Overview of PES BiocompatibleHemodialysis Membranes PES–Blood Interactions and Modiﬁcation...

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Review

Overview of PES biocompatible/hemodialysis membranes: PESbloodinteractions and modication techniques

Muhammad Irfan, Ani Idris

Department of Bioprocess Engineering, Faculty of Chemical Engineering, c/o Institute of Bioproduct Development, Universiti Teknologi Malaysia, 81300 UTM Skudai, Johor, Malaysia

a b s t r a c ta r t i c l e i n f o

Article history:

Received 20 December 2014

Received in revised form 19 May 2015Accepted 15 June 2015

Available online 19 June 2015

Keywords:

PES

Additives

Biocompatibility

Coagulation

HemodialysisHydrophilic brushes

Polyethersulfone (PES) based membranes are used for dialysis, but exposure to blood can result in numerous

interactions between the blood elementsand the membrane. Adsorption and transformation of plasma proteins,

activation of blood cells, adherence of platelets and thrombosis reactions against PES membrane can invokesevere blood reactions causing the increase rate of mortality and morbidity of hemodialysis (HD) patients. In

order to minimize blood immune response, different biomimetic, zwitterionic, non-ionic, anticoagulant

molecules and hydrophilic brushes were immobilized or blended with PES polymers. These additives modiedthe nature of the membrane, enhanced their biocompatibility and also increased the uremic waste dialysisproperties. In this review, current perspectives of the different additives which are usedwith PES are highlighted

in relation with PES membrane-associated blood reactions. The additive's purpose, compatibility, preparationtechniques, methods of addition to polymer and inuence on the chemistry and performance of hemodialysis

membranes are described. 2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5742. PES-associated blood reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5752.1. Thrombogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575

2.1.1. Platelet adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575

2.1.2. Complement activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575

2.1.3. Leukocytes and endotoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5773. Modication techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577

3.1. Chemical modication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581

3.1.1. Albumin immobilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5813.1.2. Anticoagulant immobilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582

3.1.3. PEG/PEO, pluronic and biomimetic zwitterionic-ciliary brushes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5833.1.4. Polyvinyl pyrrolidone amphiphilic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5853.1.5. Vitamin E effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588

3.1.6. Anionic functional groups effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588

3.2. Physical blending . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5883.3. Hydrophilicity and hydrophobicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589

3.4. Biocompatibility, topology, solute and itsux across membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5894. Conclusion and future trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590

1. Introduction

Some of the most commonly used materials to make hollow ber(HF) membranes include polysulfone (PSf), polyethersulfone (PES),polyamide, ethylene vinyl alcohol copolymers, cellulose triacetate,

Materials Science and Engineering C 56 (2015) 574592

Corresponding author at: Department of Bioprocess Engineering, Faculty of ChemicalEngineering, c/o Institute of Bioproduct Development, Universiti Teknologi Malaysia,

81310 Skudai, Johor, Malaysia.

E-mail address:[email protected](A. Idris).

http://dx.doi.org/10.1016/j.msec.2015.06.035

0928-4931/ 2015 Elsevier B.V. All rights reserved.

Contents lists available at ScienceDirect

Materials Science and Engineering C

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m s e c
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polymethylmethacrylate and polyacrylonitrile[1]. The use of unmodi-ed and weakly biocompatible cellulose dialyzer membranes is discour-aged and prevented because they increased the blood coagulationcascade[2]. Consequently, synthetic polymers are used in most of thedialyzer membranes, 93% of which are derived from the parentpolyarylsulfone family, with 22% produced from PES and 71% from PSF[3]. Each polymericmembranehas its own advantagesor disadvantagesand complications may arise, when the membranes are judged only by

their polymer names. Due to the varying membrane compositions,membranes with the same polymer names may differ in their adsorp-tion, ux properties and hemocompatibilitycharacteristics. Membranesin the new super high-ux dialyzers are primarily PSf and PES andfuture trends to use PES as main hemodialyzer materials are increasingbecause PES has an equivalent property to that of polysulfone (PS) but itis considered as a bisphenol-A free membrane[4,5].

PES is a high performance amorphous transparent thermoplastic ofrelatively low ammability, water sorption and dielectric loss. Its highglass transition temperatureof 230 C makes the polymer chemical resis-tant. A wide range of medical devices, articial organs, blood puricationequipments such as hemodialysis, hemodialtration, hemoltration,plasmapheresis and plasma collectors are generally equipped with PESmembranes[68].

When PES-based HD membranes were contacted with blood,proteins tend to adsorb onto the polymer surface, and this proteinlayer causes any adverse effects such as the coagulation of blood cellsand platelet adhesion. A series of factors were involved for protein ad-sorption in PES membrane including the surface chemistry, surfacecharge, pH value, morphology, hydrophilicity and operating conditions,adsorbed protein size and shape. Plasma proteins such as albumins,globulins, and brinogen in blood play key roles in coagulation andinvoke the immune system against PES surface[9,10].

Blood contact membranes experienced a gradual decline in mem-brane selectivity and ux with the passage of time, a phenomenonknown as membrane fouling. Membrane fouling is mainly caused byprotein fouling on the membrane surface irrespective of the membranematerial. Protein deposition/adsorption occurred very rapidly on themembrane surface simultaneously blocking the membrane pores just

within seconds or minutes upon contacting with blood thus affectingmembrane performance and decreases its biocompatibility. Besidesexperiencing a reduction in ux and selectivity, protein adsorptioncan trigger a series of other reactions such as activation of the coagula-tion cascade, adhesion of red blood cells, complement andbrinolysisreactions which further reduced biocompatibility of membranes [1,1113].

Some ndings disclosed that the protein adsorption occurred withinthe membrane pore as well as at the surface of the membrane. Therewas evidence that demonstrated large pore size tends to cause moresevere membrane fouling. Findings apparently revealed that thereseems to be an optimum pore size; when the pore size was below theoptimum value permeate ow was affected by membrane resistance.However, severe membrane fouling tends to occur at values above the

optimum pore size, which decreased the ux[14,15]. In order to fullyunderstand the progress and consequences of bloodpolymer interac-tion, some of the important blood related factors are briey discussed.

2. PES-associated blood reaction

Blood under normal physiological conditions when comes intocontact with endothelium does not clot due to its antithrombotic andanticoagulant properties. PES hemodialysis membrane does not haveany endothelium function so it symbolizes the introduction of a foreignsurface which triggers a multifacet series of events of adsorption andactivation of blood proteins, platelets, leukocytes and thrombus forma-tion resulting in the brin matrix. These events are highly interlinked(Fig. 1) and are inuenced by the surface properties of the materials,

ow conditions and the initial contact between blood-material [16].

Such reactions altered the surface of PES membrane and the modiedsurface determined the future course of reactions.

2.1. Thrombogenesis

Blood coagulation processes limited the application of PES mem-brane. There are two possible pathways to activate the coagulationprocess: a) extrinsic, activated by an injury, and b) intrinsic initiated

when blood contacts with foreign surface. Both pathways combine atthe common point where thebrin clots are formed [16]. The thrombinactivated the factor XIII (brin stabilizing factor), crosslinked andstabilized the brin clot into an insoluble brin gel. In each step anenzyme factor zymogene (inactive form) change into an active onewhich stimulates the next zymogene activation[17,18]. Initiation ofclotting by cells occurred either through surface-mediated reactions,or through tissue factor expression. The whole process is complex andconsists of interconnected steps; hence it is known as a blood coagula-tion cascade which is briey explained inFig. 2. Thus, when bloodcomes into contact with the hemodialysis membrane, thrombusreaction starts and resulting clots tend to adhere to the membranesurface and disrupt the blood circulation[18].

2.1.1. Platelet adhesion

The average platelet concentration in human blood is200 106 cells/mL and reacts to least stimulation and become activatedand form platelet plugs upon contact with any injured endotheliumsurfaces or thrombogenic polymer. Any extracellular interaction withthe platelet membrane starts the coupling of specic receptors, whichis the main cause of their activation[22]. Major platelet activators arederived from inammatory cells, which are brinogen, thrombin andvascular wall products.

