CN102316965A

CN102316965A - Antithrombogenic hollow fiber membranes and filters

Info

Publication number: CN102316965A
Application number: CN2010800013162A
Authority: CN
Inventors: 桑乔伊·穆利克; 张纬伦; 陈汉杰; 马克·斯蒂德曼; 露西塔·埃斯范德
Original assignee: INTERFACE BIOLOG Inc
Current assignee: INTERFACE BIOLOG Inc; Interface Biologics Inc
Priority date: 2009-05-15
Filing date: 2010-05-14
Publication date: 2012-01-11
Anticipated expiration: 2030-05-14
Also published as: KR101331056B1; JP5702857B1; CN102316965B

Abstract

The invention relates to extracorporeal blood circuits, and components thereof (e. g. , hollow fiber membranes, potted bundles, and blood tubing), including 0. 005% to 10% (w/w) surface modifying macromolecule. The extracorporeal blood circuits have an antithrombogenic surface and can be used in hemofiltration, hemodialysis, hemodiafiltration, hemoconcentration, blood oxygenation, and related uses.

Description

Anticoagulant property hollow-fibre membrane and filter

Technical field

The present invention relates to anticoagulant property extracorporeal blood loop (loop; Circuit) and assembly (parts); Like hollow-fibre membrane, blood tubulature (blood tubing) and filter, and they concentrate at blood filtration, haemodialysis, hemodiafiltration, blood, the application in blood oxygenation and the associated uses.

Background technology

In order to treat the patient who stands kidney failure, various blood purification methods have been proposed, wherein blood takes out to be cleaned from patient's live body, and the blood that purifies then is returned in the health.For example, utilize the blood purification method of extracorporal circulatory system to be divided into following type: through the haemodialysis (HD) of diffusion, the hemodiafiltration (HDF) that carries out the blood filtration (HF) of body fluid removal/replacement and wherein combine HD and HF through ultrafiltration.

Above mentioned method utilizes haemodialyser to implement.Said dialyzer be in fact filtering blood useless solute (dissolved matter) and liquid (as, urea, potassium, kreatinin and uric acid) equipment spare.The nearly all dialyzer that uses now is the doughnut kind.The doughnut of the cylinder pencil of forms (its wall is made up of pellicle) is anchored in the perfusion compound (a kind of glue) at each end.This assembly (assembling) is placed in the transparent plastic cylindrical housings with four openings subsequently.Be communicated with each end of hollow fiber bundle at cylindrical each terminal opening or blood port.This forms " the blood compartment " of dialyzer.Two other ports are cut cylindrical side.Space around these and the doughnut, " dislysate compartment " is communicated with.Blood is pumped the tow through this extremely thin capillary appearance pipe via the blood port, and dislysate is pumped through the space around the fiber.The gradient of exerting pressure in case of necessity moves to the dislysate compartment with the liquid of autoblood in future.

Haemodialysis is as artificial kidney and substitutes because the significant process of all vital functions of chronic or acute renal failure.Dislysate can be used to handle have kidney failure, the patient of body fluid overload or toxaemia situation, and can be configured to carry out HD, HF, HDF or blood and concentrate.

When blood is transported to health or when health transports or when dialyzer, cleaning, can adds anti-coagulants, like heparin in case hemostasis-coagulation or thrombosis.For the patient who accept to continue kidney replacement treatment (CRRT) (that is, continuing 24 hours/7 days/week of dialysis), heparin usually as injecting that agent (bolus) whole body gives to prevent between dialysis period because the cohesion of blood, the obstruction of filter membrane.In the situation that does not give heparin, the time of plugged filter 27%, and when having heparin, the time of plugged filter 17% (referring to Richardson et al., Kidney International 70:963-968 (2006)).For accepting intermittently haemodialysis (IHD) patient of (about 4 hours dialysis at intermittence, twice of every day), do not award heparin usually.During IHD, the time of plugged filter 20-30% (referring to Manns et al., Critical Care Medicine 31:449-455 (2003)).When filter stopped up, dialysis procedure was interrupted, and washed away filter to remove thrombus with saline solution.In the patient of experience CH (for example, each haemodialysis reach prolongation hour, and have weekly a plurality of periods), the heparin that commonly uses bolus amount is to reduce the ratio of plugged filter.

Though be favourable, in some patients the use of heparin can with allergy and hemorrhage concurrent, and in adopting the patient of some drug therapies, possibly avoid using.

Some medical procedures need use external oxygen charging method, and wherein blood is removed with by oxygenation from patient's live body, and the blood of oxygenation is returned health subsequently.For example; The oxygenator device of implementing so external oxygen charging method comprises the heart-lung by-pass unit or external diaphragm type oxygenate (ECMO) machine; Its during open heart surgery (like CBG (CABG) and cardiac valve replacement) uses, and perhaps is used to handle respiratory distress syndrome or respiratory insufficiency.During open heart surgery, be used for pachyhematous device and also can be used to increase the multiple blood constituent in the patient, minimize the risk of postoperative hemorrhage thus.These hemoconcentrators can with comprise the oxygenator device after one's own heart-the external loop of lung by-pass unit is parallel to be used.

Use pump blood to pass in and out these processing of patient based on needs, have needs for thrombotic extracorporeal blood loop with minimizing.Especially, need for the method and composition existence, so that the polymer assemblies of the extracorporeal blood loop with the surface that after being exposed to blood, minimizes the thrombosis rate to be provided.

Summary of the invention

Method and composition of the present invention is characterised in that the extracorporeal blood loop, and assembly (like, hollow-fibre membrane, encapsulation (potted) bundle and blood tubulature), comprises the big molecule of surface modification of 0.005% to 10% (w/w).

In first aspect, the invention is characterized in the extracorporeal blood loop that comprises polymer assemblies, wherein said polymer assemblies comprise fusion have 0.005% to 10% (w/w) the big molecule of surface modification (as; From 0.005% to 0.1% (w/w), from 0.005% to 5% (w/w), from 0.1% to 0.3% (w/w); From 0.1% to 5% (w/w), from 0.1% to 10% (w/w), from 0.05% to 5% (w/w); 0.05% to 8% (w/w), from 1% to 5% (w/w), from 1% to 8% (w/w); From 1% to 10% (w/w); And from 2% to 10% (w/w)) base polymer, wherein said polymer assemblies has the surface that is positioned at contact blood when the extracorporeal blood loop is in use, and wherein said surface is anticoagulation (antithrombotic formation) when contacting with blood.In one embodiment, when contacting with blood, the thrombus deposition in the surface is reduced by at least 10%, 20%, 40%, 60% or 80% (for example, 10% to 95%, 10% to 80%, 20% to 95%, 35% to 85% or 40% to 80%).In another embodiment, the extracorporeal blood loop have at least 110%, 125%, 150%, 200% or 400% (as, 110% to 1,000%, 200% to 900% or 300% to 900%) average function sex work phase (working life) of increase.In another embodiment, the extracorporeal blood loop reduces rough sledding and occurs in the patient who accepts the blood through the extracorporeal blood loop.

Any extracorporeal blood loop described herein can comprise hollow-fibre membrane of the present invention; Encapsulation bundle of the present invention (embedding bundle); Or one or more in the blood tubulature of the present invention.

In second aspect; Characteristic of the present invention is a hollow-fibre membrane; Said hollow-fibre membrane comprises that the big molecule of surface modification that fusion has 0.005% to 10% (w/w) (for example; 0.005% to 0.1% (w/w), 0.005% to 5% (w/w), 0.1% to 0.3% (w/w), 0.1% to 5% (w/w), 0.1% to 10% (w/w), 0.05% to 5% (w/w), 0.05% to 8% (w/w), 1% to 5% (w/w), 1% to 8% (w/w), 1% to 10% (w/w) and 2% to 10% (w/w)) base polymer, wherein said hollow-fibre membrane is anticoagulant when contacting with blood.In one embodiment; When contacting with blood; Thrombus deposition on the hollow-fibre membrane is reduced by at least 10%, 20%, 40%, 60% or 80% (for example, 10% to 95%, 10% to 80%, 20% to 95%, 35% to 85% or 40% to 80%).In another embodiment; Hollow-fibre membrane has the operating pressure that is reduced by at least 10%, 20%, 30%, 40% or 50% (for example, 10% to 95%, 10% to 80%, 20% to 75%, 25% to 45% or 30% to 80%) after using 4 hours.In another embodiment, the adverse events that hollow-fibre membrane reduce to be accepted to pass among the patient of blood of hollow-fibre membrane occurs.In some embodiments; Base polymer be selected from by polysulfones (as; Gather (Oxy-1,4-phenylene sulfonyl-1,4-phenylene Oxy-1; 4-phenylene isopropylidene-1,4-phenylene) or polyether sulfone), polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather the group that (methyl methacrylate), Merlon, polyamide, polypropylene and polyethylene are formed.In other embodiment, hollow-fibre membrane further comprise the hydrophily pore-forming agent (as, polyvinylpyrrolidone, ethylene glycol, alcohol, polypropylene glycol and polyethylene glycol, or their mixture).In one embodiment; Said hollow-fibre membrane comprise 80% to 96.5% (w/w) (as; 80% to 95%, 80% to 90% (w/w), 85% to 90% (w/w) and 90% to 95% (w/w)) base polymer; 3% to 20% (w/w) (as; 3% to 15% (w/w), 3% to 7% (w/w), 3% to 5% (w/w) and 5% to 10% (w/w)) the hydrophily pore-forming agent; And 0.005% to 10% (w/w) (as, 0.005% to 0.1% (w/w), 0.005% to 5% (w/w), 0.1% to 0.3% (w/w), 0.1% to 5% (w/w), 0.1% to 10% (w/w), 0.05% to 5% (w/w), 0.05% to 8% (w/w), 1% to 5% (w/w), 1% to 8% (w/w), 1% to 10% (w/w) and 2% to 10% (w/w)) the big molecule of surface modification.

In the third aspect, characteristic of the present invention is vanning (shell, a packing; Case, encasement) the encapsulation bundle of interior hollow-fibre membrane comprises: (a) array of hollow-fibre membrane; The array of this hollow-fibre membrane has inner chamber (lumens), first group of fiber ends and second group of fiber ends; (b) said first group of fiber ends is encapsulated in the sealing resin (potting resin), and it limits near first terminal first inwall of vanning; And (c) said second group of fiber ends is encapsulated in the sealing resin; It limits near second inwall of second latter end of vanning; The inner chamber of wherein said hollow-fibre membrane provides and has been used to make blood to flow to the approach of second inwall from first inwall; And wherein said sealing resin comprise the big molecule of the surface modification of 0.005% to 10% (w/w) (as, 0.005% to 0.1% (w/w), 0.005% to 5% (w/w), 0.1% to 0.3% (w/w), 0.1% to 5% (w/w), 0.1% to 10% (w/w), 0.05% to 5% (w/w), 0.05% to 8% (w/w), 1% to 5% (w/w), 1% to 8% (w/w), 1% to 10% (w/w) and 2% to 10% (w/w)).In some embodiments, said bundle has the duty cycle of prolongation.In some embodiments, said bundle have at least 110%, 125%, 150%, 200% or 400% (as, 110% to 1,000%, 125% to 1,000%, 200% to 900% or 300% to 900%) average function sex work phase of increase.In other embodiments, when contacting with blood, the thrombus deposition on the encapsulation bundle be reduced at least 10%, 20%, 40%, 60% or 80% (as, 10% to 95%, 10% to 80%, 20% to 95%, 35% to 85% or 40% to 80%).In other embodiment, said bundle has the operating pressure that is reduced by at least 10%, 20%, 30%, 40% or 50% (for example, 10% to 95%, 10% to 80%, 20% to 75%, 25% to 45% or 30% to 80%) after using 4 hours.In some embodiments, encapsulation is restrainted minimizing acceptance and is passed the adverse events appearance among the patient of the blood that encapsulates bundle.In other embodiments, sealing resin is anticoagulant when contacting with blood.

In one embodiment, in the vanning bundle of hollow-fibre membrane of encapsulation be apparatus for purifying blood (as, haemodialysis, hemodiafiltration, blood filtration, blood concentrate or the oxygenator device) part.In another embodiment; Said sealing resin be crosslinked polyurethane (as; By 4 '-methylene two (cyclohexyl isocyanate), 2; 2 '-methylene two (phenyl) isocyanates, 2,4 '-methylene two (phenyl) isocyanates or 4, the crosslinked polyurethane that 4 '-methylene two (phenyl) isocyanates forms).

On the other hand, characteristic of the present invention is the dialysis filter that comprises any hollow-fibre membrane described herein or any encapsulation bundle described herein, and wherein said filter has the duty cycle of prolongation.In one embodiment, said dialysis filter reduces acceptance through the appearance of the adverse events among the patient of the blood of dialysis filter.

On the other hand; Characteristic of the present invention be comprise fusion have 0.005% to 10% (w/w) (as; 0.005% to 0.1% (w/w), 0.005% to 5% (w/w), 0.1% to 0.3% (w/w), 0.1% to 5% (w/w), 0.1% to 10% (w/w), 0.05% to 5% (w/w), 0.05% to 8% (w/w), 1% to 5% (w/w), 1% to 8% (w/w), 1% to 10% (w/w) and 2% to 10% (w/w)) the blood tubulature of the macromolecular base polymer of surface modification, wherein said blood tubulature is anticoagulant when contacting with blood.In specific embodiment, said base polymer comprises polyvinyl chloride.In one embodiment, said blood tubulature reduces acceptance through the appearance of the adverse events among the patient of the blood of blood tubulature.In one embodiment; When contacting with blood; The thrombus of the surface of blood tubulature deposition be reduced at least 10%, 20%, 40%, 60% or 80% (as, 10% to 95%, 10% to 80%, 20% to 95%, 35% to 85% or 40% to 80%).In another embodiment; Said blood tubulature have at least 110%, 125%, 150%, 200% or 400% (as; The average function sex work phase of increase by 110% to 1,000%, 125% to 1,000%, 200% to 900% or 300% to 900%).

Further aspect of the present invention is to be used to treat the method through the experimenter of undermined renal function; Said method comprises utilizes dialysis filter the patient to be selected from haemodialysis, blood filtration, blood concentrate or the process of hemodiafiltration, and wherein said filter comprises any hollow-fibre membrane described herein or any encapsulation bundle described herein.In one embodiment, during said process, said experimenter accept to be less than standard dose anti-coagulants (as, wherein during said process, said experimenter does not accept anti-coagulants).In another embodiment, said filter has the duty cycle of prolongation.In another embodiment; Said filter have at least 110%, 125%, 150%, 200% or 400% (as; The average function sex work phase of increase by 110% to 1,000%, 125% to 1,000%, 200% to 900% or 300% to 900%).In one embodiment, when contacting with blood, thrombus on said filter deposition be reduced by at least 10%, 20%, 40%, 60% or 80% (as, 10% to 95%, 10% to 80%, 20% to 95%, 35% to 85% or 40% to 80%).In another embodiment, said filter after using 4 hours, have and be reduced by at least 10%, 20%, 30%, 40% or 50% (as, 10% to 95%, 10% to 80%, 20% to 75%, 25% to 45% or 30% to 80%) operating pressure.In another embodiment, by the adverse events minimizing of said experimenter's experience.

