular space defined between the inner and outer tubes)
brane (bothinner lumen and outer Surface during the spinning to form a cylindrical filament having an inner bore and the
process) to occupy the top 10 microns of the hollow fiber. core solution for coagulation of the spinning Solution is
Manufacture of Hollow Fiber Membranes extruded from the inner tube of the orifice into the inner bore
A porous hollow fiber membrane adapted for use in the of the filament. In this process, the filament may be directly
methods of the invention, e.g., kidney dialysis, should be extruded into the coagulation Solution, or extruded into air
capable of removing low molecular weight uremic Substances and then drawn to the coagulation solution. As noted above,
while retaining useful Substances such as albumin. Such the spinning Solution is Supplemented with a hydrophilic pore
porous hollow fiber membranes are produced using processes forming agent and a Surface modifying macromolecule and
adapted to accurately control the pore diameter in the porous 25 the resulting hollow fiber membrane contains the surface
hollow fiber membrane. The pore diameter of the hollow fiber modifying macromolecule on its Surface.
membrane can depend upon the composition of the spinning The viscosity of the spinning solution can be modified as
Solution, composition of the core solution, draft ratio, liquid needed. For example, by adding a thickener (e.g., polyvi
composition for membrane coagulation, temperature, humid nylpyrrolidone (PVP), polyethylene glycol (PEG), or
ity, among other factors. The composition of the core solution 30 polypropylene glycol) to increase viscosity, or by adding an
is an important factor as the combination and the mixing ratio aprotic low boiling solvent (i.e., tetrahydrofuran, diethyl
of the solvent and the nonsolvent in relation to the membrane ether, methylethylketone, acetone, or mixtures thereof) to the
constituting polymer determine the coagulation rate, and spinning Solution to reduce viscosity. An aprotic low boiling
hence, the morphology of the interior surface of the hollow solvent may also be included to increase the solubility of the
fiber membrane. 35 Surface modifying macromolecule in the spinning solution.
Various processes are known in the art for the production of The spinning Solution is extruded to form the shape of a
hollow fiber membranes (see, for example, U.S. Pat. Nos. filament which is precipitated using a coagulating solution,
6,001,288: 5,232,601: 4,906,375; and 4,874,522, each of resulting in formation of the desired porous hollow fiber. The
which is incorporated herein by reference) including (i) pro coagulating solution may include a nonsolvent or a mixture of
cesses wherein a tube-in-tube type orifice is used and the 40 a nonsolvent and a solvent for the base polymer of the spin
spinning solution is extruded from the outer tube (i.e., from ning solution. Typically the nonsolvent used for the coagul
the annular space defined between the inner and outer tubes) lating Solution is an aqueous solution.
and the core solution is ejected from the inner tube; (ii) by After the porous hollow fiber is formed, it may be passed
extruding the spinning Solution into air, allowing the filament through a second rinsing bath. The porous hollow fiber may
to fall down by gravity, passing the filament through a coagul 45 then be processed further, e.g., cutting, bundling, and drying,
lantbath for coagulation, and washing and drying the filament and made into a porous hollow fiber membrane Suitable, e.g.,
(dry-wet spinning); (iii) by using a bath including an upper for use in a dialyzer.
layer of a non-coagulating Solution and a lower layer of a Potted Bundles of Hollow Fiber Membranes
coagulating Solution, and extruding the spinning Solution The invention features compositions and methods for
directly into the non-coagulating solution and passing the 50 reducing the activation of blood components in contact with
filament through the coagulating solution; (iv) by using a bath the potting material of a filter (e.g., as part of a blood purifi
including an upper layer of a coagulating Solution and a lower cation device, such as a hemodialysis, hemodiafiltration,
layer of a non-coagulating solution, and extruding the spin hemofiltration, hemoconcentration, or oxygenator device) by
ning solution directly into the non-coagulating Solution and including a Surface modifying macromolecule in the potting
passing the filament through the coagulating solution; (V) by 55 material at the time that the hollow fiber membranes are
extruding the spinning Solution directly into a non-coagulat potted.
ing Solution and passing the filament along the boundary In order to filter or permeate with hollow fiber membranes,
between the coagulating Solution and the non-coagulating a large number of thin hollow fibers must be potted (i.e., fixed)
Solution; and (vi) by extruding the spinning Solution from the to a header of an encasement Such that their inner Surfaces are
orifice Surrounding a non-coagulating solution and passing 60 each completely sealed to the inside of the encasement but
the filament through a coagulating Solution. their lumens are open to pass blood from a first potted end to
In such processes, pore diameter of the hollow fiber mem a second potted end of a filter. Potting materials are an impor
brane is controlled by adjusting the rate and the extent of the tant integral part of blood purification filter as these are cured
coagulation of the extruded spinning solution through the use polymer materials (usually a polyurethane) that act as a glue
of a coagulation Solution which promotes the coagulation of 65 to hold the hollow membrane fiber bundles (e.g., numbering
the spinning Solution (a non solvent for the spinning solution) up to 20,000) firmly at the ends inside the cartridge of the
and a non-coagulation solution which inhibits the coagulation dialyzer, while at the same time leaving the ends of the hollow
US 8,877,062 B2
25 26
fibers open to allow for passage of blood into the fibers for fiber) also with surface modifying macromolecules to obtain
filtration purposes. Holding these numerous fiber bundles a header Surface that is antithrombogenic, minimizes blood
inside an encasement and ensuring that each and every hollow activation, reduces blood coagulation, and reduces the inci
fiber is properly aligned along the axis of the cartridge is a dence of hemofilter occlusion.
necessary step in a filter assembly.
The potted walls formed at either end of a blood purifica EXAMPLE 2
tion 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 Surface Modifying Macromolecule in Films of
affect blood flow and filter function. This problem is not 10 PS/PVP Polymer Blends
ameliorated by the use of antithrombogenic hollow fiber
membranes as the ends of the hollow fiber membranes are Films were prepared to demonstrate the Surface composi