A signicant feature in platelet adsorption is the shear stress, whichresulted in the conformational change thatstarted it activation and adhe-sionactivity. Low-afnity bindingsites arepresent in inactiveplatelets foradsorbed brinogen, but after platelet activation, conformational changecauses the introduction of high-afnity binding sites for solublebrino-gen. These sites are developed via cross-linking of two different platelets

bybrinogen which results in brinogen to platelet and plateletleuko-cyte aggregation[23,24].

When the protein was adsorbed on the articial surface, plateletswill either adhere or bounce offdepending on the chemistry of thelegends and state of activation of the interface. The induced plateletactivation of material is activated by the intrinsic coagulation cascadeand the release of ADP from platelets or damaged red blood cells. Onthe other hand, the failure of thrombin and kallikrein inhibitors todecrease platelet activation recommends that platelet activation is atleast in part mediated by other agonists. High complement reactionsand leukocyte activation also cause the platelet adhesion[2527].

Pristine PES membrane initiated the platelet adsorption on thesurface, thus Yin et al.[28]blended poly(vinylpyrrolidoneacryloni-trilevinylpyrrolidone) (P(VPANVP)) triblock with PES and reduced

the platelet adhesion from 100% to 0.5%. The successful reductionmight be attributed to the increased hydrophilicity and anioniccharacter of additive. Tang et al. [29] used the anionic charactercontributed by poly(acrylonitrileco-vinylpyrrolidoneco-acrylic acid(P(ANco-VPco-AA)) to decrease the platelet adsorption from 142 to30 (1 104 cells/cm2) with SPES and PES membranes respectively. Liuet al. [30] blended PES membrane with poly(vinylpyrrolidoneco-acrylic acid) (P(VPco-AA)) with grafted BSA and Nie et al. [31]used poly(styreneco-acrylic acid)b-poly(vinyl pyrrolidone)b-poly(styreneco-acrylic acid) (P(Stco-AA)b-PVPb-P(Stco-AA))additive to minimize the platelet adsorption as illustrated in Fig. 3.

2.1.2. Complement activation

Complement activations are the inammatory responses, started by

localized inammatory mediator which prompt the host defense

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system and could be quantied by the production of anaphylatoxinsC5a, C4a and C3a [33]. The constituents of a complement system consistof a number of plasma proteins that act either as binding proteins orenzymes. Formation of the C3 convertase is catalyzed by an initialenzyme which produces the C5 convertase permitting the gathering ofthe terminal complement complex[34]. These binding proteins act asmessengers that fasten on neutrophils, macrophages, monocytes, mastcells and smooth muscle cells by specic receptors. Chemotaxis,

vasodilatation, cell activation and cell adhesion like cellular responsesare inuenced by their activities[35].

Tanget al. [33] developed PES membrane withsulfonated polyether-sulfone (SPES) and poly(acrylonitrileacrylic acidvinyl pyrrolidone)(P(ANAAVP)) triblock and provided thecomplement reaction studiesfor C3a and C5a. They developed heparin like structures by creatingnegative charges in the membrane matrix which ultimately reducedthe activation of C3a and C5a to 4% and 37.5% respectively with

Fig. 1.Overview of blood and polymer interaction which results in brin matrix.

Fig. 2. Coagulation cascade model of thrombogenesis. For the sake of clarity, Ca++ and phospholipids have been omitted from the gure. These two cofactors are necessary for all of thereactions listed in thegurethatresultin theactivation of prothrombin (MW= 72,000 Da)to thrombin. Thepathway is initiated by an extrinsic mechanism thatgenerates small amounts

of factor Xa (MW = 58,900 Da), which in turn activate small amounts of thrombin. The tissue factor/factor VIIa (MW = 50,000 Da) proteolysis of factor X is quickly inhibited by tissue

factor pathway inhibitor. The small amounts of thrombin generated from the initial activation feedback to create activated cofactors (proteins, help the blood to clot), factors Va(MW = 330,000 Da) and VIIIa (MW = 330,000 Da), which in turn help to g enerate more thrombin. Tissue factor/factor VIIa (MW = 50,000 Da) is also capable of indirectly activating

factorX throughthe activation of factorIX (MW= 55,000 Da)to factor IXa.Finally, as morethrombinis created,it activates factorXI (MW= 160,000Da) to factorXIa, therebyenhancing

the ability to ultimately make more thrombin [19

21].

576 M. Irfan, A. Idris / Materials Science and Engineering C 56 (2015) 574592


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P(ANAAVP) and 19.23% and 40.62% respectively with SPES as com-pared to pristine membrane (Fig. 4). The lowering of activation of com-plement reactions was due to the high percentage of sulfonic groupsintroduced into the membrane surface which inhibited formation ofthe classical and alternative pathway C3 convertase.

Similarly, Nie et al.[36]blended SPES and carboxylic polyethersul-fone (CPES with PES polymer and studied the complement activationon C3a and C5a levels. His results also supported that increment in an-ionic character in resultant membrane decreased the complement acti-vation, as the C3a concentrations decreased from 42.5 to 34 ng/mLcompared with that of the pristine PES membrane.

2.1.3. Leukocytes and endotoxin

Circulating leukocytes include monocytes, lymphocytes, neutro-phils, basophils and eosinophils. The most abundant white bloodcells are neutrophils, which symbolize 40 to 60% of the leukocyte(35 106 neutrophils/mL), whereas monocytes represent 5%(0.21 106 monocytes/mL). The half life of neutrophils in bloodis about 820 h but the inammatory stimulus, such as lipo-polysaccharides or cytokines increased their existence up to three-

times[37]. In vitro platelet release, b-thromboglobulin activates theneutrophils which activate the inammatory mediators that mayincrease the adhesion to endothelial cells, chemo attraction for leuko-cytes, an additional activation of leukocytes or platelets [38] andoxidization of monocytes and neutrophils to release oxidants, likeoxides and hydrogen peroxides which can harm tissues and activatecells[3840]. The leukocyte activation through PES polymer increasedthe adhesive capacity on endothelium and other surfaces, releasedtheir array of proteolytic enzymes and potent oxygen metabolites

which ultimately alarmed the whole blood immune system againstexternal surface, thus contributed to localized thrombogenesis [4143].

Other enemy in vitro and in vivo studies of bloodpolymer interac-tions are endotoxins.

Endotoxins activate leukocytes, kinin and complement system,endothelial and the platelet cells. In vitro endotoxins may be harmfuland a person may experience nauseating, shivering, fever, hypotensionand shock due to septic reactions[44,45].

3. Modication techniques

The biocompatibility of pristine PES membrane can be improved bydifferent modication methods. PES can be modied using: (1) bulkmodication; (2) surface modication; and (3) blending (some timealso considered as a bulk modication). Bulk modication methodsare applied to the dope solution level, which modied the entire mem-brane. Sulfonationand carboxylation methods were mostly reported forbulk modication[30].

Pinnau and Freeman [46] summarized some modicationtechniques of membranes that produced more hydrophilic surfaces

which involved chemical treatment (uorination, cross linking, pyroly-sis), surface coating, annealing with solvent and heat treatments. Surfacealteration routes include (1) graft polymerization where hydrophilicmolecules were chemically attached, (2) physical pre-adsorption ofhydrophilic components and (3) plasma treatment which introducedspecic structural groups to the polymer membrane surface.

Others reported physical methods include surface-coating[6,46,47]using chemical methods such as photo-induced grafting [30,47],gamma rays[48,49], electron beam grafting induced by electron beam

Fig. 3.Reduction of platelet adhesion[32].

Fig. 4.Complement activation values; C3a and C5a (ng/mL) of the various formulated membranes [33].



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Table 1

A comparison of properties between BSA grafted/layered membranes with non-grafted membranes.

Name of additive Method of

preparation

wt.% of

additives

UF rate

(mL/m2 mm

Hg) 4

Contact

angle (),

3

Rejection

rate (%), 4

(BSA)

Protein absorption Platelet adhesion

P(VPco-AA) FRSP 1, 2, 4 69 to 49 BSA was 7.5 to 3.4g/cm2 and Fbg was 4.8 to 3

g/cm2 decreased.