Characteristic of the present invention is a kind of method through the experimenter of undermined cardiac function that is used to treat; Said method comprises the operation that utilizes the oxygenator device to be selected from CABG and cardiac valve replacement, and wherein said oxygenator device comprises any hollow-fibre membrane described herein or any encapsulation bundle described herein.In one embodiment, during said process, said experimenter accept to be less than standard dose anti-coagulants (as, wherein during said process, said experimenter does not accept anti-coagulants).In another embodiment, the adverse events by said experimenter's experience reduces.

Characteristic of the present invention is a kind of method that is used to treat the experimenter, and said method comprises via any extracorporeal blood loop described herein extracts blood out and blood is turned back to said experimenter from said experimenter.In one embodiment, during said process (operation), said experimenter accept to be less than standard dose anti-coagulants (as, wherein during said process, said experimenter does not accept anti-coagulants).In another embodiment, the adverse events by said experimenter's experience reduces.

Characteristic of the present invention also be a kind of be used for blood, blood products (as; The blood constituent of blood plasma or fractionation (classification)) method for purifying proteins or in their combination, said method comprises through any hollow-fibre membrane described herein or any encapsulation described herein restraints the said blood of dialysing, blood products or their combination.

Characteristic of the present invention is a kind of doughnut blood plasma purification membrane, comprises the bundle of the hollow-fibre membrane of any encapsulation described herein.

Characteristic of the present invention also is a kind of spinning solution that is used to prepare hollow-fibre membrane; Said spinning solution comprise (i) 57% to 87% (w/w) (as, 57% to 85% (w/w), 70% to 87% (w/w) and 70% to 85% (w/w)) aprotic solvent (aprotic solvent); (ii) 10% to 25% (w/w) (as, 10% to 20% (w/w), 12% to 25% (w/w) and 12% to 20% (w/w)) base polymer; (iii) 0.005% to 8% (w/w) (as, 0.005% to 5% (w/w), 0.005% to 3% (w/w), 0.005% to 2% (w/w), 0.01% to 3% (w/w) and 0.01% to 2% (w/w)) the big molecule of surface modification; And (iv) 3% to 10% (w/w) (as, 3% to 7% (w/w), 3% to 5% (w/w) and 5% to 10% (w/w)) the hydrophily pore-forming agent.In some embodiments, said aprotic solvent is selected from dimethyl formamide, methyl-sulfoxide, dimethylacetylamide, N-methyl pyrrolidone and their mixture.In other embodiments; Said aprotic solvent further comprises and is less than 25% (v/v) (promptly; 1% to 25% (v/v), 1% to 15% (v/v) or 5% to 20% (v/v)) low boiling point solvent, said low boiling point solvent is selected from oxolane, diethyl ether, MEK, acetone and their mixture.In other embodiment, said hydrophily pore-forming agent is a polyvinylpyrrolidone.Said spinning solution can be as described herein processed to produce hollow-fibre membrane of the present invention.

Characteristic of the present invention is a kind of method that is used to prepare hollow-fibre membrane, may further comprise the steps: (a) preparation homogeneous spinning solution of the present invention; And (b) from mouth the outer ring mouth of pipe (tube-in-orifice) spinning head said homogeneous spinning solution is expressed in the aqueous solution to form hollow-fibre membrane.

Characteristic of the present invention also be a kind of encapsulation (embedding, the potting) method of hollow-fibre membrane may further comprise the steps: (a) form hollow fiber membrane bundle, said hollow fiber membrane bundle has inner chamber, first group of fiber ends and second group of fiber ends; (b) said first group of fiber ends and second group of fiber ends are placed in the uncured embedding liquid (perfusion fluid, potting liquid); (c) solidify said embedding liquid to form sealing resin, wherein said hollow-fibre membrane is packed; (d) said sealing resin of cutting and fiber ends are to form packed first wall of wherein said first group of fiber ends and the second packed wall of wherein said second group of fiber ends; And (e) with said first wall and the annealing of second wall; Wherein said embedding liquid comprise 0.005% to 10% (w/w) (as, 0.005% to 0.1% (w/w), 0.005% to 5% (w/w), 0.1% to 0.3% (w/w), 0.1% to 5% (w/w), 0.1% to 10% (w/w), 0.05% to 5% (w/w), 0.05% to 8% (w/w), 1% to 5% (w/w), 1% to 8% (w/w), 1% to 10% (w/w) and 2% to 10% (w/w)) the big molecule of surface modification.

Characteristic of the present invention is a kind of dialysis kit, comprises (i) hollow-fibre membrane of the present invention, encapsulation bundle of the present invention, dialysis filter of the present invention and/or blood tubulature of the present invention; And (ii) be used for to the anti-coagulants of accepting to be less than standard dose (as, do not accept anti-coagulants) experimenter's directions for use (specification) of dialysing.

In any hollow-fibre membrane described herein, the big molecule of said surface modification is selected from VII-a, VIII-a, VIII-b, VIII-c, VIII-d, IX-a, X-a, X-b, XI-a, XI-b, XII-a, XII-b, XIII-a, XIII-b, XIII-c, XIII-d, XIV-a and XIV-b.

In one embodiment, said sealing resin comprises the big molecule of the surface modification that is selected from VII-a, VIII-a, IX-a, XI-a, VIII-d and XI-b.

In another embodiment, said blood tubulature comprises the big molecule of the surface modification that is selected from VII-a, XIV-a and XIV-b.

Extracorporeal blood loop, hollow-fibre membrane (or its encapsulation bundle or its plasma purification film), pouring material (as; Sealing resin or embedding liquid), blood tubulature, dialysis filter, spinning solution, method, system and kit any in, the big molecule of said surface modification is through any description in the following formula (I)-(XIV).

(1)F _T-(oligo)-F _T (I)

F wherein _T(gather the fluoro organic group, polyfluoroorganogroup), and oligo is an oligomeric segment for organic group for polyfluoro.

Wherein

(i) F _TFor covalently bound polyfluoro to LinkB for organic group;

(ii) C is the chain termination group;

(iii) Oligo is an oligomeric segment;

(iv) LinkB is the coupling segment; And

(v) a is the integer greater than 0.

(3)F _T-[B-(oligo)] _n-B-F _T (III)

Wherein

(i) B comprises urethane;

(ii) Oligo comprises PPOX, PEO or polytetramethylene oxide;

(iii) F _TBe that polyfluoro is for organic group; And

(iv) n is 1 to 10 integer.

(4)F _T-[B-A] _n-B-F _T (IV)

Wherein

(i) A is a soft chain segment; Comprise hydrogenated butadiene polymer, gather (2; 2-dimethyl-1-3-propyl carbonate), polybutadiene, gather (diethylene glycol) adipate ester, gather (hexa-methylene carbonic ester), gather (ethene-altogether-butylene), neopentyl glycol-phthalic anhydride (adjacent acid phthalic anhydride) polyester, diethylene glycol-phthalic anhydride polyester, 1,6-hexylene glycol-phthalic anhydride polyester,

Or bisphenol A ethoxy thing;

(ii) B is the hard segment that comprises urethane; And

(iii) F _TFor polyfluoro for organic group, and

(iv) n is 1 to 10 integer.

Wherein

(i) A is a soft chain segment;

(ii) B is for comprising the trimerical hard segment of chlorinated isocyanurates tripolymer or biuret;

(iii) each F _TFor polyfluoro for organic group; And

(iv) n is the integer between 0 to 10.

(6)F _T-[B-(Oligo)] _n-B-F _T (VII)

Wherein

(i) Oligo be comprise PPOX, PEO or gather the oligomeric segment of tetramethyl oxide and have 500 to 3,000 dalton (as, 500 to 2; 000 dalton, 1,000 to 2,000 dalton or 1; 000 to 3,000 dalton) theoretical molecular;

(ii) B is the hard segment that is formed by uretdione;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 1 to 10 integer.

Wherein

(i) A is the oligomeric segment that comprises PPOX, PEO, gathers tetramethyl oxide or their mixture, and have 500 to 3,000 dalton (as; 500 to 2,000 dalton, 1,000 to 2; 000 dalton or 1,000 to 3,000 dalton) theoretical molecular;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

(8)F _T-[B-(Oligo)] _n-B-F _T (IX)

Wherein

(i) Oligo for have 500 to 3,000 dalton (as, 500 to 2,000 dalton, 1,000 to 2,000 dalton or 1,000 to 3,000 dalton) the polycarbonate polyol of theoretical molecular;

(ii) B is the hard segment that is formed by uretdione;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 1 to 10 integer.

Wherein

(i) A have 500 to 3,000 dalton for comprising (as, 500 to 2,000 dalton, 1,000 to 2,000 dalton or 1,000 to 3,000 dalton) the oligomeric segment of polycarbonate polyol of theoretical molecular;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

Wherein

(i) A comprises first block segments that is selected from PPOX, PEO, gathers tetramethyl oxide or their mixture, and second block segments that comprises polysiloxanes or dimethyl silicone polymer, and wherein A has 1; 000 to 5,000 dalton (as, 1; 000 to 3,000 dalton, 2,000 to 5; 000 dalton or 2,500 to 5,000 dalton) theoretical molecular;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

(11)F _T-[B-A] _n-B-F _T (XII)

Wherein

(i) A for be selected from hydrogenated butadiene polymer (HLBH) glycol (like, HLBH glycol), polybutadiene (LBHP) glycol (like, LBHP glycol), hydrogenated polyisoprene (HHTPI) glycol (as; The HHTPI glycol) and the soft chain segment of polystyrene and have 750 to 3,500 dalton (as, 750 to 2; 000 dalton, 1,000 to 2,500 dalton or 1; 000 to 3,500 dalton) theoretical molecular;

(ii) B is the hard segment that is formed by uretdione;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 1 to 10 integer.

Wherein

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

Wherein

(i) A for have 500 to 3,500 dalton (as, 500 to 2,000 dalton, 1,000 to 2,000 dalton or 1,000 to 3,000 dalton) the polyester of theoretical molecular;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

In some embodiments; Formula (I) and the big molecule of surface modification (II) comprise as be less than 20 recurring units (as, 2 to 15 units, 2 to 10 units, 3 to 15 units and 3 to 10 units) branching or oligomeric (oligo) segment of nonbranched oligomeric segment.In another embodiment, formula (I) and the big molecule of surface modification (II) comprise the oligomeric segment that is selected from polyurethane, polyureas, polyamide, polyalkylene oxide (polyalkylene oxides), Merlon, polyester, polylactone, silicone, polyether sulfone, polyolefin, polythene derivative, polypeptide, polysaccharide, polysiloxanes, dimethyl silicone polymer, polyethylene-butylene, polyisobutene, polybutadiene, PPOX, PEO, polytetramethylene oxide or gathers ethylidene butylidene segment.

In some embodiments, the big molecule of surface modification of formula (IV) comprises by being selected from 3-isocyanide acyl group (isocyanate group) methyl, 3,5,5-3-methyl cyclohexanol based isocyanate; 4,4 '-methylene two (cyclohexyl isocyanate); 4,4 '-methylene two (phenyl) isocyanates; Toluene-2,4-diisocyanate, 4 vulcabond; Between-tetramethylxylene diisocyanate; And the hard segment of the vulcabond of hexamethylene diisocyanate formation; And n is 1 or 2.

In some embodiments; Formula (V) and the big molecule of surface modification (VI) comprise having 500 to 3; 500 dalton (as, 500 to 2,000 dalton, 1; 000 to 2; 000 dalton or 1,000 to 3,000 dalton) the soft chain segment and/or the said soft chain segment of theoretical molecular comprise hydrogenated butadiene polymer (HLBH), gather (2; 2-dimethyl-1-3-propyl carbonate) (PCN), polybutadiene (LBHP), polytetramethylene oxide (PTMO), (propylidene) oxide (PPO), diethylene glycol-phthalic anhydride polyester (PDP), hydrogenated polyisoprene (HHTPI), gather (hexa-methylene carbonic ester), gather (2-butyl-2-ethyl-1,3-propyl carbonate) or hydroxy-end capped dimethyl silicone polymer (C22).In formula (V) and macromolecular other embodiment of surface modification (VI); Said hard segment forms through making triisocyanate and the glycol reaction that comprises soft chain segment; Wherein, said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer or hexamethylene diisocyanate (HDI) tripolymer.

In the more macromolecular embodiments of the surface modification of formula (VII), B is by 3-isocyanide acyl group methyl, 3,5,5-3-methyl cyclohexanol based isocyanate; 4,4 '-methylene two (cyclohexyl isocyanate); 4,4 '-methylene two (phenyl) isocyanates; Toluene-2,4-diisocyanate, 4 vulcabond); Between-tetramethylxylene diisocyanate; And the hard segment of hexamethylene diisocyanate formation; And n is 1 to 3 integer.In a specific implementations, the big molecule of surface modification of formula (VII) is VII-a.The big molecule of surface modification of formula (VII) can be used in extracorporeal blood loop of the present invention; Or in its assembly; Like hollow-fibre membrane, encapsulation bundle, blood tubulature or dialysis filter, and use with any method of the present invention described herein, system and kit.For example, the big molecule of surface modification of formula (VII) be introduced in the polyvinyl chloride with the tubulature of preparation anticoagulant property blood; Join in the pouring material with preparation anticoagulant property encapsulation bundle; And/or join hollow-fibre membrane base polymer (as, polysulfones, polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather (methyl methacrylate), Merlon, polyamide, polypropylene or polyethylene) in be anticoagulant hollow-fibre membrane when contacting to form with blood.

In the more macromolecular embodiments of the surface modification of formula (VIII); B for the glycol through making triisocyanate and A (as; Oligomeric segment) hard segment that reacts and form, wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer and hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.In a specific implementations, the big molecule of surface modification of formula (VIII) is VIII-a, VIII-b, VIII-c or VIII-d.The big molecule of surface modification of formula (VIII) can be used in extracorporeal blood loop of the present invention; Or in its assembly; Like hollow-fibre membrane, encapsulation bundle, blood tubulature or dialysis filter, and use with any method of the present invention described herein, system and kit.For example, the big molecule of surface modification of formula (VIII) be introduced in the polyvinyl chloride with the tubulature of preparation anticoagulant property blood; Join in the pouring material with preparation anticoagulant property encapsulation bundle; And/or join hollow-fibre membrane base polymer (as, polysulfones, polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather (methyl methacrylate), Merlon, polyamide, polypropylene or polyethylene) in be anticoagulant hollow-fibre membrane when contacting to form with blood.