only a very Small portion of a typical wall Surface (e.g., ca. tion in the mixtures from which the hollow fiber membranes
18% of the wall surface), followed by hollow lumen (e.g., ca. of the invention can be made. A Surface modifying macro
16% of the wall Surface), and a large amount of potting 15
molecule (SMM, 5 wt %), polysulfone (PS, 10 wt %) and
material (e.g., ca. 66% of the wall surface). There is a need to polyvinylpyrrolidone (PVP 5 wt %) were dissolved in a mix
address this larger area where dynamic blood flow takes place ture of dimethylacetamide and tetrahydrofuran (ca. 80 wt %).
and where most of thrombus starts that may lead to occlusion Films having a thickness of 254 um were cast on Teflon
of the filters. There is a need for hollow fiber membranes and substrates and were then dried and analyzed for surface Fluo
blood filtration devices that have reduced thrombogenicity. rine and Nitrogen content. The results are provided in Table 2
Potting materials can be thermoset polymers formed by for the four solution cast formulation films that were ana
mixing two or more components to form a cured resin (i.e., lyzed, each utilizing a different Surface modifying macromol
typically a polyurethane). To produce an antithrombogenic ecule.
potting material of the invention a surface modifying macro
molecule is added to at least one of the components of the 25
TABLE 2
potting material prior to mixing to form the cured resin.
The Surface modifying macromolecules can be incorpo XPS in PSIPVPSMM
Films (Surface
EA of SMM
Bulk
rated into any potting material known in the art. For example,
Surface modifying macromolecules can be incorporated into SMM fi 96 F %N 96 F %N
polyurethane potting materials formed from an isocyanate 30
terminated prepolymer, the reaction product of a polyol and a VIII-a
VIII-b
42.77
43.82
4.23
4.39
33.2
23.29
5.07
6.66
polyisocyanate, and cured with one or more polyfunctional XI-a 37.34 4.93 15.94 3.9
crosslinking agents have been described in the art. Potting XIII-a 42.75 4.OS 20.63 3.49
materials that can be used in the methods, compositions, and
dialysis systems of the invention include those described in 35
U.S. Pat. Nos. 3,362.921: 3,483,150; 3,362,921: 3,962,094; The surface fluorine content is provided by the X-ray pho
2,972,349; 3,228,876; 3,228,877; 3,339,341: 3,442,088; toelectron spectroscopy (XPS) results for the four films,
3.423,491; 3,503,515; 3,551.331; 3,362.921: 3,708,071; while the elemental analysis (EA) of the bulk (neat) SMM is
3,722,695; 3,962,094; 4,031,012; 4,256,617; 4,284,506; and provided for comparison. The difference in XPS and EA data
4.332.927, each of which is incorporated herein by reference. 40 for percent fluorine content results from the migration of the
The following examples are put forth so as to provide those oligofluoro groups of the Surface modifying macromolecule
of ordinary skill in the art with a complete disclosure and to the surface of the film. The percent nitrogen content at the
description of how the methods and compounds claimed surface reflects the presence of the hydrophilic urethane por
herein are performed, made, and evaluated, and are intended tion of the Surface modifying macromolecule at the Surface of
to be purely exemplary of the invention and are not intended 45 the film in addition to the presence of the polyvinylpyrroli
to limit the scope of what the inventors regard as their inven done.
tion.
EXAMPLE 3
EXAMPLE1
50
Illustration and Calculation of Potting Area Surface Modifying Macromolecule in Fibers of
PS/PVP Polymer Blends
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 55
Fibers were also analyzed for Fluorine and Nitrogen con
bundle to provide an antithrombogenic Surface area when in tent. The results are provided in Table 3 for the four solution
spun fibers that were analyzed, each utilizing a different Sur
contact with blood. Based upon the dimensions of the potted face modifying macromolecule (VII-a, VIII-a, IX-a, and
area and the fiber, it can be estimated that if only the hollow XI-a).
fiber membranes are modified as described herein, then only
~18% of the header area occupied by the fibers (depicted by 60
TABLE 3
circles with thick lines within the dialyzer cartridge) is modi
fied with the surface modifying macromolecules (SMM) for SMM XPS (OS) XPS (IS) EA (Fibers)
providing the antithrombogenic effect. This leaves ~66% of
the area including the potted part unmodified and prone to Fibers %F 9% N 9% F 9% N 9% F(x) 9% N
thrombus formation when in contact with blood during hemo 65 VII-a 12.06 4.02 10.79 2.33 0.83 (4) 0.50
dialysis. Accordingly, this invention features a method of VIII-a 5.14 4.15 8.68 2.90 0.74 ((3) 0.52
treating this ~66% of the potted part (an integral part of the
US 8,877,062 B2
28
TABLE 3-continued EXAMPLE 4
SMM XPS (OS) XPS (IS) EA (Fibers) Surface Modifying Macromolecule in Potting
Materials
Fibers 96 F %N %F 9/o N % F(x) %N 5
IX-a O.78 2.9 2.76 1.51 0.17 (2) <0.50 Sample disks were prepared to demonstrate the Surface
XI-a 1.35 3.11 1.71 1.39 0.27 (1.6) <0.50 composition in the polymer material including the potted
Si = 1.51% Si = 2.38% aca.
Control O.OO 4.12 O.OO 147 O (O) <O.S A commercially available potting compound GSP-1555
Polysulfone/PVP 10
Fibers from GS polymers Inc. was used as the potting material. It is
a two part system consisting of Part A (HMDI based diisocy
Target incorporation of VII-a = 6% anate) and Part B (a polyol). Four SMM’s designated as VII-a,
Target incorporation of VIII-a & DX-a = 4% VIII-a, IX-a, and XI-a (structure depicted in FIGS. 2-5) were
Target incorporation of XI-a = 3% admixed with the GSP 1555 potting material as shown in
15
Table 4. VII-a was used in two concentrations of 1% and 2%,
The X-ray photoelectron spectroscopy (XPS) data indi respectively. All other SMMs, i.e., VIII-a, IX-a, and XI-a,
cated that all of the SMM modified fibers have surface fluo were prepared in only 2% (W/w) concentration according to
rine to various degrees both in the inner surface (IS) that the following method.
actually comes in contact with blood during hemodialysis and To the GSP 1555 precursor polyol was added the SMM in
the outer surface (OS). a 40ml plastic falcon tube with thorough mixing. The mixture
Table 3 also provides the elemental analysis (EA) of the was dissolved in a volume of THF. The GSP 1555 precursor
SMM’s and the '% F in the bulk, which indicates the amount diisocyanate was then added, and the reaction mixture was
of the additive incorporated into the fibers as compared to the stirred. The resulting GSP 1555 potting compound containing
targeted incorporation amount. For VII-a, the EA of the 96 F 25 SMM was allowed to cure at room temperature for 24-48
shows that of the 6 wt % additive incorporation only 4 wt % hours. The cured mixture was then dried under vacuum for 48
was actually present. This loss of ~33% can be attributed to hours to remove any residual solvent from the samples.