The adsorption amount

reduced was 18 to 6

(1 104 cells/cm2).

P(VPco-AA) + BSA

grafting

FRSP + NHS &

EDC for BSA

grafting

69 t o 32 Protein adsorption of BSA was 7 .5 t o 1 .2g/cm2 and

Fbg was 4.8 to 1.2g/cm2 decreased.


reduced was 18 to 1(1 104

cells/cm2).

P(ANco-AA) FRSP 0.2, 0.4,

0.6

0 to 3.79

0.07

74 to 60 100 BSA reduced from 18 to 8 and Fbg 10 to 8.5g/cm2 Reduced adhesion showed

by SEM pictures.

P(ANco-AA) +

BSA grafting

FRSP + NHS &

EDC for BSAgrafting

0 to 95.6

1.9

74 to 44 99.2 BSA absorption decreased from 18 to 0.5 and Fbg 10.5

to 2.5g/cm2

SEM picture showed

reduced adhesion.

P(ANco-VPco-AA) FRSP 0.8, 1.6 72 to 39 BSA was 18 to 0.5g/cm2 and Fbg was 18 to 3 g/cm2

decreased.

P(ANco-VPco-AA)

+ BSA grafting

FRSP + BSA

grafting

0.6,0.8,

1.6

72 to 23 The results were same after BSA grafting. Adsorption

of BSA was 18 to 0.5g/cm2 and Fbg was 18 to 3

g/cm2 decreased.

Albuminheparin Layer by layer

assembly

0.1, 0.2,

1.06, 1.2

Others tests;

Platelet adhesion: Number of platelets on polyethersulfone, albumin, albuminheparin

blood was 105, 103, 101 and 0 mm2 respectively.

Activation of platelet factor 4: Activation of platelets on polyethersulfone, albumin, alb

was 3500, 1800, 1400 and 1600L/mL respectively.Number of leukocytes: The adhesion of leukocytes on PES, BSA, HEP and END was 120

Activation of TAT: Activation of TAT on PES, BSA, albumin heparin and albuminendu

respectively.


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Table 2

Raft and FRSP preparation based additive and their effect on membranes performance.

Name of additive Method of preparation

wt.% ofadditives

UF rate(mL/m2

mm Hg)

4

Contact angle(), 3

Rejectionrate (%),

4 (BSA)

Proteinabsorption

Platelet adhesion Clott(PT,

P(VPco-ANco-VP) Raft 1, 2, 3, 4 27 to 42 71.5 to 53.7 82.4 to

97.5

BSA adsorption and Fbg

decreased 58% and 60%

respectively.

Adhesion amount was

reduced from 100%

to 0.5%.

The

activ

to 70

show

P(ANco-AAco-VP) FRSP 14 to 16 72 to 60 The adsorption amount

of BSA and Fbg reducedfrom 24 to 13.5 and 19

to 11g/cm2 respectively.

APTT

32 toand

was

P(Stco-AA)b-PVPb-P(Stco-AA)) Raft 1, 3, 5 23.6 to

86.2

77.5 to 60.7 60.6 to

77.5a

(PEG

10,000)


of BSA and Fbg reduced

from 26 to 5 and 17

to 7 g/cm2 respectively.

As compared to

control,

adsorption decreased

7% which was 27%

high than pristine

membrane.

The

from

gene

P(PVPb-PMMAb-PVP) Raft 5 74.3 to 60.1 APTT

52 to

P(PVPb-PMMAb-PVP) Raft 1, 3, 5 25 to 95 73 to 59 Protein adsorption of BSA

reduced up to 48% from19 to 10g/cm2.

APTT

55to 95

activ

P(ANco-AAco-VP) FRSP 0.8, 1.6 72.3 to 53 BSA reduced up to 75%

from 12 to 3 g/cm2.

PVP having 12.1 10,000 to

0.8 10,000 mol wt.

Raft After 5 s) 6876

(After 30 s) 6854

BSA adhesion reduced 88%. Decreased from 17.5

to 1

Platelet numbers

(107 cells/cm2)

APTT

38 to

PVP (12.1 10,000 mol wt.) RAFT (After 5 s)

7383 (After 30 s)6662

90% reduction in BSA

adhesion than pristinemembrane.

Decreased from 17.5

to 0.2platelet numbers

(107 cells/cm2)

APTT

35 to

PVPPES RAFT 1.11, 2.97, 4.50,6.29, 8.12 and

9.47.

96% reduction inplatelet

adsorption.

APTT93 s.

a For rejection PEG 10 K solution was used instead of BSA solution.


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[50], plasma induced grafting and plasma treatment [51,52], thermalinduced immobilization and grafting[30,53], and surface-initiated-atom-transfer-radical polymerization[5457]. With these modicationmethods several novel polymerization methods were developed, likereversible addition fragmentation chain transfer (RAFT) polymeriza-tion, free radical solution polymerization (FRSP) and click chemistrymethods.

Generally bio-compatibility can be enhanced using different modesof modication.Some researchers developed differentblocks of additivewhile others modied polymers which behaved differently whencontacted with blood. The blocks of additive developed were thenblended with the polymer or modied polymer to form the formulatedpolymer solution which was then cast to membranes and ready for use.In some cases, the membrane surfaces were coated with a layer of BSAand heparin like anticoagulants that ultimately improved the mem-brane performance[5861].

Tables 1, 2 and 3illustrate the effects of some additives used in PESmembrane to improve biocompatibility specically protein adsorption,platelet adhesion and blood clotting times. The preparation method ofadditives, their performance with membranes and some of the bioassayresults weresummarizedin thesetables. Columns 1,2and3 representthe name, preparation techniques, and wt.% of additives addedrespectively that areused in theformulations withPES membrane.Mean-while,columns 4,5,6and7 specify theUF rate(mL/m2mm Hg), contact

angle (), rejection rate percentage with BSA (otherwise mention) andprotein adsorption respectively, where the rst value corresponds to theabsence of additive (additive = 0) and the second value to maximumeffect of additives on the membrane performance. Columns 7, 8 and 9exhibit the various bioassay results of the PES based membranes.

There was evidence that when brinogen and/or beta-globulin fromthe blood were adsorbed onto the membrane material, platelet adhe-sion was promoted. Thus, it is important to minimize the adsorptionrate of blood protein when fabricating a hemocompatible membrane[62]. In order to reduce protein adsorption on the PES hemodialysismembrane, different techniques such as grafting/blending of biomimet-ic, zwitterionic, anionic or neutral, hydrophilic brushes anticoagulantmolecules and BSA grafting were used and experimented. In thefollowing sections these techniques are described in term of chemicalmodication and physical blending in detail.

3.1. Chemical modication

3.1.1. Albumin immobilization

Bovine serum albumin (BSA) is an ellipsoidal-shape naturalbio-polymeric material with dimensions of (4.16 4.16 14.09) nmand a diameter of 7.28 nm. BSA has low mechanical strength and issoluble in water and non-organic solvents[63].

Ulbricht and Riedel[61]reported the use of heterogeneous photoinitiated grafting polymerization to decrease the protein fouling. Byimmobilizing BSA to the PSF and PES membrane, acrylic acid wascovalently grafted onto the outer membrane surfaces that improvedthe protein resistance. Steffens et al. [64]grafted poly(D,L-lactide) toexamine the covalent binding and absorptive of proteins with

poly(acrylic acid). Their experimental ndings revealed that thealteration of internal areas of the HF of PES was not an easy task dueto their very small diameter via UV radiation. Furthermore, the photo-chemical technique may lead to adverse effects on the moleculararrangement of the membrane surface.

Fig. 5.BSA grafting scheme with modied PES membranes.

Fig. 6.Some important anticoagulant structures.