In the more macromolecular embodiments of the surface modification of formula (IX), Oligo comprises and gathers (2,2 dimethyl-1-3-propyl carbonate) (PCN) polyalcohol (like, PCN glycol); B is by 3-isocyanide acyl group methyl, 3,5,5-3-methyl cyclohexanol based isocyanate; 4,4 '-methylene two (cyclohexyl isocyanate); 4,4 '-methylene two (phenyl) isocyanates; Toluene-2,4-diisocyanate, 4 vulcabond); Between-tetramethylxylene diisocyanate; And the hard segment of hexamethylene diisocyanate formation; And n is 1,2 or 3.In a specific implementations, the big molecule of surface modification of formula (IX) is IX-a.The big molecule of surface modification of formula (IX) can be used in extracorporeal blood loop of the present invention; Or in its assembly; Like hollow-fibre membrane, encapsulation bundle, blood tubulature or dialysis filter, and use with any method of the present invention described herein, system and kit.For example, the big molecule of surface modification of formula (IX) be introduced in the polyvinyl chloride with the tubulature of preparation anticoagulant property blood; Join in the pouring material with preparation anticoagulant property encapsulation bundle; And/or join hollow-fibre membrane base polymer (as, polysulfones, polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather (methyl methacrylate), Merlon, polyamide, polypropylene or polyethylene) in be anticoagulant hollow-fibre membrane when contacting to form with blood.

In the more macromolecular embodiments of the surface modification of formula (X), A comprises and gathers (2,2 dimethyl-1-3-propyl carbonate) (PCN) polyalcohol (like, PCN glycol) or gather (hexa-methylene carbonic ester) (PHCN) polyalcohol; B for the hard segment of the glycol reaction formation through making triisocyanate and A (as; Oligomeric segment), wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer or hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.In a specific implementations, the big molecule of surface modification of formula (X) is X-a or X-b.The big molecule of surface modification of formula (X) can be used in extracorporeal blood loop of the present invention; Or in its assembly; Like hollow-fibre membrane, encapsulation bundle, blood tubulature or dialysis filter, and use with any method of the present invention described herein, system and kit.For example, the big molecule of surface modification of formula (X) be introduced in the polyvinyl chloride with the tubulature of preparation anticoagulant property blood; Join in the pouring material with preparation anticoagulant property encapsulation bundle; And/or join hollow-fibre membrane base polymer (as, polysulfones, polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather (methyl methacrylate), Merlon, polyamide, polypropylene or polyethylene) in be anticoagulant hollow-fibre membrane when contacting to form with blood.

In the more macromolecular embodiments of the surface modification of formula (XI), A comprises PPOX and dimethyl silicone polymer; The hard segment of B for forming through the glycol reaction that makes triisocyanate and A, wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer and hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.In a specific implementations, the big molecule of surface modification of formula (XI) is XI-a or XI-b.The big molecule of surface modification of formula (XI) can be used in extracorporeal blood loop of the present invention; Or in its assembly; Like hollow-fibre membrane, encapsulation bundle, blood tubulature or dialysis filter, and use with any method of the present invention described herein, system and kit.For example, the big molecule of surface modification of formula (XI) be introduced in the polyvinyl chloride with the tubulature of preparation anticoagulant property blood; Join in the pouring material with preparation anticoagulant property encapsulation bundle; And/or join hollow-fibre membrane base polymer (as, polysulfones, polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather (methyl methacrylate), Merlon, polyamide, polypropylene or polyethylene) in be anticoagulant hollow-fibre membrane when contacting to form with blood.

In the more macromolecular embodiments of the surface modification of formula (XII), A comprises the hydrogenated butadiene polymer glycol; B is by 3-isocyanide acyl group methyl, 3; 5; 5-3-methyl cyclohexanol based isocyanate, 4; 4 '-methylene two (cyclohexyl isocyanate), 4,4 '-methylene two (phenyl) isocyanates, Toluene-2,4-diisocyanate, 4 vulcabond) ,-hard segment that tetramethylxylene diisocyanate and hexamethylene diisocyanate form; And n is 1,2 or 3.In a specific implementations, the big molecule of surface modification of formula (XII) is XII-a or XII-b.The big molecule of surface modification of formula (XII) can be used in extracorporeal blood loop of the present invention; Or in its assembly; Like hollow-fibre membrane, encapsulation bundle, blood tubulature or dialysis filter, and use with any method of the present invention described herein, system and kit.For example, the big molecule of surface modification of formula (XII) be introduced in the polyvinyl chloride with the tubulature of preparation anticoagulant property blood; Join in the pouring material with preparation anticoagulant property encapsulation bundle; And/or join hollow-fibre membrane base polymer (as, polysulfones, polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather (methyl methacrylate), Merlon, polyamide, polypropylene or polyethylene) in be anticoagulant hollow-fibre membrane when contacting to form with blood.

In the more macromolecular embodiments of the surface modification of formula (XIII), A is selected from hydrogenated butadiene polymer (HLBH) glycol (like, HLBH glycol) and hydrogenated polyisoprene (HHTPI) glycol (like, HHTPI glycol); The hard segment (like oligomeric segment) of B for forming through the glycol reaction that makes triisocyanate and A, wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer and hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.In a specific implementations, the big molecule of surface modification of formula (XIII) is XIII-a, XIII-b, XIII-c or XIII-d.The big molecule of surface modification of formula (XIII) can be used in extracorporeal blood loop of the present invention; Or in its assembly; Like hollow-fibre membrane, encapsulation bundle, blood tubulature or dialysis filter, and use with any method of the present invention described herein, system and kit.For example, the big molecule of surface modification of formula (XIII) be introduced in the polyvinyl chloride with the tubulature of preparation anticoagulant property blood; Join in the pouring material with preparation anticoagulant property encapsulation bundle; And/or join hollow-fibre membrane base polymer (as, polysulfones, polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather (methyl methacrylate), Merlon, polyamide, polypropylene or polyethylene) in be anticoagulant hollow-fibre membrane when contacting to form with blood.

In the more macromolecular embodiments of the surface modification of formula (XIV), A is selected from and gathers (diethylene glycol) adipate ester, neopentyl glycol-phthalic anhydride polyester, diethylene glycol-phthalic anhydride polyester and 1,6-hexylene glycol-phthalic anhydride polyester; B for the hard segment of the glycol reaction formation through making triisocyanate and A (as; Polyester segment), wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer and hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.In a specific implementations, the big molecule of surface modification of formula (XIV) is XIV-a or XIV-b.The big molecule of surface modification of formula (XIV) can be used in extracorporeal blood loop of the present invention; Or in its assembly; Like hollow-fibre membrane, encapsulation bundle, blood tubulature or dialysis filter, and use with any method of the present invention described herein, system and kit.For example, the big molecule of surface modification of formula (XIV) be introduced in the polyvinyl chloride with the tubulature of preparation anticoagulant property blood; Join in the pouring material with preparation anticoagulant property encapsulation bundle; And/or join hollow-fibre membrane base polymer (as, polysulfones, polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather (methyl methacrylate), Merlon, polyamide, polypropylene or polyethylene) in be anticoagulant hollow-fibre membrane when contacting to form with blood.

For any big molecule of surface modification of the present invention that is formed by uretdione, said uretdione can be selected from: 3-isocyanide acyl group methyl, 3,5,5-3-methyl cyclohexanol based isocyanate; 4,4 '-methylene two (cyclohexyl isocyanate) (HMDI); 2,2 '-, 2,4 '-and 4,4 '-methylene two (phenyl) isocyanates (MDI); Toluene-2,4-diisocyanate, 4 vulcabond); The aromatic series aliphatic isocyanates, as 1,2-, 1,3-and 1,4-XDI; Between-tetramethylxylene diisocyanate (m-TMXDI); Right-tetramethylxylene diisocyanate (p-TMXDI); Hexamethylene diisocyanate (HDI); Ethylidene diisocyanate; Propylidene base-1, the 2-vulcabond; Tetramethylene diisocyanate; Tetramethylene-1, the 4-vulcabond; Eight methylene diisocyanates; The decamethylene vulcabond; 2,2, the 4-trimethyl hexamethylene diisocyanate; 2,4, the 4-trimethyl hexamethylene diisocyanate; Dodecane-1, the 12-vulcabond; Dicyclohexyl methyl hydride diisocyanate; Cyclobutane-1, the 3-vulcabond; Cyclohexane-1, the 2-vulcabond; Cyclohexane-1, the 3-vulcabond; Cyclohexane-1, the 4-vulcabond; Methyl-cyclohexylene vulcabond (HTDI); 2, the 4-methylcyclohexane diisocyanate; 2, the 6-methylcyclohexane diisocyanate; 4,4 '-the dicyclohexyl vulcabond; 2,4 '-the dicyclohexyl vulcabond; 1,3,5-cyclohexane triisocyanate; Isocyanide acyl group hexahydrotoluene isocyanates; 1-isocyanide acyl group-3,3-5-trimethyl-5-isocyanide acyl group hexahydrotoluene; Isocyanide acyl group ethyl cyclohexane isocyanates; Two (isocyanide acyl group methyl)-cyclohexane diisocyanates; 4,4 '-two (isocyanide acyl group methyl) bicyclohexane; 2,4 '-two (isocyanide acyl group methyl) bicyclohexane; IPDI (IPDI); 2,4-hexahydrotoluene vulcabond; 2,6-hexahydrotoluene vulcabond; 3,3 '-dimethyl-4,4 '-diphenylene vulcabond (TODI); Polymeric MDI; The liquid 4,4 of carbodiimide-modification '-methyl diphenylene diisocyanate; Right-phenylene vulcabond (PPDI); Between-phenylene vulcabond (MPDI); Triphenyl methane-4,4 '-and triphenyl methane-4,4 " triisocyanate; Naphthylene-1, the 5-vulcabond; 2,4 '-, 4,4 '-and 2, the 2-diphenyl diisocyanate; Polyphenylene polymethylene PIC (PMDI); The mixture of MDI and PMDI; The mixture of PMDI and TDI; Two polyureas diketone of any isocyanates described herein are like the urea diketone of toluene di-isocyanate(TDI), the urea diketone of hexamethylene diisocyanate and their mixture; With and substituted and isomeric mixtures.

For any big molecule of surface modification of the present invention that forms by the isocyanate trimerization body; Said isocyanate trimerization body can be selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer, hexamethylene diisocyanate (HDI) tripolymer, 2; 2; 4-trimethyl-1, the triisocyanate of 6-hexane diisocyanate (TMDI); The chlorinated isocyanurates of the trimerizing of any isocyanates described herein is like the chlorinated isocyanurates of toluene di-isocyanate(TDI), the tripolymer of methyl diphenylene diisocyanate, the tripolymer of tetramethylxylene diisocyanate and their mixture; The biuret of the trimerizing of any isocyanates described herein; Isocyanates from the modification of top vulcabond; With and substituted and isomeric mixtures.

In formula (I)-(XIV), the big molecule of top surface modification comprises group F _T, it is for having at 100-1, the theoretical molecular between the 500Da gather fluoro-alkyl.For example, F _TCan be selected from by general formula CF ₃(CF ₂) _rCH ₂CH ₂-wherein r is 2-20, and CF ₃(CF ₂) _s(CH ₂CH ₂O) _χ, wherein χ is that 1-10 and s are the group of the group composition of 1-20.Replacedly, F _TCan be selected from by general formula CH _mF _(3-m)(CF ₂) _rCH ₂CH ₂-and CH _mF _(3-m)(CF ₂) _s(CH ₂CH ₂O) _χ-the group formed of group, wherein m is 0,1,2 or 3; χ is the integer between the 1-10; R is the integer between the 2-20; And s is the integer between the 1-20.In some embodiments, F _TBe selected from 1H, 1H, 2H, 2H-perfluor-1-decyl alcohol; 1H, 1H, 2H, 2H-perfluor-1-octanol; 1H, 1H, 5H-perfluor-1-amylalcohol; And 1H, 1H, perfluor-1-butanols, and their mixture.In other embodiment, F _TBe selected from (CF ₃) (CF ₂) ₅CH ₂CH ₂O-, (CF ₃) (CF ₂) ₇CH ₂CH ₂O-, (CF ₃) (CF ₂) ₅CH ₂CH ₂O-, CHF ₂(CF ₂) ₃CH ₂O-and (CF ₃) (CF ₂) ₂CH ₂O-.

In another embodiment, the big molecule of top surface modification have less than 10,000 dalton (as, 500 to 10; 000 dalton, 500 to 9,000 dalton, 500 to 5,000 dalton, 1; 000 to 10,000 dalton, 1,000 to 6; 000 dalton or 1,500 to 8,000 dalton) theoretical molecular.

In another embodiment; Above the big molecule of surface modification comprise 5% to 40% (w/w) hard segment (as; 5% to 35% (w/w), 5% to 30% (w/w) and 10% to 40% (w/w)), the soft chain segment of 20% to 90% (w/w) (as; 20% to 80% (w/w), 30% to 90% (w/w) and 40% to 90% (w/w)), and the polyfluoro of 5% to 50% (w/w) is for organic group (like 5% to 40% (w/w), 5% to 30% (w/w) and 10% to 40% (w/w)).

In one embodiment, the big molecule of top surface modification have 0.15 to 2.0 (as, 0.15 to 1.8,0.15 to 1.5 and 0.2 to 2.0) hard segment and the ratio of soft chain segment.

As used herein, term " anticoagulant " refers to the extracorporeal blood loop, or its assembly (as; The encapsulation bundle of hollow-fibre membrane, blood tubulature, dialysis filter and/or hollow-fibre membrane), for it, test under identical blood-contact conditions; With other identical extracorporeal blood loop; Or its assembly compares (difference only be the macromolecular shortage of surface modification), and after being exposed to whole blood under, the ratio of thrombosis generation reduces.The thrombotic ratio that reduces can be confirmed through any analysis described herein and method.For example, anticoagulant property can and utilize γ-count measurement thrombosis for example to confirm with the thrombotic amount that the assessment surface exists through the radioactive label blood constituent.For extracorporeal blood loop of the present invention; Or its assembly; Can be based on the thrombotic decreased average of γ-counting for average thrombotic 70%, 60%, 50%, 40%, 30%, 20% or 10%, as determined through lacking the macromolecular γ-counting of surface modification with reference to hollow-fibre membrane.Replacedly; Anticoagulant property in filter or the hollow-fibre membrane can (for example be confirmed through the operating pressure that reduces; With compare lacking the average pressure that the macromolecular top cover with reference to filter or hollow-fibre membrane of surface modification (header) locates, be reduced at least 10%, 20%, 30%, 40%, 50% or 60% in the average reduction of the operating pressure at the top cover place of hollow-fibre membrane).

" base polymer " be meant have greater than 50,000 dalton (as, greater than 50,000,75,000,100,000,150,000,200,000 dalton) the polymer of theoretical molecular.

As used herein, " C " refers to the chain termination group.Exemplary chain termination group comprises the simple function group that comprises amine, alcohol or carboxylic acid functional.

" dialysis filter " is meant the filter that is configured in the dialysis machine that can be used by the patient through undermined renal function.

" hard segment " is meant the part of macromolecular part of surface modification or oligomeric segment; Wherein said part comprises urethane group-NH-C (O) O-(like, the urethane group that hydroxyl through making isocyanates and soft segment diol or polyfluoro form for the hydroxyl reaction of organic group).