the harsh conditions of the fiber spinning process, which
involves spinning solvent mixtures that dissolves some of the 30
TABLE 4
SMM at the same time that it dissolves the pore forming GSP 1 SSS 2A:1B
polyvinylpyrrolidone (PVP). This is true for VIII-a, IX-a, and
XI-a and is reflected in the difference between the target PartA Part B Conc of Conc of
incorporation and the actual incorporation that is calculated SMM fi
Form
(HMDI)
(g)
(Polyol)
(g)
A:B in
Sol. (%)
SMM
(g)
SMM in
(A:B)%
from the elemental analysis. However, all the SMM’s no 35
matter their final concentration are robust enough to remainin VII-a 6.7 3.3 2O O.1 1
Sufficient quantities to provide significant impact on the Sur VII-a 6.7 3.3 2O O.2 2
VIII-a 6.7 3.3 2O O.2 2
face properties, which can be reflected in the antithrombo IX-a 6.7 3.3 2O O.2 2
genic properties evidenced in the blood loop studies in XI-a 6.7 3.3 2O O.2 2
Example 5. 40
Table 3 shows that for the commercial control PS/PVP The samples were cut into appropriate sizes and Submitted
fibers (not modified with SMM) the XPS results show an for XPS. The XPS results are provided in Table 5. Values of
absence of Fluorine. The nitrogen content in the commercial the atomic '% F demonstrate that all parts of the potted mate
fiber comes from the PVP that remains after most of it is rials (i.e., the top Surface and new Surfaces generated after
washed away during the spinning process. The amount o f 45 cutting) have been modified with the additive. That the cut
PVP remaining in the unmodified and SMM modified fibers portions of the potted materials have been modified with the
will also vary. additive is important, because production of a filter from a
Considering the XPS results of the inner surface of the bundle of potted hollow fiber membranes typically includes
fibers (IS) which comes in contact with the blood, Table 3 50 generating a new Surface as the potted portion of the bundle is
shows that for VII-a, VIII-a, IX-a, and XI-a the '% F (hydro cut to produce a smooth finish to expose the hollow fiber
phobic groups) range from 1.71%-10.79% and the % N (hy openings. Values of the atomic '% F also demonstrate that
drophilic groups) are in the range 1.39%-2.90%. As deter migration of the SMM to a surface is a dynamic process and
mined from the data from Table 3, the ratio of% F to % N occurs at all Surfaces, including those surfaces newly gener
includes from 1.23-4.63 and possible ranges for the ratio of% 55 ated. For example, VII-a was incorporated at 1% (w/w) to
F to %N include from 1.20 to 10.0. As provided in Table 1, the produce a top portion which displays a surface that is 30%
ratio of hard segments to soft segments includes from 0.16 fluorine. After heating at 60° C. for 24 hours to increase the
1.49 and possible ranges for this ratio of hard segments to soft amount of Surface modifying macromolecule near the Surface
segments include from 0.15 to 2.0. of the wall, the '% F content at the surface was reduced to
60 ~13%. After cutting the sample the XPS showed that the cut
While VII-a and XI-a performed the best in this series as surface displays a surface that is ~7% fluorine, which upon
shown in Example 5, VIII-a and IX-a did not have any major heating at 60°C. for 24 hours is increased to ~26% fluorine.
failures, compared to the control nor did the failures result in Thus, the potting material Surface of the invention can be
major occlusion of the filters. Unlike the control, filters modi heated if there is insufficient fluorine at a freshly cut surface.
fied with VII-a, VIII-a, IX-a, or XI-a did not show such large 65 Similar observations were made for the other SMMs. This
variation in the header pressures and Y-count (as compared to also demonstrates that SMM’s can migrate through cured or
the standard error in Table 6.). thermoset polymers.
US 8,877,062 B2
29 30
TABLE 5 Briefly, the following protocol was used. The blood loop
system included a reservoir, a pump, a hemofilter, and tubing
Samples 96 F %N % Sl
to form a closed flow loop. The loop system was primed with
Control 1-T1 3.513 4.42 O.49 phosphate buffered saline (PBS) at 37°C. and circulated for
GSP1555
polyurethane
1-T6O2
1-C3
O.36
O.6O
4.40
4.68
O.88
1.03
1 hour before starting an experiment, and pressure was mea
#1 1-C60 Sured at the pressure port between the pump and the hemo
VII-a 2-T 30.23 3.45 O.31 filter.
196 2-T60 13.24 3.18 0.37
#2 2-C 6.77 3.96 O41 Approximately 10 liters of fresh bovine blood was
2-C60 26.10 3.32 O.24 10 obtained from a single animal for each experiment and hep
VII-a 3-T 18.00 3.80 O.09
296 3-T60 27.00 3.31 O.19
arinized (typical concentration=2 U/ml). The experiments
#3 3-C 1260 3.16 O16 were conducted within 8 h of blood collection. Radiolabeled,
3-C60
4-T
41.93
28.90
3.62
6.31
O.O1
1.79
autologous platelets (with '''Indium) were added to the
VIII-a 4-T60 31.40 6.66 O.78 15
blood prior to the commencement of the study. The PBS in the
296
ii. 4
4-C
4-C60
23.88
22.75
S.S4
5.93
1...SO
1.04
reservoir was replaced with blood, and pressure was moni
5-T 3.00 3.29 O.26 tored. Blood circulation in the loop system was typically
IX-a S-T60 9.1O 2.69 0.75 maintained for 1-2 hours (unless terminated due to significant
296
#5
S-C
S-C60
747
11.08
3.93
2.99
1.42
O.47
pressure build-up, as monitored by a pressure gauge). At the
6-T 36.71 5.72 O.OO end of the experiment, hemofilters were photographed, and
XI-a 6-T60 42.31 5.25 O.O2 Y-count was measured at the inlet, outlet, and middle of the
296 6-C 26.19 6.07 O.17
#6 6-C60 33.35 5.81 O.O1
hemofilter using a Y-probe.
FIG. 21 shows the experimental set-up for the in vitro
T = Top portion of sample at ambient temperature, 25 blood loop analysis and the configuration of the hemofilters
2T60 = Top portion of sample at 60°C, 24 hours,
C = Cut portion of sample at ambient temperature, for the study. The figure also shows the arrangement of the
“C60 = Cut portion of sample at 60°C, 24 hours. Y-probe reading for the hemofilters, where measurements
Control should be devoid of fluorine. Here a 3% F content indicates contamination. were determined end-on and in the middle of the hemofilters.
The Y-probe readings for the radiolabeled platelets were
30
determined after the filters were exposed to the blood flow
EXAMPLE 5 and rinsed with PBS solution to remove any residual blood.
FIG. 22 shows an arrangement of the hemofilters after the
In Vitro Assessment of Hemofilter Thrombosis
blood loop procedure, just before the header caps (top and
35
bottom caps) are unscrewed to visually examine for throm
bus.
Thrombotic surface activity of hemofilters was assessed Results & Discussion
using commercially available hemofilters in response to hep
arinized bovine blood. Hemofilters were surface modified Table 6 shows the results of the in vitro study of hemodi
with VII-a, VIII-a, IX-a, or XI-a and compared with control 40