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Liu et al.[65]fabricated their membranes by synthesizing a copoly-mer ofP(AAVP)and then blending it with PESpolymer. ThecopolymerP(AAVP) was known to be water-soluble and tend to elute from theresulting membrane. In order to prevent elution, the membrane surfacewas then grafted with BSA by using N-hydroxysuccinimide andcarbodiimide as initiator and catalyst respectively, for coupling ofprotein (amino groups) and carboxyl groups as shown in Fig. 5. Thebiocompatibility of the modied membranes was found to improve

signi

cantly.In order to reduce leaching process of P(AAVP) from PES [65], Fanget al. [66] used acronitrile (AN) insteadof acrylic acid (AA) andmodiedPES by blending it with a copolymer of P(ANVP). Similarly BSA wasgrafted onto the resulting membrane and its amount was directlyrelated with copolymer. The grafting yield of BSA was quite high(26.3 to 30.9 3 g/cm2) which was nearly two times larger thanP(AAVP) copolymers [65]. In the PES/P(ANAA) membrane,biocompatibility and the water ux were improved, but there was noprominent effect on the mechanical properties,lm-formingcapabilities,and thermal and hydrolytic stabilities.

In another study, Fang et al. [67]manufactured (P(ANVPAA))terpolymer by free radical copolymerization, blended with PES andfollowed by BSA grafting onto the membrane surface as listed inTable 1. Compared to other binary copolymers such as P(AAVP)[65]and P(ANAA)[5],the blending of the terpolymers with PES increasedthe grafting amounts of BSA from 31 to 49 2 g/cm2. Due to thishigh grafting amount of BSA the antithrombogenicity propertiessuch as PT, APTT and the cytocompatibility of the membranesincreased.

Yang et al.[63]explained that some pores of PES membrane wereblocked when BSA was used without PVP additive and a layer of cakeformation developed in some parts of the membrane. However, thepresence of PVP additive minimized the pore blockage on the surfaceof the modied membrane. Wolff and Zydney [68] found that thepresence of negatively charged COO and PVP groups promoted theanti-foulingbehavior ontothe membrane surfaces which were attributedto the electrostatic force of repulsion between BSA and COO (at bloodpH 7). Table 1provides comparison between BSA grafted/layered

membranes with non-grafted membranes on the enhancement ofbiocompatible properties of the membrane.

In summary, albumin immobilization can improve the protein resis-tance, biocompatibility, and waterux of membrane without affectingits mechanical properties. In fact the antithrombogenicity properties

such as PT, APTT and the cytocompatibility of the membranes werealso improved.

3.1.2. Anticoagulant immobilization

Blood plasma is an extremely complex protein containing samplethat can be altered in vivo and vitro by many biological pathways. Toovercome this problem, blood plasma itself contains many proteaseinhibitors such as a1-protease (protects tissues from enzymes'destructive action), 2-macroglobulin (inhibitor of brinolysis andcoagulation), heparin cofactor II (is a coagulation factor that inhibitsthrombin for its activity) and antithrombin III. Among these inhibitorsantithrombin III neutralized the target enzymes. In order to minimizethe thrombus reaction, anticoagulant (heparin or warfarin) is ofteninjected into the patient during dialysis. There are certain proteinsnamed as cofactorswhich help the blood to clot and the creation ofthese cofactors is controlled by vitamin K. Warfarin averts the correctworking of vitamin K whereas heparin prevents the functioning ofcofactors, namelybrin and thrombin[1821,62,69].

Biological functions of proteins (FVII (proconvertin), FIX (Christ-mas factor), FX (Stuart factor) and prothrombin which are vitaminK-dependent coagulation factors are easily degraded by Warfarin.Clopidogrel marketed under the trade name Plavix is used together

with Aspirin as an antiplatelet agent. Antistatin and thick anticoagu-lant peptide are other anticoagulants that can attach to FXa evenwithin the prothrombinase complex. Another effective inhibitors ofthrombin are Hirudin (leech-derived protein) and D-Phe-Pro-ArgCH2Cl (or PPACK). Both hirudin and PPACK were capable ofinactivating surface-bound thrombin and brin-bound via interactingwith its active sites[69].

Fig. 6 shows the structure of some important anticoagulants in whichheparin is a linear polymer consisting of repeated units of 1 4-linkedpyranosyluronic acid and 2-amino-2-deoxyglucopyranose (glucos-amine) residues. Due to the highest negative charge density and thepresence of the specic functional groups, heparin is extensivelyemployed as an injectable anticoagulant. The presence of uronic acidunits which normally contain 10% D-glucopyranosyluronic acid and 90%

L-idopyranosyluronic acid contributed to the highest negative chargedensity property. The typical heparin disaccharide contains 2.7 sulfategroups.

The existence of naturally occurring heparin sulfate or the polysac-charide heparin (on the endothelium) in PES membranes can relatively

Fig. 7.Citric acid grafted polyurethane with E G, PEG and BDO[73].



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slow down complex formation and increase clotting inhibition rates.The blood compatibility of polymeric materials was found to improvein a number of studies involving heparin-immobilization membranes.Generally, polymeric materials can be easily heparinized if theycontained functional groups of amines and carboxylic acids [60,70].

Sperling et al. [70] prepared PES polymer with a multilayer assemblyof albumin and heparin. Unmodied as well as modied PES surfaceswere tested using an in vitro assay with human whole blood.Albumin-heparinized coatings effectively reduced: i) the number ofplatelet adhesion from 105 mm2 to 10 mm2, ii) leukocyte accumulationfrom 120 mm2 to10mm2, iii) TATcomplex formationfrom 2500 g/L to2100 g/L and iv) complement activation of C5a, C5b and C3c. Thealbumin and heparin coatings on the membrane surface combined thebenets of albumin (lessening of non-specic interactions thatdecreased the intermolecular connections between blood protein andmembrane surface) and heparin (specic interactions). In the specicinteractions of protein and heparin, the negatively charged sulfo groups

on heparin tended to align with blood protein molecules electrostaticallyand maintained the blood protein conformation and its molecularsequences which ultimately increased the antithrombin properties ofthe blood[71].

Another anticoagulant citrate dextrose solution was utilized toprotect blood specimens for tissue typing and sometimes replaced the

heparin during the plasmapheresis procedure. Citrate in the form ofacid citrate dextrose and sodium citrate binds with calcium ions in theblood averts the clotting in clinical treatment and disrupts the coagula-tion cascade[33,72].

Li et al.[73]via solution polymerization method grafted citric acidonto polyurethane and blended with PES polymer. Three types of poly-urethanes (PUs) are synthesized by reacting 4,4-diphenylmethanediisocyanate with ethylene glycol (EG), 1,4-butanediol (BDO) and PEGas depicted inFig. 7and they are characterized by FTIR, NMR, GPC andXPS. Experimental results showed that the UF rate increased from 40to 160 mL1 m2mm Hg1 with prolonged APTT time from 46 to56 s, reduced the accumulation of Ca2+ (10 to 5 ppm) ions and plateletadhesions on the modied PES membranes.

In short, by using different anticoagulent based dialyzers bloodcompatibility was improved, the formation ofbrin and thrombin wasminimized, the clotting inhibition rates were increased, and lesser plate-let adhesions and reduced calcium ion accumulations were observed.

3.1.3. PEG/PEO, pluronic and biomimetic zwitterionic-ciliary brushes

Polyethylene oxide (PEO) formed hydrophilic brushes on the hydro-phobic PES surface and acted like molecular cilia and exhibited stericrepulsion that contributed to the extraordinary ability to resist proteinadsorption and cell adhesion in an aqueous medium[7476]. Chain

Fig. 8. Diagrammatic representation of a) hydrogeland b) cilia type brush developmentat PES membrane surface. The hydrogelconsists of crosslinkedwaterswellablePEG or PEO chains.

Fig. 9.Structure of SMA

g-MPEG, mPEG

PU

mPEG and CA

PU

CA compounds.