As used herein; Term " the average function sex work phase of increase " refers to and the extracorporeal blood loop; Or the average duty cycle of its assembly is compared and (under identical condition, is used; And difference only is to lack the big molecule of surface modification), the average increase of the functional duty cycle of extracorporeal blood loop of the present invention or its assembly, wherein said duty cycle can be used through external loop or its assembly and needn't confirm from the length of time of said external loop or its assembly flushing thrombus deposition (as; The duty cycle that does not have normal saline washing, or with the duty cycle of anti-coagulants flushing).Can grow to and lack 110%, 125%, 150%, 200%, 250%, 300% or 400% than lacking the macromolecular duty cycle of surface modification for average function sex work phase of the increase of extracorporeal blood loop of the present invention or its assembly with reference to extracorporeal blood loop or its assembly.

" anti-coagulants that is less than standard dose " be meant when using dialysis filter of the present invention, only is that the amount that lacks the macromolecular dialysis filter of surface modification compares with being used to distinguish, and hemodialysis session gives the minimizing of experimenter's anti-coagulants.Standard dose is usually for clinical setting, as is used for the standard openating procedure of extracorporeal blood loop or its assembly, identified by each mechanism.The standard dose of anti-coagulants refers to dosage or the dosage range of confirming through the standard openating procedure of reference mechanisms, and when comparing with said standard dose, confirms the dosage of minimizing.The dosage of the minimizing of anti-coagulants can be 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% of the standard dose of anti-coagulants (like heparin or citrate).

Use like this paper, " LinkB " refers to can covalently bound two oligomeric parts and the coupling segment of surface active groups.Usually, the LinkB molecule has the molecular weight in 40 to 700 scopes.Preferably, the LinkB molecule is selected from the group of functionalized diamines, vulcabond, disulfonic acid, dicarboxylic acids, diacid chloride and dialdehyde, and the composition of wherein said functionalization has second functionalized chemical, and its chemistry that is used to surface active groups connects.Second group like this comprises, for example, and ester, carboxylate, sulfonate, phosphonate, mercaptan, vinyl and secondary amine.Terminal hydroxyl on the oligomeric intermediates, amine or carboxylic acid can with diamine reactant to form oligomer-acid amides; With di-isocyanate reaction to form oligomer-urethane, oligomer-urea, oligomer-acid amides; React to form oligomer-sulphonic acid ester, oligomer-sulfonamide with disulfonic acid; React to form oligomer-ester, oligomer-acid amides with dicarboxylic acids; React to form oligomer-ester, oligomer-acid amides with diacid chloride; And with two aldehyde reactions to form oligomer-acetal, oligomer-imines.

" oligomer " is meant a repetitive or a plurality of repetitive of shorter length, is less than about 50 monomeric units usually, and theoretical molecular is less than 10,000 dalton, but preferred＜7,000 dalton, and in some instances,＜5,000 dalton.In some embodiments, oligomer be selected from by polyurethane, polyureas, polyamide, polyalkylene oxide, Merlon, polyester, polylactone, silicone, polyether sulfone, polyolefin, polyethylene, polypeptide, polysaccharide, with and the group formed of the segment of ether and amine link.

" polyether sulfone " refers to the polymer of following formula:

Polyether sulfone (PES)

This polymer is commercial obtainable, and trade mark is called Radel ^TM, from AmocoCorp.

" polymer assemblies " is meant any assembly in the extracorporeal blood loop, and wherein said assembly comprises like base polymer described herein.For example, polymer assemblies comprises encapsulation bundle, dialysis filter, oxygenator device and the blood tubulature of hollow-fibre membrane, hollow-fibre membrane.

" gather (Oxy-1,4-phenylene sulfonyl-1,4-phenylene Oxy-1,4-phenylene isopropylidene-1,4-phenylene) " and be meant the polymer of following formula:

This polymer is commercial obtainable, and trade mark is called Udel ^TMP-3500 is from Solvay Advanced Polymers.In order to be used in the hollow-fibre membrane of the present invention, can be preferred (that is, at 30-90kDa for the specific size of this polymer; 45-80kDa; Or in the scope of 60-80kDa).

As use in this article, term " polysulfones " refers to a base polymer, and it comprises as the part-aryl-SO that repeats subunit ₂-aryl-.Polysulfones comprises, be not limited to, polyether sulfone with gather (Oxy-1,4-phenylene sulfonyl-1,4-phenylene Oxy-1,4-phenylene isopropylidene-1,4-phenylene).

" duty cycle of prolongation " is meant such dialysis filter; For it; Only being to lack the macromolecular dialysis filter of surface modification with the difference of using under the same terms compares; The become speed of obstruction (for example, and subsequently needing normal saline washing to remove the obstruction of filter) of filter reduces during the blood dialysis.The duty cycle that is used for the prolongation of dialysis filter can be grown to and lacks 110%, 125%, 150%, 200%, 250%, 300% or 400% than lacking the macromolecular duty cycle with reference to dialysis filter of surface modification.

As used herein; The term thrombus of the minimizing " deposition " be meant with for using under the same conditions; And difference only is to lack the observed average γ of the macromolecular extracorporeal blood loop of surface modification-counting and compares, for extracorporeal blood loop of the present invention or its assembly, after one period operating period (as; 60,90,120,360 or 720 minutes), the decreased average of γ-counting.γ-counting is through incorporating the big molecule of surface modification in the extracorporeal blood loop said film to be provided and to pass through the anticoagulant property interface between the blood flow of said film; Wherein γ-counting is measured in the surface of any processing of loop, and the amount that is included in the anti-coagulants in the blood therein is not enough to prevent measure under the thrombotic condition when the big molecule of surface modification lacks.γ-counting can be confirmed through any analysis described herein and method.For example, the blood of the blood platelet that γ-counting can be through will comprising labelled with radioisotope (or other blood constituents, like red blood cell) or blood plasma flow into the extracorporeal blood loop and measure in the extracorporeal blood loop and confirm from the radiation of labelled with radioisotope.These are analyzed and method can be carried out repeatedly to obtain on average reducing of average γ-counting or γ-counting.With the average thrombus sedimentary facies ratio that lacks the macromolecular extracorporeal blood loop of surface modification or its assembly, can decreased average 10%, 20%, 30,40%, 50%, 60%, 70%, 80%, 90% or 95% for the thrombus deposition of extracorporeal blood loop of the present invention or its assembly.

" operating pressure that reduces " be meant use down with the same terms and difference only be to lack the observed average pressure of the macromolecular hollow-fibre membrane of surface modification and compare; For hollow-fibre membrane of the present invention; Or filter or its encapsulation bundle; In use for some time (as, 2 hours, 4 hours, 8 hours, 12 hours or 16 hours), the average reduction of operating pressure.The operating pressure that reduces is through incorporating the big molecule of surface modification into hollow-fibre membrane said film to be provided and to obtain through the anticoagulant property interface between the blood flow of said film, and wherein pressure is measured at the top cover place of film.Have the array of the hollow-fibre membrane of sealing resin for the end at array, the operating pressure that reduces can be through utilizing the big molecule of surface modification said film and/or sealing resin to be provided and to obtain through the anticoagulant property interface between the blood flow of said encapsulation bundle.Operating pressure can be confirmed through any analysis described herein and method.For example, operating pressure can be through making blood flow into hollow-fibre membrane and measuring that the pressure in the hollow-fibre membrane changes to confirm in one period.These are analyzed and method can be carried out repeatedly to obtain the average reduction of average operating pressure or operating pressure.With surface modification is macromolecular to be compared with reference to hollow-fibre membrane, filter or the observed average pressure of encapsulation bundle for lacking; For hollow-fibre membrane of the present invention (or its filter or encapsulation bundle); After 2,4,8,12 or 16 hours use, the operating pressure that reduces can be less than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%.

As used herein; Term " minimizing adverse events " refers to quantity or degree by the adverse events of the experimenter's experience that links to each other with extracorporeal blood loop of the present invention or its assembly with " by the adverse events of experimenter's experience "; That wherein use down and difference only is to lack the macromolecular extracorporeal blood loop of surface modification or assembly is compared with the same terms; During using a period of time or afterwards, such adverse events reduces or reduces.The quantity of adverse events or degree can confirm through any useful method, comprise animal model use (referring to Livigni et al., Critical Care 10:R151 (2006); Walker et al., Artificial Organs 8:329-333 (1984); Cheung, Blood Purification5:155-161 (1987); Kamler et al., Journal of Thoracic andCardiovascular Surgery 49:157-161 (2001); And Kamler et al., European Journal of Cardio-Thoracic Surgery 11:973-980 (1997)).That adverse events comprises is hemorrhage (as, measure through clotting time of activation), the blood count of haemolysis, minimizing, serious Hemodynamics instability, embolism, thromboembolism, thrombus dependent event and need the experimenter to take any other incident of red blood cell generation-stimulant (like hematopoietin and/or intravenous iron).The existence of one or more adverse events can be the indication of the activation of blood complement in the existence of thrombus or the coagulation cascade.

" soft chain segment " is meant the part of macromolecular part of surface modification or oligomeric segment, and wherein said part comprises ether group, ester group (like polyester), alkyl group, carbonate group, siloxane group or their mixture.For example, said soft chain segment can have 500 to 3,000 dalton (as, 500 to 2,000 dalton, 1,000 to 2,000 dalton or 1,000 to 3,000 dalton) theoretical molecular or mean molecule quantity.

Use like this paper, " the big molecule of surface modification " refers to and comprises the big molecule of polyfluoro for organic group, and through type (I)-(XIV) is described in this article, and be described in United States Patent (USP) the 6th, 127, in No. 507; U.S. Patent Publication 20080228253; And the interim series number 6I/092 of the U.S., in 667 (the submitting on August 28th, 2008), each is incorporated herein with way of reference with it.The big molecule of surface modification can be like United States Patent (USP) the 6th, 127, No. 507; U.S. Patent Publication 20080228253; With preparing of describing among the PCT publication number WO/2010/025398 (submitting to) on August 28th, 2009.Simply, the big molecule of surface modification is like XI-a and X-a; Can be under the situation that catalyst exists; Under 25 ℃, in organic solvent (like anhydrous THF or DMAC), synthesize from dropwise reacting the PIC (like Desmodur N3200 or DesmodurZ4470) that reaches 2 hours with fluoroalkyl alcohol.Behind the alcohol that adding is fluoridized, continue down to stir 1 hour at 50 ℃, and continue to stir other 1 hour down at 70 ℃.These steps cause the formation of partially fluorinated intermediate, its subsequently 70 ℃ down and polyalcohol soft chain segment (like polydimethylsiloxanediols diols or gather (2,2 dimethyl-1-3-propyl carbonate) glycol) coupling 14 hours to provide surface modification big molecule.Because reaction is a humidity sensitive, so they are usually at inertia N ₂Carry out under atmosphere and the anhydrous condition.Product precipitates in the 1%MeOH/ aqueous mixtures, and water washes several times subsequently, and the big molecule of surface modification is dried before use.The macromolecular soft chain segment of surface modification can with act on the big molecule of surface modification after fusion at the intrabasement anchor of base polymer.Surface active groups partly is responsible for the big molecule of surface modification is transported to the surface of alloy, and wherein said surface active groups exposes from the teeth outwards.The big molecule of said surface modification is a dynamic process to the migration on surface, and depends on surperficial environment.The process of migration is by driving towards the trend of setting up low-surface-energy on the surface of mixture.When the balance between realization grappling and the surface migration, the big molecule of said surface modification stably is retained in the surface of polymer, changes surface property simultaneously.

Characteristic of the present invention be can be used to reduce blood platelet adhere to, reduce obstruction, reduce needs to heparin and/or other anti-coagulants, reduce with some medical procedures as the relevant cost of dialysing, prolong the blood loop duty cycle, improve the blood loop of patient safety and minimizing refuse.

Through accompanying drawing, detailed description and claim, it is obvious that other features and advantages of the present invention will become.

Description of drawings

Fig. 1 is the sketch map of exemplary extracorporeal blood loop.

Fig. 2 is a diagram of describing the big molecule VII-a of surface modification of the present invention.

Fig. 3 is a diagram of describing the big molecule VIII-a of surface modification of the present invention.

Fig. 4 is a diagram of describing the big molecule VIII-b of surface modification of the present invention.

Fig. 5 is a diagram of describing the big molecule VIII-c of surface modification of the present invention.

Fig. 6 is a diagram of describing the big molecule VIII-d of surface modification of the present invention.

Fig. 7 is a diagram of describing the big molecule I X-a of surface modification of the present invention.

Fig. 8 is a diagram of describing the big molecule X-a of surface modification of the present invention.

Fig. 9 is a diagram of describing the big molecule X-b of surface modification of the present invention.

Figure 10 is a diagram of describing the big molecule XI-a of surface modification of the present invention.

Figure 11 is a diagram of describing the big molecule XI-b of surface modification of the present invention.

Figure 12 is a diagram of describing the big molecule XII-a of surface modification of the present invention.

Figure 13 is a diagram of describing the big molecule XII-b of surface modification of the present invention.

Figure 14 is a diagram of describing the big molecule XIII-a of surface modification of the present invention.

Figure 15 is a diagram of describing the big molecule XIII-b of surface modification of the present invention.

Figure 16 is a diagram of describing the big molecule XIII-c of surface modification of the present invention.

Figure 17 is a diagram of describing the big molecule XIII-d of surface modification of the present invention.

Figure 18 is a diagram of describing the big molecule XIV-a of surface modification of the present invention.

Figure 19 is a diagram of describing the big molecule XIV-b of surface modification of the present invention.

Figure 20 A and Figure 20 B show exemplary doughnut and exemplary fibre bundle.

Figure 20 A is the scanning electron micrograph of single doughnut, has drawn outer surface, inner surface and fiber thickness.The hollow fiber bundle (5 of Figure 20 B in the header field of dialyzer cylinder (tube), arranging; 000) diagrammatic sketch; Follow exposure perfusion area (through the zone that the arrow of being labeled as in the inner chamber of dialyzer cylinder " untreated encapsulation region " is pointed out, comprise in the inner chamber of dialyzer cylinder thick dotted line and with the zone of X mark).

Figure 21 is the representative configuration of extracorporeal blood ring analysis and the photo of γ probe reading.

Figure 22 is the photo of blood filter after the blood ring process.

Figure 23 is for to show for the average top cover pressure (Δ Pr) of contrast and VII-a and XI-a (n=6) and the figure of γ-count distribution.

Figure 24 A and Figure 24 B are as the photo of the blood filter from the experiment among the embodiment 54 described herein.Figure 24 A shows the thrombus that forms in the porch of blood filter.Figure 24 B shows the thrombus that forms in the exit of blood filter.

Figure 25 A-25C is as the photo from the experiment among the embodiment 54 described herein that it shows cohesion widely.Figure 25 A shows the thrombus that forms in the porch of contrast blood filter (not having surface modification).Figure 25 B shows the thrombus that forms in the exit of contrast blood filter (not having surface modification).Figure 25 C shows the residue on the sieve after discharging blood.