alysis filters thrombus for control (C1) versus VII-a, VIII-a,
(hemofilter that was not surface modified). IX-a, and XI-a. Table 6 also shows the header pressure change
Materials (AP) at the inlet (top cap in FIG.22) and the Y-probe readings
Commercially available hemofilters containing PS/PVP of the radiolabeled activated platelets at the inlet (top cap in
were used as the control. Four Surface modifying macromol FIG. 22), middle, and outlet (bottom cap in FIG.22) regions
ecules (SMM’s) of VII-a, VIII-a, IX-a, and XI-a (as shown in 45 of the hemofilters after blood contacting for Experiments 1-6.
the Figures) having various chemical constituents were used In Experiment 1, the first filter to fail after 25 minutes was
to modify the commercial hemofilters, which were used as the IX-a, where the header pressure was 180 mm Hg. This is
test samples together with the control filters. Commercial called the failure or occlusion time. Failure here means when
filters modified with VII-a had 4% additive incorporation. 50
the header pressure reached a 175 mm Hg over the base pres
Commercial filters modified with VIII-a had 3% additive Sure. At this point, the y-count of the activated platelets was
incorporation. Commercial filters modified with IX-a had 2% 3582, while it was 3250 in the middle and 2223 at the outlet.
additive incorporation. Commercial filters modified with VII-a performed the best in this experiment not only amongst
XI-a had 1.6% additive incorporation. A total of 30 filters the SMM’s but also compared to the control with the lowest
were analyzed in the study. Heparinized bovine blood (2 55 header pressure of 20 vs. 53 mm Hg (control). The y-count at
units/ml) was used for each experiment, where the study this point was 2631. However, the y-count in the middle was
included 3 or 6 cows. QC release tests were performed on the higher (at 4534) and lower in the outlet (at 2454). The higher
modified filters for dialyzer function and assessment of fiber Y-count in the middle may be indicative of loosely bound
dimensions. These were compared to the control filters. micro-thrombi that slips through into the fiber (due to the
60
Methods additive nature of the SMM), which does not allow the
An in vitro assessment of hemofilter thrombosis was made thrombi to accumulate. The higher concentration of activated
using a standard blood loop system and protocol (see Suka platelets in the middle of the filters is generally true for most
vaneshvar et al., Annals of Biomedical Engineering 28:182 of the SMM modified filters, as is evident in Experiments 1, 2,
193 (2000), Sukavaneshvar et al., Thrombosis and Haemo 65 3, 5, and 6. In this experiment (Experiment 1), XI-a modified
stasis 83:322-326 (2000), and Sukavaneshvar et al., ASAIO filters also performed well with a header pressure of 35 mm
Journal 44:M388-M392 (1998)). Hg, as compared to the control.
US 8,877,062 B2
31 32
TABLE 6 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
Total
Expt Header pr Y-Drobe read, (CDIn Radia mm Hg. These are actual values in the in vitro analysis due to
a pulsating blood flow under high shear stress through the
Flow = 200 Filters A Pir R M B tion fibers, which can result in a slight negative pressure and
ml/min i Inlet (red) Inlet Middle Outlet cpm should actually be interpreted as 0 for all intents and pur
Expt 1 C 53 2231 216S 1410 4396 poses.
Occlusion VII-a 2O 2631. 4534 2454 71.65
ime VIII-a 53 2667 3683 2049 63SO TABLE 7
= 25 mins DX-a 18O 3582 3250 2223 6832 10
XI-a 35 2701 4631 2527 7332 Occlusion T
Expt2 C 86 1905 1536 1078 3441 Expt. Control VII-a VIII-a DX-a XI-a min
Occlusion VII-a 158 3293 3557 2O85 68SO
ime VIII-a 18S 2623 2806 1512 S429 Header Pressure Change - Inlet (Red)
= 57 mins DX-a 155 241.3 2510 1821 4923
XI-a 176 2791 2942 1770 5733 15 1 53 2O 53 18O 35 25
3 C 154 2O339 4-624 2619 24963 2 86 158 18S 155 176 57
Occlusion VII-a 21 6SS4 4608 2662 1162 3 154 21 227 217 36 30
ime VIII-a 227 19816 S799 2692 25615 4 926 9 12 133 51 8
= 30 mins DX-a 217 19982 6876 393O 26858 5 362 -3 8 8 -5 10
XI-a 36 766O 2962 1867 O622 6 33 41 222 35 63 40
4 C1G 926 17982 4342 5707 22324 Av 269 41 118 121 59
Occlusion VII-a 9 1915 2547 1479 4462 STD 343 59 105 83 62
ime VIII-a 12 1941 2106 1311 4047 STE 140 24 43 34 25
= 8 mins DX-a 133 6433 3893 2554 O326 Gamma Count - Inlet (Red)
XI-a 51 1404 1993 1196 3397
5 C1G 362 4836 2747 1984 7583 1 2231 2631 2667 3582 2.701
Occlusion VII-a -3 225S 3442 2301 5697 2 1905 3.293 2623 2413 2791
ime VIII-a 8 5577 8065 4.835 3642 25 3 20339 6SS4 19816 19982 7660
= 10 mins DX-a 8 905 917 913 1822 4 17982 1915 1941 6433 1404
XI-a -5 1012 1098 435 2110 5 4836 2255 5577 905 1012
6 C 33 2465 1717 1082 4.182 6 2465 SO91 SO19 228O 3644
Occlusion VII-a 41 SO91 5762 2967 O853 Av 8.293 3623 6274 5933 32O2
ime VIII-a 222 SO19 3664 1850 8683 AV 10 829.3 362 627 593 320
= 40 mins DX-a 35 228O 2348 1519 4628 30 STD 85.14 1824 6791 713O 2388
XI-a 63 3644 3186 1673 683O STE 3476 744 2772 2911 975
STE10 348 74 277 291 97
Filters that failed in each experiment
In Experiment 2, VIII-a failed within 57 minutes with a Table 8 illustrates the time to failure and the corresponding
header pressure of 185 mmHg. In this experiment, the control 35
filters that failed first in each experiment. It can be seen that in
performed the best with the lowest header pressure at 86 mm Experiments 4 and 5 the control filters failed catastrophically,
Hg compared to VII-a or IX-a. The corresponding Y-counts
are also shown in the Table 6. However, in the next 4 experi whereas in Experiment 1, IX-a failed in 25 minutes. In
ments, VII-a performed the best among all the filters tested Experiments 2, 3, and 6, VIII-a failed (57, 30, and 40 minutes
with the lowest header pressure, except in Experiment 6 40 respectively), but none of these were major failures nor did
where the header pressure for XI-a was slightly higher than they result in filters becoming fully occluded with thrombus.
the control. The y-counts at the header inlet are also reflective Table 8 also summarizes the header pressure of the two best
of its performance. XI-a performed second best in this series. SMM formulations (VII-a and XI-a) and how these compare
Experiments 4 and 5 showed some interesting results, where relative to the control.
the control filters failed catastrophically within 8 and 10 45
minutes, respectively, with massive fibrin rich thrombus and TABLE 8
complete occlusion of the filters. Table 6 shows how high the Parameters Expt 1 Expt2 Expt 3 Expt 4 Expt 5 Expt 6
pressure was (926 and 362 mm Hg) of the control filters
relative to the SMM modified filters and the corresponding Time to 25 57 30 8 10 40
high platelet count at this point. None of the SMM modified 50 Failure
minutes'
filters failed within 10 minutes in any of the experiments nor First Filter IX-a VIII-a VIII-a Control Control VIII-a
did they reach Such high pressures at any point during the to Fail