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length and surface density of PEO brushes controlled the proteinresistance ability. The movement of the PEO brushes promotes themicro-ow of water and thus prevents protein adsorption on themembrane surface. Generally, long chain, terminally attached PEO andits high surface density on the membrane surface exhibited optimalprotein resistance[77]. Most favorable types of polymer brushes wereobtained by using (1) chemical grafting and (2) permanent adsorptionof copolymer chains containing di- or triblock. The irreversible adsorp-

tionof these amphiphilic copolymers on the solid surface hasthe poten-tial to reduce protein adsorption. In diblock or triblock copolymers PEObrushes can be used and some hydrophobic component can be addedusing LangmuirBlodgett technique; such as polypropylene oxide insolution. The hydrophobic part of PEO copolymer was rst adsorbedonto the surface of the polymer while the hydrophilic portionfunctioned as a barricade to protein adsorption[78,79].Fig. 8a and brepresents the polymer hydrogel and the polymer brushes at PESsurface respectively. Thus, the steric repulsion effect of the polymerwhich prevented the protein from reaching the membrane surfacewas attributed by the resistance of PEO chains to the adsorption ofproteins[79].

According to Zhu et al. the adsorption of protein on the membranesurface was correlated to the equilibrium between Van der Waalsforce and steric repulsion. The elastic and osmotic components of stericrepulsion of PEO surface becomeefcient when protein compressed thePEO layer. Subsequently, the steric repulsion can be controlled by thedensity and length of PEO chains[80,81].

PEO's inertness is very much related to its minimum interfacial freeenergy with water. When protein molecules approached the PEOsurface in water, the rapidly moving hydrated PEO chains with largelyexcluded volume repelled them[70].The fundamentals of minimalinterfacial free-energy hypothesized that as the interfacial free energyapproaches zero, the driving force for protein adsorption minimizes.Therefore, the possibility of adsorption for non-specic proteins arereduced, and the proteins close to the low interfacial energy interfacewill only experience minor effects from the surface similar to thatfrom the bulk solution[82].

Theuse of PEG for biomedical applications has been investigated ex-

tensively because it is known to reduce platelet adhesion and proteinadsorption when immobilized onto membrane surfaces[8385]. PEGis highly hydrophilic, and its evolution from the resulting PES mem-brane is inevitable when blended alone,whichis the commonoccurringphenomena for most hydrophilic additives. This problem was resolvedby using PEG amphiphilic copolymers where its hydrophobic partacted as anchor in the PES membrane and inhibits the hydrophilic(PEG) branches from being eluted[72,86].

Wang et al. [72]used variable chain lengths of PEO, synthesizedamphiphilic pluronic polymers and blended them with PES so as toimprove fouling-resistant ability of membranes. Results revealed thatthe chain length of PEO or percentage of pluronic content improved thefouling-resistant properties signicantly with excellent ux recovery.

Zhu et al . [86] prepared copolymer which composed ofmethoxylpoly(ethylene glycol) (mPEG) grafts and poly(styrene-alt-maleic anhydride) (SMA) backbones, and then they were blended into

PES membranes. The comb like orientation of SMA-g-mPEG (Fig. 9)was preserved on the membrane surface and its high molecular weightprevented its elimination from the resulting membrane during washingand operation. Thus the membrane formulation approximatelyremained constant before and after use.

Huang et al.[83]via solution polymerization prepared triblock ofmethoxylpoly(ethylene glycol)polyurethanemethoxylpoly(ethyleneglycol) (mPEGPUmPEG) with mPEG of mol. wt. 500 and 2000 andblended with PESas depicted in Fig. 9. Theadditionof copolymer alteredthe morphology of the membrane, increased the pore size of themembrane and nger like entities slowly vanished. The hydrophilicityand antifouling behavior of membrane improved with reduced plateletadhesion and good anticoagulant performances which were conrmedby prolonged APTT tests (34.5 to 44 1 s).

Currently, most copolymers of PEO are linear, but comb like copoly-mers are more effective as they have regular and dense side chainswhich provide greater steric stabilization, which lead to exceptionalprotein-adsorption-resistance. Moreover, comb copolymers form lessmicelle and tend to oat on the membrane surface which consequentlyreduces the membrane entropy[87,88].

Maet al. [89] prepared comb copolymer using PEG as the hydrophil-ic part and polystyrene as the hydrophobic part and blended them withPES. This copolymer showed amphiphilic effect on the membrane sur-face where its hydrophobic part integrated with PES and a hydrophilicpart segregated onto the surface of the membrane. The resultantmembranes exhibited a reduction in protein adsorption from 6.8 to0.5 g/cm2 due to PEG enriched surface that was hydrophilic. UF exper-iments demonstrated that its antifouling property greatly enhancedwith decreased irreversible fouling resistance from 2.70 1012 to

0.34 1012 m1 while maintaining 80.4% ratio ofux recovery afterthree repeated testing with BSA solutions.

The protein adsorption for synthetic polymeric membranes canalso be reduced by additives such as biological and zwitterionicmolecules; where phosphorylcholine (PC), deoxyribonucleic acid(DNA) and polybetaine are more important[9092]. The main groupof sphingomyelin and phosphatidylcholinebelong is PC; which iscomposed of the ectoderm part of intact blood cells. Ueda et al. [93]

Fig. 10.The chemical structures of biomimetic and zwitterionic molecules.



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manufactured methacryloyloxyethylphosphorylcholine (MPC)which has a zwitterionic PC head group due to methacrylatederivative as depicted inFig. 10a. The copolymers of long-chainalkyl methacrylates and MPC can closely copy the congurationof dipalmitoylphosphatidylcholine (natural lipid membrane)having amphiphilic properties.

There aretwo theories relating to the mechanismof protein interfer-ence to PC restraining polymers. Onetheorysuggests that the formationofan articial organized bilayer of the PC and itsderivatives at the poly-mer surface acts as a shield to the material's surface from theprotein in-teraction[93,94]as depicted inFig. 11. The other theory suggested thatthe large hydration layer developed by abundant free water moleculesaround the PC group, such as MPC, forced the protein to maintain in astable conformation during contact time with the external surfacewhile the other hydrophobic surfaces caused prominent conformationchanges in protein structure[95]. Thus, the hydration layer of PC or itsderivatives was supposed to drive the force for sustainability of proteinconformation in PC containing polymers. However, the PC and MPCcontaining polymer have the phosphoester groups that are sensitiveto hydrolysis which make them difcult to be handled and synthesized

[90,96].The carboxybetaine and sulfobetaine polymers illustrated in Fig. 10b

andc belongto thepolybetaine class which hasboth anionic and cation-ic groups (zwitterionic) on the same molecule similar to PC-containingpolymers. However, their derivatives carboxybetainemethacrylate and

sulfobetainemethacrylate are more stable and easy to prepare ascompared to MPC[90]. Consequently, the biomimetic and zwitterioniccharacters with easy preparation techniques made these polybetainepolymers more attractive than PC and MPC polymers.

Zhao et al. [92]immobilized single-strand DNA (Fig. 10d) to thepolymer membrane so as to increase the hemocompatibility and itwas found to be stable in water and in normal saline solution. Thehydrophilicity increased when DNA was immobilized onto the mem-branes by UV-irradiation. However, the stability of the product couldnot be retained for a long time.

In summary, the addition of PEG/PEO exhibited steric repulsion toprotein adsorption and cell adhesion on membrane surface that im-proved the biocompatibility. By increasing chain length of PEG/PEOthe hydrophilicity and fouling-resistant ability of membranes werefurther improved. The pore size is increased and nger like entitiesslowly decreased. Similarly, using biomimetic molecules improved theprotein resistance on the membrane surface but they are unstable ifstore for long time and their leaching ratio were also high.

3.1.4. Polyvinyl pyrrolidone amphiphilic effect

PVP is a nonionic, highly polar, amphiphilic, physiologically inertwater-soluble polymer, available in different molecular weights inliquid and powder form. PVP acts as hydrophilic agent and formed mis-cible blend with PES due to strong donor/acceptor interaction betweenO = CN functional groups from PVP and O = S = O from the benzene

Fig. 11.Schematic representation of working behavior of PC/MPC containing PES membrane against protein absorption.