Figure 26 A-26D is as the photo of the blood filter from the experiment among the embodiment 55 described herein.Figure 26 A shows the thrombus that forms in the porch of blood filter.Figure 26 B shows the thrombus that forms in the exit of blood filter.The contrast blood filter demonstrates completely and blocks, and wherein inlet (Figure 26 C) and the outlet (Figure 26 D) to contrast provides feature.

Figure 27 shows the photo like the inlet of the blood filter from the experiment 1-6 among the embodiment 5 described herein.Show the photo of contrast (C, top row), VII-a (middle row) and XI-a (end row).

Figure 28 A and Figure 28 B are as the photo of the blood filter from the experiment among the embodiment 51 described herein.Figure 28 A shows the thrombus that forms in the porch of blood filter.Figure 28 B shows the thrombus that forms in the exit of blood filter.

Figure 29 A and Figure 29 B are as the photo of the blood filter from the experiment among the embodiment 52 described herein.Figure 29 A shows the thrombus that forms in the porch of blood filter.Figure 29 B shows the thrombus that forms in the exit of blood filter.

Figure 30 A and Figure 30 B are as the photo of the blood filter from the experiment among the embodiment 53 described herein.Figure 30 A shows the thrombus that forms in the porch of blood filter.Figure 30 B shows the thrombus that forms in the exit of blood filter.

Figure 31 A and Figure 31 B are as the photo of the blood filter from the experiment among the embodiment 56 described herein.Figure 31 A shows the thrombus that forms in the porch of blood filter.Figure 31 B shows the thrombus that forms in the exit of blood filter.

The specific embodiment

The characteristic of method and composition of the present invention is to comprise anticoagulant, extracorporeal blood loop and the assembly (hollow-fibre membrane, encapsulating material and blood tubulature etc.) thereof that fusion has the macromolecular synthetic base polymer of surface modification of 0.005% to 10% (w/w).Extracorporeal blood loop assembly of the present invention can be used in the treatment; As haemodialysis, blood filtration, blood concentrate, hemodiafiltration and oxygenation, be used to treat suffer from kidney failure, the patient of liquid overload, toxaemia situation, heart failure or cardiac distress.They also can be used for Protein Separation, plasmapheresis and blood separation.

The selection of the combination of big molecule of particular surface modification (SMM) and adhoc basis polymer can be confirmed through method described herein and scheme.At first; Whether the type that is added into the SMM in the base polymer partly forms single stable by alloy with amount is confirmed mutually; Wherein SMM dissolve in the base polymer (as, the separation of alloy with form two or more separate will show unsettled solution mutually).Then, the compatibility of alloy can be tested through various known analytical methods.Can analyze through any useful spectroscope method as film or as the surface of the alloy of fiber, as have the x-ray photoelectron spectroscopy method (XPS) of elementary analysis (EA).The degree of the modification on the surface through migration SMM can be shown from the data of XPS, and the degree of the modification of bulk material (bulk material) can be shown from the data of EA.Stable alloy subsequently can be to be tested to confirm the thrombotic on surface under various conditions.

The extracorporeal blood loop

Characteristic of the present invention be through in one or more parts of extracorporeal blood loop, comprise the big molecule of surface modification reduce with any part of extracorporeal blood loop (as, blood tubulature, hollow-fibre membrane, package surface or blood tubulature are connected to the end of filter wherein) composition and the method for the activation of the blood constituent of contact.Said haemodialysis control unit pumping dislysate and patient's blood passes through dialyzer.Blood and dislysate separate through the semi permeability hollow-fibre membrane each other, and blood is through the extracorporeal blood loop of haemodialysis control unit, and dislysate is through the dislysate loop of haemodialysis control unit.In the extracorporeal blood loop of dialysis machine any one or a plurality of blood-contact surface can use the big molecule of surface modification described herein to handle to produce the anticoagulant property surface.Medical separator of the present invention can be the artificial kidney or the relevant apparatus of doughnut type, like blood filter, blood oxygenators or other separate impurities devices from health.

Said device comprises dialysate chamber and a pair of each terminal drip chamber that is connected to dialysis fluid chamber (drip chamber) of separating.Each drip chamber stops at the port that leads to the blood tubulature, and it finally leaves and get into the experimenter of experience haemodialysis.The hollow semi permeability fibre bundle that said dialysis fluid chamber is provided with conventional entrance and exit dialysis port and extends around axis.

That said fibre bundle comprises is thousands of (as; 3,000 to 30,000) independent fiber; It can by cellulose (as; Through like United States Patent (USP) the 3rd, 546, the cellulose acetate of instruction takes off the acetyl preparation in No. 209), cellulose acetate, cellulose esters, polyester, polyamide, polysulfones or any other hollow-fibre membrane known in the art form.Typically, said fiber is thin and is capillary dimensions that its common inside diameter ranges is about 150 to about 300 microns, has at about 20 wall thickness to about 50 micrometer ranges.

With reference to Fig. 1, typical extracorporeal blood loop 100 comprises tubing, through its blood flow, and is used for assembly that blood is filtered and dialyses.

Blood flows through artery tubing 110 from patient 105.Blood splashes into drip chamber 115, and wherein the tube connector from drip chamber 115 is connected to the sensor 125 on the haemodialysis control unit, the pressure of the blood of the arterial side of its mensuration extracorporeal blood loop.Pump 120 forces blood to continue along the path through said extracorporeal blood loop.Dialyzer 130 separates excreta from blood.

After passing through dialyzer 130, blood flow is crossed vein tubing 140 and is got into second drip chamber 150.Drip chamber 150 can be used as air collector.Free gas in the blood can be fled from into drip chamber 150 before blood continues to flow to the patient.Sensor 170 is through the air communication in pipe 165 and the drip chamber.Sensor 170 can be measured the pressure of the venous side of extracorporeal blood loop.

Heparin 160 be introduced in the blood in the drip chamber 115.When blood during in oxygen, blood begins to solidify.Drip chamber 150 can comprise and is used to prevent that any grumeleuse from leaving drip chamber 150 and getting into patient 105 filter.Blood continues to pass through air-foam detector 175 through vein tubing 180 and before getting back to patient 105 from drip chamber.

Any blood contact assembly of said extracorporeal blood loop can be used like the big molecule modification of surface modification described herein, to produce the anticoagulant property surface.Said extracorporeal blood loop can be used for haemodialysis, like top explanation, and can be used to relate to that blood concentrates, the other treatment of oxygenation, Protein Separation, plasmapheresis and blood separation.

The big molecule of surface modification

VII-a is shown among Fig. 2-19 to the diagrammatic sketch of XI-b.For all SMM, the quantity of soft chain segment can for any integer or non-integer so that the approximation theory molecular weight of soft chain segment to be provided.For formula (XII) and compound (XIII), the quantity of the moieties of hydrogenation can be for any integer or non-integer with any integer that soft chain segment is provided or non-integer so that the approximation theory molecular weight of soft chain segment to be provided.The instance of XII-a, XII-b, XIII-a, XIII-b and XIII-c comprises SMM, wherein x=0.225, y=0.65 and z=0.125.

Table 1 shows hard segment, soft chain segment and the SMM of end-group (F end group) of fluoridizing distributes.Table 1 also shows the ratio of hard segment and soft chain segment, and its scope is 0.16 to 1.49.

Table 1

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

Hollow-fibre membrane

Hydrophobic polymer has been as the popular selection of polymeric material, like polysulfones, aromatic polyimide and acid amides in the doughnut spinning.Any base polymer described herein can be with the hydrophobic polymer that acts on the doughnut spinning.For haemodialysis; Hollow-fibre membrane usually by native cellulose, cellulose derivative (as; Two-or three-cellulose acetate) or synthetic polymer (wherein as, polysulfones, polyacrylonitrile or polyamide) prepare, to they biocompatibility and select them.Yet verified the providing of neither one is required with the anticoagulant property of minimizing to the expectation of the dependence of anti-coagulants in these materials.

Especially, because their good fiber spinning properties and biocompatibility, polysulfones (PS) is the synthesizing hydrophobic polymer that extensively is used in the hollow-fibre membrane.Yet pure hydrophobicity PS can not directly be used for some application, like dialysis membrane, because this will reduce the wet characteristic of film and influence for the essential wet performance of the removing of toxin in aqueous environment.In order to address this problem, polyvinylpyrrolidone (PVP) forms hydrophilic polymer as the hole usually and is added among the PS, wherein great majority dissolving and forfeiture in the doughnut spinning technique, and hydrophilically modified PS is so that it is suitable as pellicle.Though some PVP are retained in the fiber, when blood coagulation between the dialysis period that needs the anticoagulant heparin agent still take place or the normal saline washing dialyzer when remove blocking, this is insufficient.

Method and composition of the present invention solves these problems through in hollow-fibre membrane, comprising the big molecule of surface modification.The big molecular migration of said surface modification to the surface (inner chamber during spinning technique and outer surface) of hollow-fibre membrane with 10 microns at the top that occupies doughnut.

The manufacturing of hollow-fibre membrane

Be suitable for being used in method of the present invention, should remove the low-molecular-weight level of uremic substances, remain with the material such as the albumin of usefulness simultaneously like the how aerial hollow fiber film in the kidney dialysis.Such porous hollow fiber membrane utilization is suitable for the technology in the aperture in the many aerial hollow fiber films of accurately control and produces.The aperture of said hollow-fibre membrane can depend on composition, the core solution of spinning solution composition, ventilating ratio (air-flow than), be used for liquid composition, temperature, humidity and other factors of film cohesion.The composition of core solution is the key factor as combination, and constitutes the relevant solvent of polymer with film and confirm setting rate with the mixing ratio of non-solvent, so the form of the inner surface of definite hollow-fibre membrane.

In this area known a plurality of technologies be used to produce hollow-fibre membrane (referring to, for example, United States Patent (USP) the 6th, 001, No. 288; The 5th, 232, No. 601; The 4th, 906, No. 375; And the 4th, 874, No. 522; Incorporate wherein each into this paper with way of reference); Comprise: (i) such technology, wherein use pipe-in-mouth of tubing type, and (promptly from outer tube; From the annulus that limits between interior pipe and the outer tube) extruding spinning solution, and core solution is ejected from interior pipe; (ii) through spinning solution is expressed in the air, allow filament to fall through gravity, the coagulating agent that filament is passed be used to solidify is bathed, and flushing and dry filament (doing-the wet spinning silk); The upper strata that (iii) comprises non-cohesion solution through utilization and the bath of the lower floor of cohesion solution, and spinning solution directly is expressed in the non-cohesion solution and makes filament pass cohesion solution; (iv) comprise the bath of the lower floor of the upper strata of condensing solution and non-cohesion solution, and spinning solution directly is expressed in the non-cohesion solution and makes filament pass cohesion solution through utilization; (, and filament is passed along the border between cohesion solution and the non-cohesion solution v) through spinning solution directly is expressed in the non-cohesion solution; And (vi) through from mouth extruding spinning solution and make filament pass cohesion solution around non-cohesion solution.

In such technology, the speed and the degree of the cohesion of the spinning solution that extrude through non-cohesion solution (solvent that the is used for spinning solution) adjusting of cohesion solution (non-solvent that is used for spinning solution) that uses the cohesion that promotes spinning solution respectively or in mixture and the cohesion that suppresses spinning solution in the aperture of hollow-fibre membrane are controlled.

In order to be used in the compositions and methods of the invention; Typical spinning solution will comprise base polymer (as; Polysulfones), the hydrophily pore-forming agent (as; Polyethylene is than pyrrolidone, ethylene glycol, alcohol, polypropylene glycol or polyethylene glycol), be used for the solvent (that is, dimethyl formamide, methyl-sulfoxide, dimethylacetylamide, N-methyl pyrrolidone or their mixture) and the big molecule of surface modification of polymer.

Hollow-fibre membrane of the present invention can be for example, through in cohesion solution from pipe--spinning-drawing machine of tubing type mouth in extruding spinning solution produce to form hollow-fibre membrane.The said spinning solution that comprises polymer is extruded the cylindrical filament that has interior thorax with formation from outer tube (that is, the annulus that limits between interior pipe and the outer tube), and the core solution that is used for the cohesion of spinning solution is expressed into the interior thorax of filament from the interior pipe of mouth.In this process, said filament can directly be expressed in the cohesion solution, perhaps is expressed in the air, is pulled into subsequently in the cohesion solution.As stated, said spinning solution is supplemented with hydrophily pore-forming agent and the big molecule of surface modification, and the hollow-fibre membrane of gained comprises the big molecule of surface modification in its surface.

Can change the viscosity of spinning solution when needed.For example; Through add thickener (as; Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) or polypropylene glycol) to improve viscosity; Or join in the spinning solution to reduce viscosity through dredging proton low boiling point solvent (that is, oxolane, diethyl ether, MEK, acetone or their mixture).Also can comprise and dredge the proton low boiling point solvent to increase the macromolecular solubility of surface modification in the spinning solution.

Said spinning solution is extruded to form the shape of filament, and it utilizes cohesion solution to be precipitated, the formation of the porous hollow fiber that causes expecting.Said cohesion solution can comprise non-solvent or non-solvent and be used for the mixture of solvent of the base polymer of spinning solution.Typically, the non-solvent that is used to condense solution is the aqueous solution.

After forming porous hollow fiber, can make it pass through second flushed channel.Said porous hollow fiber can for example, be cut, tie up and drying, and be made into to be suitable for as being used in the porous hollow fiber membrane in the dialyzer by further processing subsequently.

The encapsulation bundle of hollow-fibre membrane

Characteristic of the present invention be through when hollow-fibre membrane is packed, in pouring material, comprise the big molecule of surface modification reduce with filter (as; As apparatus for purifying blood, concentrate or the part of oxygenator device such as haemodialysis, hemodiafiltration, blood filtration, blood) the composition and the method for activation of blood constituent of pouring material contact.

For with doughnut membrane filtration or infiltration; A large amount of thin doughnuts is necessary packed (promptly; Fixing) to the top cover of casing; Make they inner surface for the inboard of vanning each by sealing fully, blood is delivered to second potted ends from first potted ends of filter but their chamber is open.Pouring material is the important major part of blood purification filter; Because they are to keep the hollow membrane fibre bundle securely with the end in the cylinder of dialyzer (quantity is from 5 as glue; 000-20; 000), keep the open-ended of doughnut to be used to filter the cured polymer material (being generally polyurethane) of purpose through getting into filter simultaneously to allow blood.The fibre bundle that these are numerous remains in the vanning and guarantees that each doughnut is a necessary step in the filter assembling along correct arrangement of the axle of cylinder.

The enclosure wall that forms in any end of blood purification filter is under shearing condition, to tend to the zone of the blood flow of turbulent flow, and it causes the activation of blood constituent and at first causes thrombosis, and it can influence blood flow and filter function unfriendly.This problem can not be enhanced through utilizing anticoagulant hollow-fibre membrane; Because the end of said hollow-fibre membrane only be typical wall surface very little part (as; Wall surface about 18%), follow by cavity (as; Wall surface about 16%), and a large amount of pouring materials (as, wall surface about 66%).Should big zone existence need solving, dynamic blood flow wherein takes place and wherein can cause most of thrombus of the obstruction of filter to begin.There are needs for hollow-fibre membrane with the thrombotic that reduces and blood filter device.