entire analysis. APat Header (Inlet) for VII-a & XI-a Filters vs Control’
Table 7 shows the average header pressure and the y-count
at the inlet for the control and VII-a, VIII-a, IX-a, and XI-a 55 VII-a 2O 158 21 9 -3 41
XI-a 35 176 36 51 -5 63
modified filters with the corresponding standard deviation Control 53 86 154. 926 3623 33
and standard error for six experiments (n=6). The high value
of the standard error (STE) for the control in comparison to Each experiment was terminated if the pressure was a 175 mmHg, relative to the baseline
pressure. This was deemed as filter failure. Control in Expt4 and 5 failed within 10 minutes.
any of the SMMs is also an indication of the large variability AP denote the change in header pressure relative to the baseline pressure.
in the control filter performance. The table also indicates that 60 The filters in Expt 4 and 5 were fully occluded with thrombus
the header pressures (inlet) of VII-a and XI-a had the least
variability, evident from the STE values of 24 and 25 respec FIG. 23 illustrates graphically the average header pressure
tively. The y-counts of the activated platelets at the header and Y-counts of VII-a and XI-a in comparison to the control
inlet (Table 7) also show a much lowerSTE for VII-a and XI-a filters. The error bars are an indication of variability in both
compared to the control filters. Both these values are in con 65 the pressure and Y readings; both of which are higher in the
formity with the filter performance of VII-a and XI-a vs. control vs. VII-a and XI-a. On average, VII-a had 85% less
control filters. header pressure and XI-a had 78% less header pressure than
US 8,877,062 B2
33 34
the control while the y-counts were 56% and 61% lower in What is claimed is:
VII-a and XI-a, respectively, as compared to the commercial 1. A method of performing a procedure selected from
control. hemodialysis, hemofiltration, hemoconcentration, or hemo
FIGS. 24A-24B and FIGS. 25A-25C are thrombus photos diafiltration on a Subject using a dialysis filter, wherein said
of Experiment 4, and FIGS. 26A-26D are thrombus photos of 5 filter comprises
Experiment 5. In these experiments, the control filters failed (a) a hollow fiber merbre comp.sing a base polymer
within 10 minutes or less with massive thrombus formation admixed with from 0.005% to 10% (w/w) of a surface
and filter occlusion. FIGS. 24A-24B and FIGS. 25A-25C modifying macromolecule, wherein said base polymer
especially shows that not only the headers had thrombus but R ple a E. tes said
there was thrombus residue on the sieve after the draining of 10 ollow Iber membrane is anuunrombogenic winen con
the blood indicative of hypercoagulation tacted with blood, wherein said Surface modifying mac
FIG. 27 compares the thrombus photos of VII-a and XI-a romolecule has a structure according to:
with control filters for all the 6 experiments. From the degree (a1) formula (VII):
of redness of the header inlet indicative of red thrombus is FB-(Oligo)-B-F (VII),
build-up and platelet activation, it can be seen that VII-a and wherein Oligo is an oligomeric segment including
XI-a on an average, performed better than the control (besides polypropylene oxide or polytetramethylene oxide and
the pressure values). having a theoretical molecular weight of from 500 to
Thrombus photos were taken of the filter headers at the 3,000 Daltons; B is a hard segment formed from hex
inlet and outlet positions after the blood loop analysis for all 20 amethylene diisocyanate; F is a polyfluoroorgano
the 6 experiments. Experimental results are shown as throm- group; and n is an integer from 1 to 10;
bus photos for Experiment 1 (FIGS. 28A-28B), Experiment 2 (a2) formula (VIII):
(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 25 FT FT F (VIII)
unlike the control in experiment 4 and 5. N /T
In addition, all the SMM modified filters (VII-a, VIII-a, B-A-B-A--B
IX-a, or XI-a) were able to be spun into fibers. When 14 \,
assembled into dialyzer filters, the hemofilters were tested, T t
and all were able to function as a hemofilter, as compared to 30
a control hemofilter. In general, all of the hemofilters func- wherein A is an oligomeric segment including polytet
tioned as a dialyzer. ramethylene oxide and having a theoretical molecular
Conclusions weight of from 500 to 3,000 Daltons; B is a hard
The in vitro blood loop studies using heparinized bovine segment formed from hexamethylene diisocyanate
blood indicated that VII-a and XI-a performed the best among 35 biuret trimer; F is a polyfluoroorgano group; and n is
all the filters tested. These two formulations showed no filter an integer from 0 to 10;
failure with the lowest average header pressure (>75% less (a3) formula (IX):
ressure), low average y-count (>55% less), low thrombus
E. ASRs. than R.S. the F-B-(Oligo)-B-F (IX),
control filters performed the worst, failing catastrophically in 40 wherein Oligo is an oligomeric segment including poly
two experiments within 10 minutes. It also had the highest (2.2 dimethyl-1,3-propylcarbonate and having a theo
average header pressure, y-count and variability of all the retical molecular weight of from 500 to 3,000 Dal
filters tested in the 6 experiments. VIII-a failed in 3 experi- tons; B is a hard segment formed from 4,4'-methylene
ments and IX-a failed in 1 experiment, but all of these were bis(cyclohexyl isocyanate); F is a polyfluoroorgano
within 25-57 minutes and none of the filters had any major 45 group; and n is an integer from 1 to 10; or
occlusion. All of the hemofilters function as a dialyzer in (a4) formula (XI):
various degrees and adjustments can be made easily to con
form to the desired specifications. (XI)
OTHER EMBODIMENTS 50 V ?t
B-A-B-A-B
All publications, patents, and patent applications men- M -- -- V
tioned in this specification are herein incorporated by refer- FT FT,
ence to the same extent as if each independent publication or
patent application was specifically and individually indicated 55 wherein A is a block copolymer comprising polypropy
to be incorporated by reference. lene oxide and polydimethylsiloxane and having a
While the invention has been described in connection with theoretical molecular weight of from 1,000 to 5,000
specific embodiments thereof, it will be understood that it is Daltons; B is a hard segment formed from hexameth
capable of further modifications and this application is ylene diisocyanatebiuret trimer; F is a polyfluoroor
intended to cover any variations, uses, or adaptations of the 60 gano group; and n is an integer from 1 to 10;
invention following, in general, the principles of the invention (a5) formula (IV),
and including such departures from the present disclosure
that come within known or customary practice within the art F-B-A-B-F (IV),
to which the invention pertains and may be applied to the wherein A is a soft segment including hydrogenated