0

10

20

30

40

50

60

70

80

PES Pvp=3

NT=0.05

Pvp=3

NT=0.1

Pvp=3

NT=0.2

Pvp=5

NT=0.05

Pvp=5

NT=0.1

Pvp=5

NT=0.2

Clearancewt.%a

fter4hrs.

Additive Concentration wt. %

Urea Creatinine Lysozyme

Fig. 12.Urea, creatinine andlysozyme clearance ratio.Horizontalvalue showed theweightpercentage formulation functionalizedmultiwall carbonnanotubes(NT) andPVP whereasver-

tical line shows the clearance data after 4 h[108].



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ring during membrane formation. PVP increased the viscosity ofPES-based dope solution and provided the macrovoid-free membranestructure [97,98]. The presence of macrovoids in UF hollow bermembrane is usually unfavorable for medical applications becausethey may lead to membrane failure when it is reused or operatedunder high pressure[99].

In order to improve the biocompatibility of PES membrane, PVP isused as an antifouling or a hydrophilic agent in mono[63,100], binary[101,102], ternary blocks[31,103,104]and also in the form of nanopar-ticles as mentioned inTable 2. PVP inhibits the protein adsorption onthe membrane surface and acts as a pore forming agent and increases

the diffusive transport properties of solutes through the PES membrane[105].

Barzin et al. [100] studied theinuence of varying the percentage ofPES and PVP on morphology and performance of dialysis membrane. Heblended nine different membranes by using various concentrations ofPES (12, 18, 22 wt.%) with PVP (0, 2.8 and 5 wt.%). A comparisonbetween the membranes in the absence of PVP showed that when PESconcentration increased (from 12 to 22 wt.%.) the number and size ofnger-like voids changed to sponge-like structure. The presence ofsuch macrovoids decreased the permeability of creatinine, urea anduric acid.

Fig. 13.Chemical structures of PVP blocks.

OH

O

HH

Position 8Position 4

Position 2

(S or R)

(S or R)(S or R)

Synthetic Vitamin E

OH

O

H

H

Natural Vitamin E

(RRR alpha -Tocopherol

Position 4

Position 2(R)

Position 8

(R)

(R)

Fig. 14.Structure of Vitamin E.



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Similar observations were described by Barth et al.[106]and Kaiserand Stropnik[107]. The addition of 2.8 wt.% PVP to the dope solutionincreased the size, numberand nger-like voids in the resultant PES he-modialysis membrane and this is followed by themassive improvementin clearance of creatinine, urea and uric acid.

Recently Irfan at el.[108]synthesized acid functionalized multiwallcarbon nanotubes and PVP nanocomposites and blend them with PESpolymer. They reported that these nanocomposites increased the clear-

ance ratio of urea, creatinine and lysozyme (56.3%, 55.08% and 28.40%)respectively as depicted inFig. 12.Yanget al. [63] studied the effect of different molecular weight PVPs

on solute separation, performance and biocompatibility of resultingmembrane. They used PVP K30 (Mw: 4555 kDa), K85 (Mw:9001200 kDa) and K90 (Mw: 90 k360 kDa) and blended them withPES where the ratio PES/PVPs was kept at the ratio of 16/10 (wt.%).The resultant membranes showed that the HF spun with the PVP K-90was the most hydrophilic with the contact angle of (79.3) and arehighly negatively charged. They exhibited least fouling behavior witha regulated ux above 90% and can achieve more than 90% BSA reten-tion and very good2-microglobulin clearance. Meanwhile blendedmembrane with K-30 PVP has the contact angle value of 95 whichreected that most of K-30 additives were washed out during thephase inversion process.

Many researchers also believe that PVP do not form strong miscibleblends with different grades of PES, so most of the PVPs were leachedduring membrane formation and only a small portion of PVP remainedin the pore wall as well as the membrane matrix. In order to retain thePVP in PES, polymer scientists synthesized, copolymer binary[66,101,102] and ternary blocks [31,103,104] by covalent and compositesmeans and then blended with PES.

Ran et al. [104]synthesized amphiphilic tri block co-polymer ofpoly(vinyl pyrrolidone)b-poly(methyl methacrylate)b-poly(vinylpyrrolidone) P(PVPb-PMMAb-PVP) (Fig. 13a) and Nie et al. [31]prepared triblock copolymer of poly(styreneco-acrylic acid)b-poly(vinyl pyrrolidone)b-poly(styreneco-acrylic acid) (P(Stco-AA)b-PVPb-P(Stco-AA))(Fig. 13b) via reversible additionfragmentation chain transfer (RAFT) polymerization and directly

blended them with PES. The PMMA block integrated and PVP blocksegregated as a hydrophilic brush on the surface of PES membrane.

Meanwhile, in the second block, the polystyrene which is hydrophobicis attached rmly with PES through hydrophobichydrophobic interac-tion and reduces the elusion of PVP whereas ANprovides the negativecharge to the whole nal block as shown inFig. 13. After blendingco-polymers to PES the blood compatibility was improved withprolonged blood clotting time, lower platelet adhesion and lesser BSAadsorption than pristine PES membrane as described inTable 2.

Liet al. [109] also prepared terpolymers of poly(acrylonitrileacrylic

acid

vinyl pyrrolidone) (P(AN

AA

VP)) (Fig. 13c) via free radical solu-tion polymerization and Yin et al. [28]synthesized poly(vinylpyrroli-doneacrylonitrilevinylpyrrolidone) (P(VPANVP)) (Fig. 13d) witha three-step solution free radical polymerization and blended themdirectly in PES. Both resulting membranes showed lower plateletadhesion, negligible PVPs elusion, high rejection of BSA adsorption (upto 75%), high APTT (72 s), low contact angle (53) which were betteras compared to the pure PES membrane.Table 1shows the enhance-ment of membrane properties towards improved biocompatibilitywhen using different blocks of additives.

The use of PVP semi-interpenetrating network (semi-IPN) polymer-ic nanoparticles, which was prepared via solution polymerization bycross-linking VP on PES chains, was also reported in the literature. Thesize of the nanoparticles ranged from 38 to 820 nm and was directlyblended with PES polymer[110]. The contact angles and the adsorbedprotein values decreased from 74 to 53 and 9.5 g/cm2 to 0.7g/cm2

respectively. Meanwhile the resultant membrane water ux, proteinantifouling property increase signicantly and APTT is prolonged asillustrated inTable 3.

Barzin[105]studied the effect of heat on PESPVP hemodialysishollow ber membrane. He formulated two membranes havingPES/PVP ratio of 18/6 (wt.%) and 18/3 (wt.%) and post treated themin hot water for 30 min at 95 C and for 5 min at 150 C in an oven instress free conditions. Findings showed that the post treatment inoven signicantly decreased the MWCO from 200 kDa to 35 and45 kDa for both formulated HF membranes respectively. The obtainedmembranes were suitable for hemodialysis applications. Other similarndings were also reported by Gholami et al. [111]. The PES HF mem-branes depicted an increase in the solute separation, but decreased

the ux rate which proved that the heat treatment shrunk the poresize of the membranes without visibly inuencing the dimension of

Fig. 15.Synthetic procedure for the SPES and CPES polymers[36].



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the HF membranes. In another study it was reported that non contactheating in a microwave irradiation altered the surface of the at sheetmembranes and surface parameters (such as surface roughness)[112].

The addition of PVP and its different block improved the antifoulingand hydrophilicity of the resultant membranes. The morphology andperformance of dialysis membrane in term of uremic wastes werehighlyimproved. It prolonged theblood clotting time; lower theplateletadhesion and lesser the BSA adsorption.

3.1.5. Vitamin E effect

Pathogenesis of vascular injury with progression of atherosclerosiswas seen in dialysis patients when patients received oxidative stressduring dialysis treatment[113]. In order to reduce the participation ofpolymorph nuclear leucocytes on the membrane surface, vitamin E(Fig. 14) was coated on it. This membrane reduced the oxidative stressassociated during the dialysis treatment[114]. During hemodialysis,monocyte and neutrophils produced the oxidative stress by reactiveoxygen species through lipid and protein oxidation[115,116]. Highlyreactive oxygen species are responsible for hypertension, atherosclero-sis, chronic inammatory diseases and nephritis[117]. According toDahe et al.[118]antioxidant agent such as vitamin E (D--tocopherylpolyethylene glycol succinate) in composite membranes revealedsignicant enhancement in hematocrit and neutrophil functions andquality of life [119,120]. Hydrophobicity was the major drawbackwhen vitamin E was used which imparted resistance to ux and innersurface of hollow ber might reduce and partially block the pores onthesurface which canreducethe separation ability of membranes [121].