Pouring material can be through mixing thermosetting polymer that two kinds or more kinds of composition form to form cured resin (that is, typically polyurethane).In order to produce anticoagulant property pouring material of the present invention,, the big molecule of surface modification is joined at least one parts of pouring material mixing with before forming cured resin.

The big molecule of said surface modification can be merged in any pouring material known in the art.For example, the big molecule of surface modification can be merged in the polyurethane pouring material that is formed by the prepolymer of isocyanates-termination (product of polyalcohol and PIC), and solidifies with one or more polyfunctional crosslinking agent, describes in the art.The pouring material that can be used in method of the present invention, composition and the dialysis system is included in U.S. Patent number 3,362,921; 3,483,150; 3,362,921; 3,962,094; 2,972,349; 3,228,876; 3,228,877; 3,339,341; 3,442,088; 3,423,491; 3,503,515; 3,551,331; 3,362,921; 3,708,071; 3,722,695; 3,962,094; 4,031,012; 4,256,617; 4,284,506; With 4,332, those that describe in 927, each is incorporated herein with way of reference with it.

Embodiment below setting forth is so that complete disclosure content and the description that provides method that this paper requires and compound how to carry out, prepare and assess for those of ordinary skill in the art; And to be intended to be of the present invention pure exemplary, and be not used in the restriction inventor and be regarded as their scope of invention.

The diagram and the calculating of embodiment 1. encapsulation regions

Figure 20 A is the scanning electron micrograph of single doughnut.Figure 20 AB is the diagram of hollow fiber bundle.Anticoagulant surface area when the ability of Figure 20 A-20B and the outstanding fibre bundle of following calculating contacts with blood to be provided at.

Following calculating is based on Figure 20 B, and it is the concept map by the CRRT blood filter that is purchased of 5,000 fibre bundles compositions with following size:

A) diameter=3.5cm of encapsulation region+pars fibrosa

B) external diameter of fiber (OD)=290 μ m, and internal diameter (ID)=200 μ m

C) total encapsulation and fiber area=π r ²=3.142 (3.5/2) ²Cm ²=9.623cm ²

D) area=π of hollow space (ID/2) ²=3.142/4 * (0.020) ²Cm ²=3.142 * 10 ^-4Cm ²

E) for area=5,000 * 3.142 * 10 of the hollow space of 5,000 fibers ^-4Cm=1.571cm ²

F) area of solid portion (additive treating)=π (OD/2) ²-π (ID/2) ²

G) for 5000 fibre solids area (additive treating)=5,000 * 3.142/4 * [(0.029) partly ²-(0.020) ²] cm ²=1.73cm ²

H) percentage area of solid portion (additive treating)=(1.73/9.623) * 100～18%

I) percentage of hollow space=(1.571/9.623) * 100～16%

J) percentage of packed part (not having additive treating)=100-(16+18)～66%

Based on said calculating, can find out that only about 18% the top cover district that is occupied by fiber (circle with the thick line in the dialyzer cylinder is described) is used to provide the big molecule of surface modification (SMM) modification of anticoagulant property effect.This makes about 66% the zone that comprises packed part be unmodified and tend to when contacting with blood, form thrombus in hemodialysis session.To any hollow-fibre membrane (as, CRRT or Chronic) can similarly calculate, if wherein unmodified, then about 66% the top cover district that is occupied by pouring material is used to solidify and thrombotic key area.Characteristic of the present invention is also to handle the method for this packed part of about 66% (major part of fiber) with the big molecule of surface modification, and obtaining comprehensive anticoagulant top cover surface, it is with the minimize blood activation and prevent to condense with subsequently blood filter and block.

The big molecule of surface modification in the film of embodiment 2.PS/PVP polymeric blends

The preparation film can be by the surface composition in the mixture of its preparation to present hollow-fibre membrane of the present invention.With the big molecule of surface modification (SMM, 5wt%), polysulfones (PS, 10wt%) and polyvinylpyrrolidone (PVP 5wt%) is dissolved in the mixture of dimethylacetylamide and oxolane (about 80wt%).The film that will have 254 μ m thickness casts in and also carries out drying subsequently on the Teflon matrix and analyze surperficial fluorine and nitrogen content.For four solution-cast prescription films being analyzed, the result is provided in the table 2, and each utilizes the big molecule of different surface modification.

Table 2

For four films, the result provides surperficial fluorine content through x-ray photoelectron spectroscopy (XPS), and the elementary analysis (EA) of provider (bulk) (only) SMM is used for comparison.The surface of moving to film by the macromolecular oligomeric fluorin radical of surface modification for the difference of the XPS of percentage fluorine content and EA data produces.The percentage nitrogen content of surface has reflected in the surface of film except the existence that has the macromolecular hydrophily urethane part of outer surface modification of polyvinylpyrrolidone.

The big molecule of surface modification in the fiber of embodiment 3.PS/PVP polymeric blends

Also analyze the fluorine and the nitrogen content of fiber.Four kinds of solution for being analyzed are spun into fiber, and the result is provided in the table 3, and each utilizes the big molecule of different surface modification (VII-a, VIII-a, IX-a and XI-a).

Table 3

The fiber that x-ray photoelectron spectroscopy (XPS) data show all SMM modifications has surperficial fluorine in various degree in inner surface (IS) that in fact hemodialysis session contacts with blood and outer surface (OS).

Table 3 also provides the elementary analysis of SMM in the main body (EA) and %F, and it shows with the amount of incorporating into of target compares, and is incorporated into the amount of the additive in the fiber.For VII-a, the EA of %F shows that the additive of 6wt% incorporates into, and only in fact 4wt% exists.This loss of about 33% can be owing to the harsh conditions of fiber spinning process, and it relates to some SMM of dissolving and dissolves the spin solvent mixture that the hole forms polyvinylpyrrolidone (PVP) simultaneously.This is suitable for for VIII-a, IX-a and XI-a, and be reflected in that target is incorporated into and the difference between actual incorporating into of calculating by elementary analysis in.Yet no matter all SMM their ultimate density, keep so that the appreciable impact to surface property to be provided with the amount of abundance to being enough to all by force, and it can be reflected in the anticoagulant property performance that proves in the blood loop research among the embodiment 5.

Table 3 shows that XPS result shows the shortage of fluorine for commerce contrast PS/PVP fiber (SMM modification of no use).Nitrogen content in the commercial fibres comes from the PVP that stays after its major part is rinsed in spinning process.The amount of staying the PVP in the fiber of unmodified and SMM modification is also with different.

Consider the XPS result of the fiber inner surface (IS) that contacts with blood; Table 3 shows for VII-a, VIII-a, IX-a and XI-a; %F (hydrophobic grouping) is in the scope of 1.71%-10.79%, and %N (hydrophilic radical) is in the scope of 1.39%-2.90%.As from what confirm from the data of table 3, the ratio of %F and %N comprises 1.23-4.63, and comprises from 1.20 to 10.0 for the possible scope of the ratio of %F and %N.Like what in table 1, provide, the ratio of hard segment and soft chain segment comprises 0.16-1.49, and comprises from 0.15 to 2.0 for the possible scope of this ratio of hard segment and soft chain segment.

As shown in the embodiment 5, though VII-a and XI-a put up the best performance in this series, compare with contrast, VIII-a and IX-a do not have any main failure, and failure does not cause the bigger obstruction of filter yet.Different with contrast, do not show the so bigger change (comparing) in top cover pressure and the γ-counting with the filter of VII-a, VIII-a, IX-a or XI-a modification with the standard error in the table 6.

The big molecule of surface modification in embodiment 4. pouring materials

The preparation sample disc is to present the surface composition in the polymeric material that comprises encapsulation region.

Use from the perfusion compound GSP-1555 that is purchased of GS polymers Inc. as pouring material.It is two parts system that is made up of part A (based on the vulcabond of HMDI) and part B (polyalcohol).Be appointed as four SMM and the GSP 1555 pouring material fusion of VII-a, VIII-a, IX-a and XI-a (structure is depicted among Fig. 2-5), as shown in table 4.VII-a uses with two concentration 1% and 2% respectively.Every other SMM, that is, VIII-a, IX-a and XI-a, according to following method only with the prepared at concentrations of 2% (w/w).

Under well-mixed situation, in 40ml plastics falcon pipe, in GSP 1555 precursor polyalcohols, add SMM.Mixture is dissolved among a large amount of THF.Add GSP 1555 precursor vulcabond subsequently, and stirred reaction mixture.The GSP that the comprises SMM 1555 perfusion compounds of gained allowed at room temperature to solidify 24-48 hour.The mixture that solidifies is dry 48 hours solvents with any remnants of removal from sample under vacuum subsequently.

Table 4

Sample is cut into suitable size and stands XPS.XPS result provides in table 5.The value of atom %F shows that all parts (that is the new surface of top surface and the generation of cutting back) of encapsulating material have been added the agent modification.It is important that the said cutting part of pouring material is added the agent modification because produce by the hollow fiber membrane bundle of encapsulation that packed part that filter is usually included in said bundle is cut to produce smooth, polished face (finish) thus produce new surface when exposing the doughnut opening.The value of atom %F shows that also SMM is dynamic process and takes place on all surface to the migration on surface, comprises those surfaces of new generation.For example, VII-a is merged in to produce the top section on the surface that shows 30% fluorine with 1% (w/w).Annealing is after 24 hours down at 60 ℃, and the %F content of surface reduces to about 13%.Behind cutting sample, XPS shows the surface that the cutting surface presents about 7% fluorine, and it is increased to about 26% fluorine in annealing under 60 ℃ after 24 hours.Therefore, if do not have enough fluorine on the surface of fresh cutting, can be annealed in encapsulating material then of the present invention surface.For other SMM, obtain similar observed result.This shows that also SMM can move through cured polymer or thermosetting polymer.

Table 5

1.T=the top section of sample under the environment temperature.

2.T60=under 60 ℃, the top section of 24 hours samples.

3.C=the cutting part of sample under the environment temperature.

4.C60=under 60 ℃, the cutting part of 24 hours samples.

5. contrast should lack fluorine.Here 3%F content shows pollution.

The thrombotic external assessment of embodiment 5. blood filters

The thrombotic surface-active of blood filter is assessed in utilization in response to the blood filter that is purchased of the bovine blood of heparinize.Blood filter compares with VII-a, VIII-a, IX-a or XI-a surface modification and with contrast (not by the blood filter of surface modification).

Material

The blood filter that is purchased that comprises PS/PVP is used as contrast.Four kinds of big molecules of surface modification (SMM) with VII-a, VIII-a, IX-a and XI-a (shown in figure) of different chemical composition are used to the commercial blood filter of modification, and it is used as specimen with the contrast filter.Have 4% additive incorporates into the commercial filter of VII-a modification.Have 3% additive incorporates into the commercial filter of VIII-a modification.Have 2% additive incorporates into the commercial filter of IX-a modification.Have 1.6% additive incorporates into the commercial filter of XI-a modification.30 filters have altogether been analyzed under study for action.(2 units/ml) be used to each experiment, wherein said research comprises 3 or 6 cows to the bovine blood of heparinize.QC discharges test to carry out on the filter of the modification that is used for the assessment of dialyzer function and fiber size.These compare with the contrast filter.

Method

Utilize standard blood loop systems and scheme (referring to Sukavaneshvar et al.; Annalsof Biomedical Engineering 28:182-193 (2000); Sukavaneshvar et al.; Thrombosis and Haemostasis 83:322-326 (2000) and Sukavaneshvar etal., ASAIO Journal 44:M388-M392 (1998)) carries out the thrombotic external assessment of blood filter.

Simply, use following scheme.The blood loop systems comprises that bank, pump, blood filter and tubing are to form the closed jet rotating ring.Said loop systems be poured PBS (PBS) under 37 ℃ and beginning to test before circulation 1 hour, and the pressure port place gaging pressure between pump and blood filter.

About 10 liters fresh bovine blood obtains from single animal, is used for each experiment, and by heparinize (typical concentrations=2U/ml).Experiment is carried out in 8 hours of blood collection.Before research beginning, radiolabeled, (have from the blood platelet of body ¹¹¹Indium) is added in the blood.With the PBS in the blood replacement bank, and monitoring pressure.1-2 hour (only if stop owing to significant pressure increases, like what monitor through pressure gauge) kept in blood circulation in the loop systems usually.Last what test, blood filter is taken pictures, and utilize inlet, outlet and the middle measurements γ-counting of γ-probe at blood filter.

Figure 21 shows the structure of experiment setting that is used for the extracorporeal blood ring analysis and the blood filter that is used to study.Also shown is the arrangement of the γ-probe reading that is used for blood filter, wherein measure measured value at the end points and the middle part of blood filter.Be used for radiolabeled hematoblastic γ-probe reading and after filter is exposed to blood flow, be determined, and wash to remove any residual blood with PBS solution.Figure 22 shows the arrangement of blood filter after the blood ring process, preceding being outwarded winding visually to check thrombus of top cover cap (top cap and end cap).

Result and discussion

Table 6 shows for the results of in vitro studies of contrast (C1) with the hemodiafiltration device thrombus of VII-a, VIII-a, IX-a and XI-a.Table 6 also shows hematoblastic γ-probe reading that the top cover pressure of locating at enter the mouth (the top cap among Figure 22) changes (Δ P) and the radiolabeled activation of locating for the inlet (the top cap among Figure 22) of testing 1-6 blood filter after blood contacts, middle part and outlet (end cap among Figure 22) district.In experiment 1, first filter of failure is IX-a after 25 minutes, and wherein top cover pressure is 180mm Hg.This is called as out-of-service time or blocking time.Here failure means that this moment, top cover pressure reached on the pressure of foundation >=175mm Hg.At this some place, the hematoblastic γ of activation-count is 3582, and is 3250 at the middle part, and is 2223 in the exit.In this experiment, VII-a not only compares also in SMM but also with contrast and puts up the best performance, and has minimum top cover pressure and the 53mm Hg (contrast) of 20mm Hg.γ-counting at this some place is 2631.Yet, at the γ-counting at middle part higher (at 4534 places), and in outlet lower (at 2454 places).Higher γ-the counting in middle part possibly be the indication (because additive character of SMM) of microthrombus of the lax combination penetrate fiber of sliding, and it does not allow the thrombus gathering.For the filter of most SMM modifications, the hematoblastic higher concentration of the activation of filter middle portion normally is suitable for, as obvious in experiment 1,2,3,5 and 6.In this experiment (experiment 1), to compare with contrast, the filter of XI-a modification also shows well, has the top cover pressure of 35mm Hg.