essential features hereinbefore set forth, and follows in the 65 polybutadiene, poly (2.2 dimethyl-1,3-propylcarbon
Scope of the claims. ate), polybutadiene, poly (diethylene glycol)adipate,
Other embodiments are within the claims. poly (hexamethylene carbonate), poly (ethylene-co
US 8,877,062 B2
35 36
butylene), neopentylglycol-orthophthalic anhydride prising a Surface modifying macromolecule having a struc
polyester, diethylene glycol-orthophthalic anhydride ture according to formula VII-a, VIII-a, IX-a, and XI-a.
polyester, 1.6-hexanediol-ortho phthalic anhydride 5. The method of claim 1, wherein said filtercomprises said
polyester, or bisphenol A ethoXVlate; B is a hard seg potted bundle, said potted bundle comprising a potting resin
ment including a urethane; F is a polvfluoroorgano 5
that comprises a Surface modifying macromolecule selected
group, and n is an integer from 1 to 10; and/or from VII-a, VIII-a, IX-a, XI-a, VIII-b, VIII-d, and XI-b.
(b) a potted bundle of hollow fiber membranes within an 6. The method of claim 1, wherein said filtercomprises said
encasement comprising: hollow fiber membrane comprising said Surface modifying
(i) an array of hollow fiber membranes, said array of macromolecule,
hollow fiber membranes having lumens, a first set of 10
fiber ends, and a second set of fiber ends; wherein the thrombi deposition on said surface said hollow
(ii) said first set of fiber ends being potted in a potting fiber membrane is reduced by at least 10% when con
resin which defines a first internal wall near a first end tacted with blood,
of the encasement; and wherein said hollow fiber membrane has an operating pres
(iii) said second set offiber ends being potted in a potting 15 sure after 4 hours of use that is reduced by at least 10%,
resin which defines a second internal wall near a sec O
ond end of the encasement, wherein said hollow fiber membrane reduces adverse
wherein said lumens of said hollow fiber membranes advents in a subject receiving blood passing through said
provide a path for the flow of blood from said first hollow fiber membrane.
internal wall to said second internal wall, and 7. The method of claim 1, wherein said filtercomprises said
wherein said potting resin comprises from 0.005% to hollow fiber membrane comprising said Surface modifying
10% (w/w) of a surface modifying macromolecule macromolecule admixed with said base polymer, wherein
having a structure according to: said base polymer is a polysulfone.
(b 1) formula (III),
25 8. The method of claim 7, wherein said polysulfone is
F-B-(oligo)-B-F (III), poly(oxy-1,4-phenylene Sulfonyl-1,4-phenyleneoxy-1,4-
phenyleneisopropylidene-1,4-phenylene) or polyether Sul
wherein B includes a urethane; oligo includes polypro fone.
pylene oxide, polyethylene oxide, or polytetrameth
ylene oxide; F is a polyfluoroorgano group; and n is 9. The method of claim 1, wherein said filtercomprises said
an integer from 1 to 10; 30 hollow fiber membrane, said hollow fiber membrane further
(b2) formula (VII), comprising a hydrophilic pore forming agent
10. The method of claim 9, wherein said hydrophilic pore
F-B-(Oligo)-B-F (VII), forming agent is selected from polyvinylpyrrolidone, ethyl
wherein Oligo is an oligomeric segment including ene glycol, alcohols, polypropylene glycol, and polyethylene
35
polypropylene oxide, polyethylene oxide, or polytet glycol, or mixtures thereof.
ramethylene oxide and having a theoretical molecular 11. The method of claim 9, wherein said hollow fiber
weight of from 500 to 3,000 Daltons; B is a hard membrane comprises from 80% to 96.5% (w/w) of said base
segment formed from an isocyanate dimer; F is a polymer, from 3% to 20% (w/w) of said hydrophilic pore
polvfluoroorgano group; and n is an integer from 1 to 40
forming agent, and 0.005% to 10% (w/w) of said surface
10; or modifying macromolecule.
(b3) formula (IV), 12. The method of claim 1, wherein said filter comprises
said potted bundle,
F-B-A-B-F (IV), wherein said potted bundle has a prolonged working life,
wherein A is a soft segment including hydrogenated 45
wherein said bundle has an increased average functional
polybutadiene, poly (2.2 dimethyl-1,3-propylcarbon working life of at least 125%,
ate), polybutadiene, poly (diethylene glycol)adipate, wherein the thrombi deposition on said potted bundle is
poly (hexamethylene carbonate), poly (ethylene-co
butylene), neopentylglycol-orthophthalic anhydride reduced by at least 10% when contacted with blood,
polyester, diethylene glycol-orthophthalic anhydride 50 wherein said bundle has an operating pressure after 4 hours
polyester, 1.6-hexanediol-ortho phthalic anhydride of use that is reduced by at least 10%,
polyester, or bisphenol A ethoxylate; B is a hard seg wherein said potting resin is antithrombogenic when con
ment including a urethane; F is a polyfluoroorgano tacted with blood, or
group, and n is an integer from 1 to 10. wherein said potted bundle reduces adverse advents in a
2. The method of claim 1, wherein during said procedure 55 Subject receiving blood passing through said potted
said Subject receives less than a standard dose of anticoagul bundle.
lant or receives no anticoagulant. 13. The method of claim 1, wherein said filter comprises
3. The method of claim 1, wherein said filter has a pro said bundle of potted hollow fiber membranes, wherein said
longed working life, wherein said filter has an increased aver bundle of potted hollow fiber membranes within an encase
age functional working life of at least 125%, wherein the 60
ment is part of a blood purification device.
thrombi deposition on said filter is reduced by at least 10%
when contacted with blood, wherein said filter has an oper 14. The method of claim 13, wherein said blood purifica
ating pressure after 4 hours of use that is reduced by at least 10 tion device is a hemodialysis, hemodiafiltration, hemofiltra
%, or wherein the adverse events experienced by said subject tion or hemoconcentration device.
are reduced. 65 15. The method of claim 1, wherein said filter comprises
4. The method of claim 1, wherein said filter comprises said said potted bundle, wherein said potting resin comprises a
hollow fiber membrane, said hollow fiber membrane com cross-linked polyurethane.
US 8,877,062 B2
37 38
16. The method of claim 1, wherein said filter comprises 23. The method of claim 1, wherein said filter comprises
said hollow fiber membrame, said hollow fiber membrane said hollow fiber membrane, said hollow fiber membrane
comprising a Surface modifying macromolecule having a comprising a Surface modifying macromolecule having a
structure according to formula (VII), structure according to formula (XI),
F-B-(Oligo)-B-F (VII),
wherein F (XI)
(i) Oligo is an oligomeric segment including polypropy FT T FT
lene oxide or polytetramethylene oxide having a theo
retical molecular weight of from 500 to 3,000 Daltons; 10 M
Y A-l A-YV pi
(ii) B is a hard segment formed from hexamethylene diiso FT FT