3.1.6. Anionic functional groups effects

Most of the blood proteins are negatively charged and thus exhibitreduced adsorption behavior towards anionic character polymers.Sulfonation and carboxylation of PES are the bulk modication methodswhich canincreasethe percentage of negative chargepolarity dueto theaddition ofSO3H and COOH groups. Various methods of sulfonationand carboxylation are reported and some of them are discussed in thefollowing session.

3.1.6.1. Sulfonation. In the PES aromatic ring, covalent attachment of sul-fonic group SO3H via electrophilic aromatic substitution reaction bythe removal of one hydrogen atomis called sulfonation of PES. Compareto the other oxygen atom in the polymer chain,sulfonicgroup is local-ized at the ortho position on the aromatic ring as shown in Fig. 15 [122].

The activation of clotting factor was decreased by sulfonation of PES(Table 3) as most of the blood proteins have negative charges. Differentsulfonating agents were used for sulfonation like chlorosulfonic acid[123], sulfuric acid (H2SO4)[124], trimethyl-silylchlorosulfate[125],sulfur trioxide[126], sulfurtrioxidetriethylphosphate complex andoleum[127,128].

Chlorosulfonic and concentrated sulfuric acids are the cheapreagents used for sulfonation of PES, but both have some disadvantages.Chlorosulfonic acid causes chaindegradation, branching or crosslinking

but under controlled conditions works well. When the reaction time istoo long or the temperature is also high, sulfuric acid degrades themain PES polymer chain which alters the mechanical resistance of themembrane [124]. When chlorosulfonic acid was utilized in combinationwith sulfuric acid and in cold deionized, water precipitation occurred,and the product was ltered and washed to pH 67[129].

Kim et al.[130] used chlorosulfonic acid to complete the sulfonationreaction and the resultant negatively charged SPES formed coulddecrease fouling at different pH other than at the isoelectric point ofBSA. Blanco et al. [131] developed sulfonated PES Cardo with concentrat-ed sulfuric acid by solvent free reaction. Shi et al. [132] synthesizedzwitterionic PES, containing anionic sulfonic tertiary amine-modiedPES part and cationic tertiary amine groups. Similarly Zhang et al.[133]developed antifouling membrane using poly(aryleneethersulfone)

which also have zwitterionic effect. Unveren et al. [124] prepared

sulfonated poly(etherethersulfone) membrane using conc. sulfuricacid to minimize the degradation process. This SPEES membraneimprovedin termsof protonconductivity (28% more) than that of Naon.With different degree of sulfonation, Benavente et al. [134]also devel-oped SPEES membrane and showed degrees of grafting increased themembrane electrical properties but reduced its resistance. The studiesre-ported for SPEES membranes were mostly on the electrical propertiesand evaluation of other properties were not completed yet and require

more studies. Different functional groups such as carboxyl, methyl,hydroxyl and amino groups could be attached to PES membrane by thereaction of chlorosulfonic and amino groups [135]. These functionalgroups have signicant inuence towards adsorption of protein.

Wang and his coworker[110]prepared SPES using chlorosulfuricacid and they were blended in PES in different ratios with PEG400 asthe pore forming agent. The mass percent ratio of SPES to PES were 5,15, 30 and 50%. They concluded that the hydrophilicity and wateruxof PES/SPES blend membrane were improved as compared to PES.Reduced BSA adsorption and longer blood coagulation time were alsoobserved for PES/ SPES blend membranes.

3.1.6.2. Carboxylation. Grafting of carboxylic group (COOH) to PESaromatic ring was also an electrophilic aromatic substitution reaction

like sulfonation that can increase the hydrophilicity of the polymerand this was proven by contact angle measurements[136]. By increas-ing the degree of grafting (DG) of carboxylic group in PES polymer,themean poresizeandux rate increasedbut themembranecharacter-isticsbecame reliant on thepH values. Carboxylation of PES involved theformation of lithiated intermediate to approximately two lithium atomsper unit due to a strong activation effect of sulfonic group towards lith-ium[48,49].

Wang et al.[137]prepared carboxylic polyethersulfone (CPES) bythe chemical method of controlled-oxidation and acetylating reactionso as to avoid the degradation of PES (Fig. 15). Deng et al.[48]also pre-pared grafted PES powder of poly(methacrylic-acid) using gamma-rayirradiation-induced graft polymerization but during irradiation someform of degradation occurred.

Nie et al.[36]synthesized heparin type polymer by blending SPESand CPES with PES polymer by evaporation and phase inversion tech-niques. The sulfonic and carboxylic acid groups increased the anioniccharacter in the PES/CPES/SPES membranes and demonstrated goodblood compatibilitywith low complement activation and platelet adhe-sion. The improvement might be due to the different surface morpholo-gy formed, which was the result of different solvent migration timesand driving forces during membrane preparation processes.

In short, the negative charged of sulfonation and carboxylation onthe membrane surface increased the static repulsion to the bloodproteins that improved the protein resistance, hydrophilicity, bloodcompatibility and antifouling properties of the PES membranes.

3.2. Physical blending

The easiest technique to alter PES HD membrane is blending andit is considered as very efcient. Generally 16 wt.% of additiveswereblended with PES membranes and both the hydrophilicity and overallsurface properties were improved. When polymer such as PEG andPVP were blended with PES the hydrophilicity, blood compatibilityand antifouling property increased but they were slowly eluted fromthe resulting membrane with the time[138,139].In order to overcomethis problem researchers synthesized di and tri amphiphilic copolymersand nanocomposites with diverse molecular conguration and shape inwhich one part of the chain was hydrophobic, miscible with PESmaterials while the hydrophilic sections of chain increased the mem-brane fouling resistance and hydrophilicity[101,138,140]. Tables 1and 3clearly explain the improvement of membrane performance by

blending different additive blocks.



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Sun et al.[101]blended nanocomposites of silica-PVP with PES andreported that protein antifouling properties were better as comparedto PVP additive. Wang et al. [141] blended soybean phosphatidylcholineand the prepared surface posses' resistance against protein adsorption.Pure water permeation and BSA adsorption decreasedwhile antifoulingproperties improved by increasing additive percentage. When amphi-philic copolymers of different shapes like comb-like, chain-sphere-like, linear and dumbbell-like were blended with PES and otherpolymers, it was revealed that amphiphilic additives migrated sponta-neously to the surface of the membrane and are self-organized, thusimproved the membrane's anti-fouling ability, hydrophilicity andbiocompatibility[140]. Ho et al. [142]prepared uorinated surfacemodied macromolecules with different element compositions andblended them with PES that completely modied the surface propertiesand improved biocompatibility.

Theblendingof selected organic and inorganic moleculeswith PES isa simple method than that of chemical modication of additives to im-prove the antifouling, hydrophilicity and biocompatibility of PES basedHD membranes. In blending process, most of the chemicals in the mem-brane formulation combined together by hydrogen bonding and theyshowed a high leaching ratio of the membrane surface as compared tochemically modied membranes.