Table 6

^aThe filter of failure in each experiment

In experiment 2, VIII-a failed in 57 minutes, had the top cover pressure of 185mm Hg.In this experiment, to compare with VII-a or IX-a, contrast is put up the best performance, and has minimum top cover pressure at 86mm Hg place.Corresponding γ-counting also is presented in the table 6.Yet in 4 experiments below, in the filter of all tests, VII-a puts up the best performance, and has minimum top cover pressure, except in test 6, and the wherein a little higher than contrast of top cover pressure of XI-a.γ-the counting of top cover porch also is the reflection of its performance.The XI-a performance is inferior good in this series.Experiment 4 and 5 shows the result that some are interesting, wherein contrasts filter and in 8 and 10 minutes, fails respectively calamitously, follows thrombus and the total blockage of filter of the fibrin-rich of bulk.Table 6 demonstrates the filter with respect to the SMM modification, and how high the pressure of contrast filter be (926 with 362mm Hg), and in this corresponding high platelet count in some place.During whole analysis, there is not filter failure in 10 minutes in any experiment of SMM modification, they do not reach high like this pressure at any some place yet.

Table 7 shows for the filter of contrast and VII-a, VIII-a, IX-a and XI-a modification average top cover pressure and the γ-counting in the porch, follows corresponding standard deviation and standard error for 6 experiments (n=6).Comparing with any SMM, also is big variational indication in the performance of contrast filter for the high value of standard error (STE) of contrast.This table shows that also the top cover pressure (inlet) of VII-a and XI-a has minimum variability, and is obvious from 24 and 25 STE value respectively.Hematoblastic γ-the counting (table 7) of the activation of top cover porch also shows and the contrast filter in comparison, for the much lower STE of VII-a and XI-a.These values are all consistent with the filter performance of VII-a and XI-a and contrast filter.

Should be noted that the experiment 5 in the table 7 shows that the top cover pressure of VII-a is-3mm Hg, and XI-a is-5mm Hg.These are the actual values in the analyzed in vitro, reason be under shearing force through the pulsatile blood flow of fiber, it can cause slight negative pressure, and in fact should be interpreted as " 0 " for all intentions and purpose.

Table 7

Table 8 shows the Time To Failure and the corresponding filter device of at first failing in each experiment.Can see, in

experiment

4 and 5, the calamitous failure of contrast filter, and in experiment 1, IX-a failed in 25

minutes.In experiment

2,3 and 6, VIII-a fails (being respectively 57,30 and 40 minutes), but neither one is great failure in these, and they do not cause filter to become by the thrombus total blockage yet.Table 8 has also been summed up the top cover pressure of two best SMM prescriptions (VII-a and XI-a) and how has been compared with contrast with these.

Table 8

¹With respect to baseline pressure, if pressure>=175mm Hg, then each experiment is terminated.This is considered to the

filter failure.In experiment

4 and 5, fail to impinging upon in 10 minutes.

²Δ P representes with respect to baseline pressure, the variation in the top cover pressure.

³Filter in

experiment

4 and 5 is by the thrombus total blockage.

Figure 23 diagram shows and contrasts filter in comparison, average top cover pressure and the γ-counting of VII-a and XI-a.Error bar is the variational indication of pressure and γ-reading; Two all higher in contrast and VII-a and XI-a.On average, compare with contrast, VII-a has 85% littler top cover pressure, and XI-a has 78% littler top cover pressure, and compares with the commerce contrast, and γ-counting is respectively 56% and 61% lower among VII-a and the XI-a.

Figure 24 A-24B and Figure 25 A-25C are the thrombus photos of experiment 4, and Figure 26 A-26D is the thrombus photo of experiment 5.In these experiments, the contrast filter is failed in 10 minutes or shorter time, follows the thrombosis and the filter blocks of bulk.Figure 24 A-24B and Figure 25 A-25C show that especially not only top cover has thrombus, and after the blood indication of height cohesion is discharged, on sieve, also have the thrombus residue.

Figure 27 compares for all 6 experiments, the thrombus photo of VII-a and XI-a and contrast filter.Increase the degree with the redness of the top cover inlet of platelet activation from the indication red thrombus, can find out that the contrast of VII-a and XI-a average specific shows better (except force value).

For all 6 experiments, after the blood ring analysis in the entrance and exit position thrombus photo of acquisition filter device top cover.For testing 1 (Figure 28 A-28B), experiment 2 (Figure 29 A-29B), experiment 3 (Figure 30 A-30B) and testing 6 (Figure 31 A-31B), experimental result shows as the thrombus photo.In all these situation, VIII-a or IX-a failure, but filter never blocks, unlike the contrast in the

experiment

4 and 5.

In addition, the filter of all SMM modifications (VII-a, VIII-a, IX-a or XI-a) can be spun in the fiber.In the time of in being assembled into dialysis filter, blood filter is to be tested, and compares with the contrast blood filter, all can work as blood filter.Usually, all blood filters work as dialyzer.

Conclusion

Utilize the extracorporeal blood ring research of the bovine blood of heparinize to show that VII-a and XI-a put up the best performance in the filter of all tests.Compare with contrast, these two prescriptions show there is not the filter failure, follow minimum average top cover pressure (＞75% less pressure), harmonic(-)mean γ-counting (＞55% is less), low thrombus and less thrombotic.On the contrary, the performance of contrast filter is the poorest, in two experiments, in 10 minutes, fails calamitously.In 6 experiments, in the filter of all tests, it also has the highest average top cover pressure, γ-counting and variability.VIII-a fails in 3 experiments, and IX-a fails in 1 experiment, but all these in 25-57 minute, and the said filter of neither one has any great obstruction.All blood filters are working as dialyzer in varying degrees, and can easily regulate to meet the specification of expectation.

Other embodiment

All publications, patent and the patent application of mentioning in this specification mode by reference is incorporated herein, as each independently publication or patent application by clearly with the identical degree of pointing out respectively to be merged in way of reference.

Though described the present invention together with its specific embodiment; But should be appreciated that and further to revise, and the application is intended to cover generally of the present invention any variation, application or change according to principle of the present invention; And comprise departing from of such and the application's disclosure content; It and can be applied to the essential characteristic of preceding text statement under the present invention in the field in the known or conventional practice, and falls in the scope of claim.

Other embodiment is in claim.

Claims

1. extracorporeal blood loop that comprises polymer assemblies; Wherein, Said polymer assemblies comprises that fusion has the macromolecular base polymer of surface modification of 0.005% to 10% (w/w); Wherein when said extracorporeal blood loop was in use, said polymer assemblies had the surface that is positioned to contact blood, and wherein when contacting with said blood said surface be anticoagulant.

2. extracorporeal blood loop according to claim 1, wherein, when contacting with blood, the thrombus of said surface deposition is reduced by at least 10%.

3. extracorporeal blood loop according to claim 1, wherein, said extracorporeal blood loop has the average function sex work phase of at least 125% increase.

4. extracorporeal blood loop according to claim 1, wherein, said extracorporeal blood loop reduces acceptance and occurs through the adverse events among the experimenter of the blood of said extracorporeal blood loop.

5. hollow-fibre membrane, said hollow-fibre membrane comprises that fusion has the macromolecular base polymer of surface modification of 0.005% to 10% (w/w), wherein when contacting with blood, said hollow-fibre membrane is anticoagulant.

6. hollow-fibre membrane according to claim 5, wherein, when contacting with blood, the said lip-deep thrombus deposition of said hollow-fibre membrane is reduced by at least 10%.

7. hollow-fibre membrane according to claim 5, wherein, said hollow-fibre membrane has after using 4 hours and is reduced by at least 10% operating pressure.

8. hollow-fibre membrane according to claim 5, wherein, the adverse events that said hollow-fibre membrane reduces among the experimenter of the blood of accepting to pass said hollow-fibre membrane occurs.

9. hollow-fibre membrane according to claim 5; Wherein, said base polymer is selected from by polysulfones, polyacrylonitrile, cellulose acetate, two-or three-cellulose acetate, polyimides, gather the group that (methyl methacrylate), Merlon, polyamide, polypropylene and polyethylene are formed.

10. hollow-fibre membrane according to claim 9, wherein, said base polymer is to be selected from the polysulfones that gathers (Oxy-1,4-phenylene sulfonyl-1,4-phenylene Oxy-1,4-phenylene isopropylidene-1,4-phenylene) or polyether sulfone.

11. hollow-fibre membrane according to claim 5 further comprises the hydrophily pore-forming agent.

12. hollow-fibre membrane according to claim 11, wherein, said hydrophily pore-forming agent is selected from polyvinylpyrrolidone, ethylene glycol, alcohol, polypropylene glycol and polyethylene glycol or their mixture.

13. hollow-fibre membrane according to claim 11 comprises the said base polymer of 80% to 96.5% (w/w), the said hydrophily pore-forming agent of 3% to 20% (w/w) and the big molecule of said surface modification of 0.005% to 10% (w/w).

14. extracorporeal blood loop according to claim 1, wherein, said extracorporeal blood loop comprises each described hollow-fibre membrane among the claim 4-11.

15. the encapsulation bundle of the hollow-fibre membrane in the vanning comprises:

(a) array of hollow-fibre membrane, the array of said hollow-fibre membrane have inner chamber, first group of fiber ends and second group of fiber ends;

(b) said first group of fiber ends is encapsulated in the sealing resin, and said sealing resin limits near first terminal first inwall of said vanning; And

(c) said second group of fiber ends is encapsulated in the sealing resin, and said sealing resin limits near second terminal second inwall of said vanning,

Wherein, the said inner chamber of said hollow-fibre membrane is provided for making blood to flow to the path of said second inwall from said first inwall, and

Wherein said sealing resin comprises the big molecule of the surface modification of 0.005% to 10% (w/w).

16. encapsulation bundle according to claim 15, wherein, said bundle has the duty cycle of prolongation.

17. encapsulation bundle according to claim 15, wherein, said bundle has the average function sex work phase of at least 125% increase.

18. encapsulation bundle according to claim 15, wherein, when contacting with blood, the thrombus deposition on the said encapsulation bundle is reduced at least 10%.

19. encapsulation bundle according to claim 15, wherein, said bundle has after using 4 hours and is reduced by at least 10% operating pressure.

20. encapsulation bundle according to claim 15, wherein, the adverse events that said encapsulation bundle reduces among the experimenter of the blood of accepting to pass said encapsulation bundle occurs.

21. encapsulation bundle according to claim 15, wherein, when contacting with blood, said sealing resin is anticoagulant.

22. according to each described encapsulation bundle among the claim 15-21, wherein, the said bundle of the hollow-fibre membrane of the encapsulation in the vanning is the part of apparatus for purifying blood.

23. encapsulation bundle according to claim 22, wherein, said apparatus for purifying blood is haemodialysis, hemodiafiltration, blood filtration, blood is concentrated or the oxygenator device.

24. according to each described encapsulation bundle among the claim 15-23, wherein, said sealing resin comprises crosslinked polyurethane.

25. encapsulation bundle according to claim 24; Wherein, said crosslinked polyurethane by 4 '-methylene two (cyclohexyl) isocyanates, 2,2 '-methylene two (phenyl) isocyanates, 2; 4 '-methylene two (phenyl) isocyanates or 4,4 '-methylene two (phenyl) isocyanates forms.

26. extracorporeal blood loop according to claim 1, wherein, said blood loop comprises each described encapsulation bundle among the claim 15-25.

27. a dialysis filter comprises among the claim 4-12 each described encapsulation bundle among each described hollow-fibre membrane or the claim 13-23, wherein, said filter has the duty cycle of prolongation.

28. dialysis filter according to claim 27, wherein, the adverse events that said dialysis filter reduces among the experimenter of the blood of accepting to pass said dialysis filter occurs.

29. a blood tubulature comprises that fusion has the macromolecular base polymer of surface modification of 0.005% to 10% (w/w), wherein, when contacting with blood, said blood tubulature is anticoagulant.

30. blood tubulature according to claim 29, wherein, said base polymer comprises polyvinyl chloride.

31. blood tubulature according to claim 29, wherein, the adverse events that said blood tubulature reduces among the experimenter of the blood of accepting to pass said blood tubulature occurs.

32. extracorporeal blood loop according to claim 1, wherein, said extracorporeal blood loop comprises each described blood tubulature among the claim 29-31.

33. one kind is used to treat the method through the experimenter of undermined renal function; Said method comprises utilizes dialysis filter said experimenter to be selected from haemodialysis, blood filtration, blood concentrate or the process of hemodiafiltration; Wherein, said filter comprises among the claim 5-14 each described encapsulation bundle among each described hollow-fibre membrane or the claim 15-26.

34. method according to claim 33, wherein, during said process, said experimenter accepts to be less than the anti-coagulants of standard dose.

35. method according to claim 34, wherein, during said process, said experimenter does not accept anti-coagulants.

36. method according to claim 33, wherein, said filter has the duty cycle of prolongation.

37. method according to claim 33, wherein, said filter has the average function sex work phase of at least 125% increase.

38. method according to claim 33, wherein, when contacting with blood, the thrombus deposition on the said filter is reduced by at least 10%.

39. method according to claim 33, wherein, said filter has after using 4 hours and is reduced by at least 10% operating pressure.

40. method according to claim 33, wherein, the adverse events that is experienced by said experimenter is reduced.

41. one kind is used to treat the method through the experimenter of undermined cardiac function; Said method comprises the operation that utilizes the oxygenator device to be selected from CABG and cardiac valve replacement; Wherein, said oxygenator device comprises among the claim 5-14 each described encapsulation bundle among each described hollow-fibre membrane or the claim 15-26.

42. according to the described method of claim 41, wherein, at said intra-operative, said experimenter accepts to be less than the anti-coagulants of standard dose.

43. according to the described method of claim 42, wherein, at said intra-operative, said experimenter does not accept anti-coagulants.

44. according to the described method of claim 41, wherein, the adverse events that is experienced by said experimenter is reduced.

Extract blood and blood is turned back to said experimenter from said experimenter 45. a method that is used to treat the experimenter, said method comprise via the described extracorporeal blood loop of claim 1.

46. according to the described method of claim 45, wherein, at said intra-operative, said experimenter accepts to be less than the anti-coagulants of standard dose.

47. according to the described method of claim 46, wherein, at said intra-operative, said experimenter does not accept anti-coagulants.

48. according to the described method of claim 45, wherein, the adverse events that is experienced by said experimenter is reduced.

49. method that is used at blood, blood products or their combination purification of protein; Said method comprises through each described encapsulation bundle among each described hollow-fibre membrane or the claim 15-26 among the claim 5-14, the said blood of dialysing, said blood products or said their combination.

50. a doughnut blood plasma purification film comprises the bundle of the hollow-fibre membrane of each described encapsulation among the claim 15-26.

51. a spinning solution that is used to prepare hollow-fibre membrane, said spinning solution comprises the aprotic solvent of (i) 57% to 87% (w/w); The (ii) base polymer of 10% to 25% (w/w); The (iii) big molecule of the surface modification of 0.005% to 8% (w/w); And the (iv) hydrophily pore-forming agent of 3% to 10% (w/w).

52. according to the described spinning solution of claim 51, wherein, said aprotic solvent is selected from dimethyl formamide, methyl-sulfoxide, dimethylacetylamide, N-methyl pyrrolidone and their mixture.