cyanate;
(iii) F is a polyfluoroorgano group; and wherein
(iv) n is an integer from 1 to 10. (i) A is a block copolymer comprising polypropylene oxide
17. The method of claim 16, wherein n is an integer from 1 15 and polydimethylsiloxane having a theoretical molecu
to 3. lar weight of from 1,000 to 5,000 Daltons;
18. The method of claim 17, wherein Fis selected from the (ii) B is a hard segment formed from hexamethylene diiso
group consisting of CHF.s. (CF), CH2CH2- and cyanatebiuret trimer;
CH.F.s. (CF2),(CH2CH2O), , (iii) F is a polyfluoroorgano group; and
wherein m is 0, 1, 2, or 3; r is an integer from 2 to 20; s is (iv) n is 0, 1, 2, or 3.
an integer from 1 to 20; and X is an integer from 1 to 10. 24. The method of claim 23, wherein said hollow fiber
19. The method of claim 16, wherein said surface modify membrane comprises a Surface modifying macromolecule
ing macromolecule of formula (VII) is VII-a. having a structure according to formula XI-a.
20. The method of claim 1, wherein said filter comprises 25. The method of claim 1, wherein said filter comprises
said potted bundle, said potted bundle comprising a Surface 25 said hollow fiber membrane, said hollow fiber membrane
modifying macromolecule having a structure according to comprising a Surface modifying macromolecule having a
formula (III), structure according to formula (VIII),
F-B-(oligo)-B-F (III)
wherein 30 (VIII)
(i) B includes a urethane; FT FT FT
(ii) oligo includes polypropylene oxide, polyethylene
oxide, or polytetramethylene oxide; YM A-l A-Y\
(iii) F is a polyfluoroorgano group; and FT FT,
(iv) n is an integer from 1 to 10. 35
21. The method of claim 1, wherein said filter comprises wherein
said potted bundle, said potted bundle comprising a Surface (i) A is an oligomeric segment including polytetramethyl
modifying macromolecule having a structure according to ene oxide and having a theoretical molecular weight of
formula (VII), from 500 to 3,000 Daltons;
40
F-B-(Oligo)-B-F (VII), (ii) B is a hard segment formed from hexamethylene diiso
wherein cyanatebiuret trimer;
(i) Oligo is an oligomeric segment including polypropy (iii) F is a polyfluoroorgano group; and
lene oxide, polyethylene oxide, or polytetramethylene (iv) n is 0, 1, 2, or 3.
oxide and having a theoretical molecular weight of from 45
26. The method of claim 1, wherein said hollow fiber
500 to 3,000 Daltons: membrane comprises a Surface modifying macromolecule
(ii) B is a hard segment formed from an isocyanate dimer; having a structure according to formula VIII-a.
(iii) F is a polyfluoroorgano group; and 27. The method of claim 1, wherein said filter comprises
(iv) n is an integer from 1 to 10. said hollow fiber membrane, said hollow fiber membrane
22. The method of claim 1, wherein said filter comprises 50
comprising a Surface modifying macromolecule having a
said potted bundle, said potted bundle comprising a Surface structure according to formula (IX),
modifying macromolecule having a structure according to
formula (IV), wherein
(i) Oligo is an oligomeric segment including poly (2.2dim
F-B-A-B-F (IV) 55 ethyl-1,3propylcarbonate and having a theoretical
wherein molecular weight of from 500 to 3,000 Daltons;
A is a soft segment including hydrogenated polybutadiene, (ii) B is a hard segment formed from 4,4'-methylene bis
poly (2.2 dimethyl-1,3-propylcarbonate), polybutadi (cyclohexyl isocyanate);
ene, poly (diethylene glycol)adipate, poly (hexamethyl (iii) F is a polyfluoroorgano group; and
ene carbonate), poly (ethylene-co-butylene), neopentyl 60 (iv) n is 0, 1, 2, or 3.
glycol-orthophthalic anhydride polyester, diethylene 28. The method of claim 27, wherein said hollow fiber
glycol-ortho phthalic anhydride polyester, 1.6-hex membrane comprises a Surface modifying macromolecule
anediol-orthophthalic anhydride polyester, or bisphenol having a structure according to formula IX-a.
Aethoxylate: 29. The method of claim 1, wherein said filter comprises
(ii) B is a hard segment including a urethane; and 65 said hollow fiber membrane, wherein Fis selected from the
(iii) F is a polyfluoroorgano group, and group consisting of CHF.s. (CF), CH2CH2- and
(iv) n is an integer from 1 to 10. CHF (CF2),(CH2CH2O), ,
US 8,877,062 B2
39 40
wherein m is 0, 1, 2, or 3; r is an integer from 2 to 20; s is 31. The method of claim 30, wherein said surface modify
an integer from 1 to 20; and X is an integer from 1 to 10. ing macromolecule has a structure according to formula
30. A method of performing a procedure selected from (VII):
hemodialysis, hemofiltration, hemoconcentration, or hemo
diafiltration on a Subject using a dialysis filter, wherein said 5 F-B-(Oligo)-B-F (VII),
filter comprises a hollow fiber membrane comprising a base wherein Oligo is an oligomeric segment including
polymer admixed with from 0.005% to 10% (w/w) of a sur polypropylene oxide, polyethylene oxide, or polytet
face modifying macromolecule, wherein said hollow fiber ramethylene oxide and having a theoretical molecular
membrane is antithrombogenic when contacted with blood, 10 weight of from 500 to 3,000 Daltons; B is a hard segment
wherein said Surface modifying macromolecule has a struc formed from hexamethylene diisocyanate; F is a poly
ture according to: fluoroorgano group; and n is an integer from 1 to 10.
(a1) formula (VII): 32. The method of claim 31, wherein n is an integer from 1
to 3.
F-B-(Oligo)-B-F (VII), 15 33. The method of claim 32, wherein Oligo is an oligo
wherein Oligo is an oligomeric segment including meric segment including polypropylene oxide.
polypropylene oxide or polytetramethylene oxide and 34. The method of claim 32, wherein Oligo is an oligo
having a theoretical molecular weight of from 500 to meric segment including polytetramethylene oxide.
3,000 Daltons; B is a hard segment formed from hexam 35. The method of claim32, wherein Fis selected from the
ethylene diisocyanate; F is a polyfluoroorgano group; group consisting of CHF.CF), CH2CH2- and
and n is an integer from 1 to 10; CHF (CF2),(CH2CH2O), -,
(a2 )formula (VIII): 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.
25
36. A method of performing a procedure selected from
F
T FT F
(VIII) hemodialysis, hemofiltration, hemoconcentration, or hemo
diafiltration on a Subject using a dialysis filter, wherein said
Y---A-Y T filter comprises a hollow fiber membrane comprising a base
M n \ polymer admixed with from 0.005% to 10% (w/w) of a sur
FT FT,
30 face modifying macromolecule, wherein said hollow fiber
membrane is antithrombogenic when contacted with blood,
wherein A is an oligomeric segment including polytetram wherein said surface modifying macromolecule has a struc
ethylene oxide and having a theoretical molecular ture according to:
weight of from 500 to 3,000 Daltons; B is a hard segment (a1) formula (VII):
formed from hexamethylene diisocyanatebiuret trimer; 35
F is a polyfluoroorgano group; and n is an integer from F-B-(Oligo)-B-F (VII),
Oto 10; wherein Oligo is an oligomeric segment including
(a3) formula (IX): polypropylene oxide or polytetramethylene oxide and
40
having a theoretical molecular weight of from 500 to
3,000 Daltons; B is a hard segment formed from hexam
wherein Oligo is an oligomeric segment including poly ethylene diisocyanate; F is a polyfluoroorgano group:
(2.2dimethyl-1,3-propylcarbonate and having a theo and n is an integer from 1 to 10;
retical molecular weight of from 500 to 3,000 Daltons: B (a2) formula (VIII):
is a hard segment formed from 4,4'-methylene bis(cy 45
clohexyl isocyanate); F is a polyfluoroorgano group:
and n is an integer from 1 to 10; or F (VIII)
T FT F
(a4) formula (XI):
Y-A-I-A-Y T
M n \
50 FT FT,
F (XI)
T FT F
Y-A-B-A-Y T wherein A is an oligomeric segment including polytetram