53. according to the described spinning solution of claim 52, wherein, said aprotic solvent further comprises the low boiling point solvent that is less than 25% (v/v), said low boiling point solvent is selected from oxolane, diethyl ether, MEK, acetone and their mixture.

54. according to the described spinning solution of claim 51, wherein, said hydrophily pore-forming agent is a polyvinylpyrrolidone.

55. according to each described spinning solution among the claim 51-54, wherein, the outer annular mouth of pipe spinning head is expressed in the aqueous solution said spinning solution to form said hollow-fibre membrane from mouth.

56. a method that is used to prepare hollow-fibre membrane may further comprise the steps:

(a) each described homogeneous spinning solution among the preparation claim 51-54; And

(b) the outer annular mouth of pipe spinning head is expressed in the aqueous solution said homogeneous spinning solution to form said hollow-fibre membrane from mouth.

57. a method that encapsulates hollow-fibre membrane may further comprise the steps:

(a) bundle of formation hollow-fibre membrane, the bundle of said hollow-fibre membrane has inner chamber, first group of fiber ends and second group of fiber ends;

(b) said first group of fiber ends and said second group of fiber ends are placed uncured embedding liquid;

(c) solidify said embedding liquid to form sealing resin, wherein be packaged with said hollow-fibre membrane;

(d) said sealing resin of cutting and fiber ends are to form second wall that wherein is packaged with the first wall of said first group of fiber ends and wherein is packaged with said second group of fiber ends; And

(e) said first wall and said second wall are annealed,

Wherein, the said embedding liquid big molecule of surface modification that comprises 0.005% to 10% (w/w).

58. a dialysis kit comprises among (i) claim 5-14 among each described hollow-fibre membrane, the claim 15-26 among each described encapsulation bundle, the claim 27-28 each described blood tubulature among each described dialysis filter and/or the claim 29-32; And (ii) be used for the directions for use that the experimenter to the anti-coagulants of accepting to be less than standard dose dialyses.

59. according to each described hollow-fibre membrane among the claim 5-14; Wherein, the big molecule of said surface modification is selected from VII-a, VIII-a, VIII-b, VIII-c, VIII-d, IX-a, X-a, X-b, XI-a, XI-b, XII-a, XII-b, XIII-a, XIII-b, XIII-c, XIII-d, XIV-a and XIV-b.

60. according to each described encapsulation bundle among the claim 15-26, wherein, said sealing resin comprises the big molecule of the surface modification that is selected from VII-a, VIII-a, IX-a, XI-a, VIII-d and XI-b.

61. according to each described blood tubulature among the claim 29-32, wherein, the big molecule of said surface modification is selected from VII-a, XIV-a and XIV-b.

62. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (I) is described:

F _T-(oligo)-F _T (I)

F wherein _TFor polyfluoro for organic group, and oligo is an oligomeric segment.

63. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (II) is described:

Wherein

(i) F _TFor covalently bound polyfluoro to LinkB for organic group;

(ii) C is the chain termination group;

(iii) Oligo is an oligomeric segment;

(iv) LinkB is the coupling segment; And

(v) a is the integer greater than 0.

64. according to claim 62 or 63 described extracorporeal blood loops, wherein, said oligo is branching or the nonbranched oligomeric segment that is less than 20 repetitives.

65. according to the described extracorporeal blood loop of claim 64; Wherein, said oligomeric segment comprises polyurethane, polyureas, polyamide, polyalkylene oxide, Merlon, polyester, polylactone, silicone, polyether sulfone, polyolefin, polythene derivative, polypeptide, polysaccharide, polysiloxanes, dimethyl silicone polymer, polyethylene-butylene, polyisobutene, polybutadiene, PPOX, PEO, polytetramethylene oxide or gathers ethylidene butylidene segment.

66. according to the described extracorporeal blood loop of claim 62, wherein, the further through type of the big molecule of said surface modification (III) is described:

F _T-[B-(oligo)] _n-B-F _T (III)

Wherein

(i) B comprises urethane;

(ii) oligo comprises PPOX, PEO or polytetramethylene oxide;

(iii) F _TFor polyfluoro for organic group, and

(iv) n is 1 to 10 integer.

67. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (IV) is described:

F _T-[B-A] _n-B-F _T (IV)

Wherein

(i) A is for comprising hydrogenated butadiene polymer, gathering (2; 2-dimethyl-1-3-propyl carbonate), polybutadiene, gather (diethylene glycol) adipate ester, gather (hexa-methylene carbonic ester), gather (ethene-altogether-butylene), neopentyl glycol-phthalic anhydride polyester, diethylene glycol-phthalic anhydride polyester, 1, the soft chain segment of 6-hexylene glycol-phthalic anhydride polyester or bisphenol A ethoxy thing;

(ii) B is the hard segment that comprises urethane;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 1 to 10 integer.

68. according to the described extracorporeal blood loop of claim 67; Wherein, said hard segment is by being selected from 3-isocyanide acyl group methyl, 3,5; 5-3-methyl cyclohexanol based isocyanate, 4; 4 '-methylene two (cyclohexyl isocyanate), 4,4 '-methylene two (phenyl) isocyanates, Toluene-2,4-diisocyanate, 4 vulcabond ,-vulcabond of tetramethylxylene diisocyanate and hexamethylene diisocyanate forms; And n is 1 or 2.

69. extracorporeal blood loop according to claim 1, wherein, big molecule through type of said surface modification (V) or (VI) description:

Wherein

(i) A is a soft chain segment;

(iii) each F _TFor polyfluoro for organic group; And

(iv) n is the integer between 0 to 10.

70. according to the described extracorporeal blood loop of claim 69, wherein, said soft chain segment has 500 to 3,500 daltonian theoretical moleculars.

71. according to the described extracorporeal blood loop of claim 70; Wherein, Said soft chain segment comprises hydrogenated butadiene polymer (HLBH), gathers (2; 2-dimethyl-1-3-propyl carbonate) (PCN), polybutadiene (LBHP), polytetramethylene oxide (PTMO), diethylene glycol-phthalic anhydride polyester (PDP), hydrogenated polyisoprene (HHTPI), gather (hexa-methylene carbonic ester), gather (2-butyl-2-ethyl-1,3-propyl carbonate) or hydroxy-end capped dimethyl silicone polymer (C22).

72. according to the described extracorporeal blood loop of claim 69; Wherein, Said hard segment forms through making triisocyanate and the glycol reaction that comprises said soft chain segment, and wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer or hexamethylene diisocyanate (HDI) tripolymer.

73. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (VII) is described:

F _T-[B-(Oligo)] _n-B-F _T (VII)

Wherein

(i) Oligo is for comprising PPOX, PEO or polytetramethylene oxide and having the oligomeric segment of 500 to 3,000 daltonian theoretical moleculars;

(ii) B is the hard segment that is formed by uretdione;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 1 to 10 integer.

74. according to the described extracorporeal blood loop of claim 73, wherein, said hard segment is by 3-isocyanide acyl group methyl, 3,5,5-3-methyl cyclohexanol based isocyanate; 4,4 '-methylene two (cyclohexyl isocyanate); 4,4 '-methylene two (phenyl) isocyanates; Toluene-2,4-diisocyanate, 4 vulcabond; Between-tetramethylxylene diisocyanate; And hexamethylene diisocyanate forms; And n is 1 to 3 integer.

75. according to the described extracorporeal blood loop of claim 73, wherein, the big molecule of said surface modification is VII-a.

76. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (VIII) is described:

Wherein

(i) A is the oligomeric segment that comprises PPOX, PEO, polytetramethylene oxide or their mixture, and has 500 to 3,000 daltonian theoretical moleculars;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

77. according to the described extracorporeal blood loop of claim 76; Wherein, Said hard segment forms through the glycol reaction that makes triisocyanate and A, and wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer and hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.

78. according to the described extracorporeal blood loop of claim 76, wherein, the big molecule of said surface modification is VIII-a, VIII-b, VIII-c or VIII-d.

79. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (IX) is described:

F _T-[B-(Oligo)] _n-B-F _T (IX)

Wherein

(i) Oligo is for having the polycarbonate polyol of 500 to 3,000 daltonian theoretical moleculars;

(ii) B is the hard segment that is formed by uretdione;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 1 to 10 integer.

80. according to the described extracorporeal blood loop of claim 79, wherein, said Oligo comprises and gathers (2,2-dimethyl-1-3-propyl carbonate) (PCN) polyalcohol; B is by 3-isocyanide acyl group methyl, 3,5,5-3-methyl cyclohexanol based isocyanate; 4,4 '-methylene two (cyclohexyl isocyanate); 4,4 '-methylene two (phenyl) isocyanates; Toluene-2,4-diisocyanate, 4 vulcabond; Between-tetramethylxylene diisocyanate; And the hard segment of hexamethylene diisocyanate formation; And n is 1,2 or 3.

81. according to the described extracorporeal blood loop of claim 79, wherein, the big molecule of said surface modification of formula (IX) is IX-a.

82. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (X) is described:

Wherein

(i) A is for comprising the oligomeric segment of the polycarbonate polyol with 500 to 3,000 daltonian theoretical moleculars;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

83. 2 described extracorporeal blood loops according to Claim 8, wherein, A comprises and gathers (2,2-dimethyl-1-3-propyl carbonate) (PCN) polyalcohol or gather (hexa-methylene carbonic ester) (PHCN) polyalcohol; The hard segment of B for forming through the glycol reaction that makes triisocyanate and A, wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer and hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.

84. 2 described extracorporeal blood loops according to Claim 8, wherein, the big molecule of said surface modification is X-a or X-b.

85. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (XI) is described:

Wherein

(i) A comprises first block segments that is selected from PPOX, PEO, polytetramethylene oxide or their mixture; And second block segments that comprises polysiloxanes or dimethyl silicone polymer; Wherein A has 1,000 to 5,000 daltonian theoretical molecular;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

86. 5 described extracorporeal blood loops according to Claim 8, wherein, A comprises PPOX and dimethyl silicone polymer; The hard segment of B for forming through the glycol reaction that makes triisocyanate and A, wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer and hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.

87. 5 described extracorporeal blood loops according to Claim 8, wherein, the big molecule of said surface modification is XI-a or XI-b.

88. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (XII) is described:

F _T-[B-A] _n-B-F _T (XII)

Wherein

(i) A is for to be selected from the soft chain segment of hydrogenated butadiene polymer (HLBH) glycol, polybutadiene (LBHP) glycol, hydrogenated polyisoprene (HHTPI) glycol and polystyrene and to have 750 to 3,500 daltonian theoretical moleculars;

(ii) B is the hard segment that is formed by uretdione;

(ii) F _TFor polyfluoro for organic group; And

(ii) n is 1 to 10 integer.

89. 8 described extracorporeal blood loops according to Claim 8, wherein, said Oligo comprises the hydrogenated butadiene polymer glycol; B is by 3-isocyanide acyl group methyl, 3,5,5-3-methyl cyclohexanol based isocyanate; 4,4 '-methylene two (cyclohexyl isocyanate); 4,4 '-methylene two (phenyl) isocyanates; Toluene-2,4-diisocyanate, 4 vulcabond; Between-tetramethylxylene diisocyanate; And the hard segment of hexamethylene diisocyanate formation; And n is 1,2 or 3.

90. 8 described extracorporeal blood loops according to Claim 8, wherein, the big molecule of said surface modification is XII-a or XII-b.

91. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (XIII) is described:

Wherein

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

92. according to the described extracorporeal blood loop of claim 91, wherein, A is selected from hydrogenated butadiene polymer (HLBH) glycol and hydrogenated polyisoprene (HHTPI) glycol; The hard segment of B for forming through the glycol reaction that makes triisocyanate and A, wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer and hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.

93. according to the described extracorporeal blood loop of claim 91, wherein, the big molecule of said surface modification is XIII-a, XIII-b, XIII-c or XIII-d.

94. extracorporeal blood loop according to claim 1, wherein, the big molecule through type of said surface modification (XIV) is described:

Wherein

(i) A is for having the polyester of 500 to 3,500 daltonian theoretical moleculars;

(iii) F _TFor polyfluoro for organic group; And

(iv) n is 0 to 10 integer.

95. according to the described extracorporeal blood loop of claim 94, wherein, A is selected from and gathers (diethylene glycol) adipate ester, neopentyl glycol-phthalic anhydride polyester, diethylene glycol-phthalic anhydride polyester and 1,6-hexylene glycol-phthalic anhydride polyester; The hard segment of B for forming through the glycol reaction that makes triisocyanate and A, wherein said triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, IPDI (IPDI) tripolymer and hexamethylene diisocyanate (HDI) tripolymer; And n is 0,1,2 or 3.

96. according to the described extracorporeal blood loop of claim 94, wherein, the big molecule of said surface modification is XIV-a or XIV-b.

97. according to each described extracorporeal blood loop among the claim 62-94, wherein, F _TFor having 100-1, the theoretical molecular between the 500Da gather fluoro-alkyl.

98. according to each described extracorporeal blood loop among the claim 62-94, wherein, F _TBe selected from by general formula CF ₃(CF ₂) _rCH ₂CH ₂-wherein r is 2-20, and CF ₃(CF ₂) _s(CH ₂CH ₂O) _χWherein χ is that 1-10 and s are the group of the group composition of 1-20.

99. according to each described extracorporeal blood loop among the claim 62-94, wherein, F _TBe selected from by general formula CH _mF _(3-m)(CF ₂) _rCH ₂CH ₂-and CH _mF _(3-m)(CF ₂) _s(CH ₂CH ₂O) _χ-the group formed of group, wherein

M is 0,1,2 or 3;

χ is the integer between the 1-10;

R is the integer between the 2-20; And

S is the integer between the 1-20.

100. according to each described extracorporeal blood loop among the claim 62-94, wherein, F _TBe selected from 1H, 1H, 2H, 2H-perfluor-1-decyl alcohol, 1H, 1H, 2H, 2H-perfluor-1-octanol, 1H, 1H, 5H-perfluor-1-amylalcohol and 1H, 1H-perfluor-1-butanols and their mixture.

101. according to each described extracorporeal blood loop among the claim 62-94, wherein, F _TBe selected from (CF ₃) (CF ₂) ₅CH ₂CH ₂O-, (CF ₃) (CF ₂) ₇CH ₂CH ₂O-, (CF ₃) (CF ₂) ₅CH ₂CH ₂O-, CHF ₂(CF ₂) ₃CH ₂O-and (CF ₃) (CF ₂) ₂CH ₂O-.

102. according to each described extracorporeal blood loop among the claim 62-94, wherein, the big molecule of said surface modification has less than 10,000 daltonian theoretical moleculars.

103. according to any one described extracorporeal blood loop among the claim 62-94; Wherein, the big molecule of said surface modification comprise 5% to 40% (w/w) the said polyfluoro of said soft chain segment and 5% to 50% (w/w) of said hard segment, 20% to 90% (w/w) for organic group.

104. according to each described extracorporeal blood loop among the claim 62-94, wherein, the big molecule of said surface modification has 0.15 to 2.0 the hard segment and the ratio of soft chain segment.