M * V ethylene oxide and having a theoretical molecular
FT FT, weight of from 500 to 3,000 Daltons; B is a hard segment
55
formed from hexamethylene diisocyanatebiuret trimer;
wherein A is a block copolymer comprising polypropylene Fis a polyfluoroorgano group; and n is an integer from
oxide and polydimethylsiloxane and having a theoreti O to 10;
cal molecular weight of from 1,000 to 5,000 Daltons: B (a3) formula (IX):
is a hard segment formed from hexamethylene diisocy 60
anatebiuret trimer Fis a polyfluoroorgano group; and in
is an integer from 1 to 10; wherein Oligo is an oligomeric segment including poly
wherein the blood and dialysate are separated from each (2.2dimethyl-1,3-propylcarbonate and having a theo
other by said hollow fiber membraneata semipermeable retical molecular weight of from 500 to 3,000 Daltons: B
surface of said hollow fiber membrane during said pro 65 is a hard segment formed from 4,4'-methylene bis(cy
cedure, said semipermeable Surface comprising said Sur clohexyl isocyanate); F is a polyfluoroorgano group;
face modifying macromolecule. and n is an integer from 1 to 10; or
US 8,877,062 B2
41 42
(4) formula (XI): 37. The method of claim 36, wherein said surface modify
ing macromolecule has a structure according to formula
(VII):
F-B-(Oligo)-B-F (VII),
F (XI)
T FT F wherein Oligo is an oligomeric segment including
Y-a-b-a-Y T polypropylene oxide or polytetramethylene oxide and
M * V having a theoretical molecular weight of from 500 to
FT FT, 3,000 Daltons; B is a hard segment formed from hexam
ethylene diisocyanate; F is a polyfluoroorgano group;
10 and n is an integer from 1 to 10.
wherein A is a block copolymer comprising polypropylene 38. The method of claim 37, wherein n is an integer from 1
oxide and polydimethylsiloxane and having a theoreti to 3.
cal molecular weight of from 1,000 to 5,000 Daltons: B 39. The method of claim 38, wherein Oligo is an oligo
is a hard segment formed from hexamethylene diisocy meric segment including polypropylene oxide.
anatebiuret trimer; F is a polyfluoroorgano group; and 15 40. The method of claim 38, wherein Oligo is an oligo
n is an integer from 1 to 10; meric segment including polytetramethylene oxide.
41. The method of claim38, wherein Fis selected from the
wherein said hollow fiber membrane is formed from a group consisting of CHF.s. (CF), CH2CH2- and
spinning Solution by extruding said spinning Solution CHF (CF2),(CH2CH2O), ,
through a tube-in-tube type orifice, wherein said spin wherein m is 0, 1, 2, or 3; r is an integer from 2 to 20; s is
ning solution comprises said base polymer and said Sur an integer from 1 to 20; and X is an integer from 1 to 10.
face-modifying macromolecule. k k k k k

HollowFiberMembranes US8877062

Uploaded by

Document Informationclick to expand document information

Copyright:

Available Formats

HollowFiberMembranes US8877062

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

HollowFiberMembranes US8877062

Uploaded by

Copyright:

Available Formats

US008877O62B2

(12) United States Patent (10) Patent No.: US 8,877,062 B2

Biti Fly &r Cartridge

(51) Int. Cl. 2008/0228253 A1 9, 2008 Mullicket al.

(56) References Cited Tang et al., “Synthesis of Surface-Modifying Macromolecules for

No.terw-ºf,^~ )—, ^,…)

Average change in Pr: Control vs. V-a and X-a (n - 6)

Figure 25A igur e 25B

Figure 26C Figure 26D

(ii) B is a hard segment formed from hexamethylene diiso FT FT

Y-A-B-A-Y T wherein A is an oligomeric segment including polytetram

You might also like