3.3. Hydrophilicity and hydrophobicity

The chemical structure of the PES hemodialysis membrane is a keyfeature which inuences the zeta () potential, surface energy, contact

angle, polarity and wettability. For example, the oxygen-boundedfunctional groups raised the wettability, surface energy and polarity ofsurfaces[143]. On the basis of contact angle of water, the degree ofhydrophilicity/ hydrophobicity and interaction of energies betweenthe membrane and surface can be determined [144,145]. The contactangle of surfaces was determined by the statistic sessile drop andcaptive air bubble techniques, whereas surface energy was calculatedusing Fowke's equation[146149]. The theoretical value of contactangles () for hydrophilic and hydrophobic surfaces are b 30 and N 90respectively, whereas surface tensions (dynes/cm) are N45 and b35respectively. It was qualitatively proven that hydrophilic membranesresisted protein fouling when hydrophilic membranes carried thesame signed electric charge as the biomolecules contained in thesolution [15]. Thezeta potentialis applied to measure thesurface chargeof membranes that further characterized the hydrophobic and hydro-

philic characters.Attractive non-fouling membranes can be obtained when a small

part of the hydrophilic polymer was grafted onto hydrophobic polymersurfaces[150].Due to the absence of interaction between hydrophobicpolymer and hydrophilic grafted part, hydrophilic polymer chainstend to stretch away from the surface when the density of hydrophilicgrafted polymer was high enough. In this way the grafted polymersform a hydrophilic brushon the surface as shown inFig. 16. It wasfound that the highest degree of the different protein rejection wasgenerally observed by this so called brush regime[151,152].

During the phase inversion, the hydrophilicity and hydrophobicityratios determine the nal orientation of mixing blocks. Ran et al.[103]synthesized PVP-bPMMA-bPVP triblock and blended it with PES.They found that the PVPs block has the tendency to move away from

the PES surface (Fig. 17) and the degree of surface coverage of PVPmolecules was 96.88%, whereas PMMA block tends to move towardsthe PES due to contact angle differences. The contact angle for PES,PMMA and PVP are 74.3, 71.5 and 37.1 respectively.

3.4. Biocompatibility, topology, solute and itsux across membranes

In accordance with US Renal Data Systems, composition of hemodi-alysis membrane has great effect on a patient's health, either in terms ofenhanced uremic waste removal or membrane biocompatibility[153,154]. As membrane biocompatibility does not depend on a single factorthus different modication techniques are used to improve this proper-ty. Some techniques arefocused to increase the blood clotting time, thusanticoagulants (heparin) like structures are developed[33]whereas in

some cases, biomimetic molecules like BSA and DNA were used or

Fig. 16. Diagrammatic representationof polymerbrushmade of PES hydrophobicpolymer andgrafted hydrophilicpart.The graftedpart is stretched away from the base dueto absenceof

hydrophobichydrophilic attractions.

Fig. 17.Orientation of PVPPMMAPVP triblock in PES polymer after phase separation

process. a) In (PVPb-PMMAb-PVP) block PMMA components are represented by darkand thick line as compared to PVP; b) Polymer solution containing block additive;

c) Membrane surface showing PMMA is more towards PES and PVP tends to move far

away than PES polymer.



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coated [30,55]. Duringhemodialysis, themonocyteand neutrophils pro-duced the oxidative stresswhich might be responsible for hypertension,atherosclerosis,and chronic inammatory diseases which could be min-imized by using vitamin E coated dialysis membranes [118]. Since itwasproven that higher cationic membranes have poor biocompatibility,hence anionic functional groups containing (sulfonated and carboxylgroups) were introduced in dialysis membrane so as to reduce thebloodmembrane interaction steric repulsion[36,155]. In addition

ciliary and amphiphilic brushes on the membrane surfaces weredeveloped that provide the same steric repulsion to blood[31,104].The membranes utilized in clinical dialyzers, consist of bundles of

~ 10,000 HFs having an internal diameter of ~ 200m. The molecularweights of proteins that should be removed from dialysis patients, arein a range of 10,00055,000 Da. that involved middle (2-microglobu-lin) and low molecular weight uremic toxins (urea, uric acid, creatinineetc.).However,proteinssuch as albumin (66,000Da) should be retained[156].

In the 1990s, the need to remove amyloidogenic beta2-microglobulin(2-m) hassledto thepopularity of high-ux dialysis and the use of high-ux (dened as ultraltration coefcient clearance N 20 mL/h/mm Hg),high permeability (2-mclearance N20 mL/min) and high-efciency(mass transfer coefcient/area N 600 mL/min) membranes[157159].The eliminated quantity of uremic solutes, excess ions and water fromkidney patients determined the efciency of dialysis therapy, althoughits percentage clearances varied from patient to patient. Membranethickness and porosity directly inuence the rate of solute diffusions.High-efciency dialyzer required large surface area (A), high mass trans-fercoefcientor both high bloodow (350mL/min)and highbicarbon-ate based dialysate ow (500 mL/min). Sometime The limitations ofthese conditions led to hemodynamic instability, potential vascularaccess damage, dialysis disequilibrium syndrome and has low margin ofsafety for dialysis patients (if short treatment time is prescribed). Inhigh ux dialyzer, the treatment time is low but it also requiressupplemental dosage after dialysis and dialyzers are more expensive[160,161].

There are two mechanisms possible for uremic solute transportacross hemodialysis membranes irrespective of its compositions;

i) diffusive solute transport, effective for small solutes and its efciencydecreases with increasing molecular weight. ii) Convection or solventdrag depends upon sieving coefcient ofuid movements[162,163].In general, clearance of small solutes (e.g., urea, creatinine etc.) can becontrolled by the dialysate ow rate and convective transport governsthe middle molecules (2-m) clearance, especially with proteins ofdifferent sizes. High ux rate PES membranes show a good clearancecapacity for large sized uremic molecule, and their pore size are in anacceptable range (b65 kDa.), however most dialysis patients cannotbear with its operational stress.

In the development of biocompatible PES HD membrane, thebiocompatibility factor is signicant as it prevents the cell systemfrom treating membranes as external invaders, thus helps to maintainthe membrane physical conditions and performance throughout the

therapy. The membrane key role in uremic solute removal with otherphysical parameters like diffusive solute transport and solvent dragsystems can be improved and maintained throughout the hemodialysisoperation.

4. Conclusion and future trends

PES is an important material and is extensively employed in separa-tion elds, but it lacks good biocompatibility and there is always a questfor simple additives and modication methods which not only enhancethe biocompatibility of PES but also increase itsability to removeuremicsolutes. To date different additives are commercially available and areused with dialyzers. Some acted like anticoagulants, slowed down com-plex formation and increased the clotting inhibition rates. Biomimetic

molecules like BSA grafting produced anti-thrombogenicity effect and

enhanced the cytocompatibility of the membranes with better antifoul-ing behavior whereas albumin-heparinized coating effectively reducedthe platelet adhesion and decreased complement activation of C5a,C5b and C3c. However, BSA is highly dissolvable in aqueous mediaand its elusion was also observed. Sulfate and carboxylate anioniccharacter containing polymers exhibited reduced protein adsorptionsand ciliary brushes of PEO produced steric hindrance that showedextraordinary ability to resist protein adsorption and cell adhesion. In

addition, its comb copolymer with higher density has greater stericstabilization. Phorylcholine, DNA and polybetaine demonstratedzwitterionic and amphiphilic effects and acted as shields to resist themembrane surface from protein interaction and forced the protein tomaintain a stable conformation during contact time, but PC and MPCcontaining polymer have the phosphoester groups that were sensitiveto hydrolysis thus handling and synthesis becomes difcult.

The most common modication technique used to modify PESmembrane is blending and PVP is extensively used as hydrophilic andamphiphilic additives that also acts as a pore forming agent in mem-brane formation. The elution problem of PVP was reduced by bindingit with some hydrophobic anchoring materials like AN, styrene andPMMA which made hydrophobichydrophobic interaction with PESpolymer. Protein adsorption and platelet adhesion on the materialsurface seemed to be remarkably reduced by the presence of additivesthat were used in small quantities of only 0.1 to 5 wt.%.

The swift progress of nanotechnology has increased the option ofapplying nanoparticles (NPs) in biological membrane environments.The application of NPs in biological systems and membranes due totheir size-dependent chemical and physical properties, have shownoutstanding potential, mainly in areas of biomedical application suchas bio-sensing, bio-imaging and drug delivery system but they are notwell explored in hemodialysis membrane systems. If NPs were used inbiological systems, then the blood compatibility aspects need to befully understood and evaluated both quantitatively and qualitativelyas there is a high risk of NPs leaching. The surface functionalization ofNPs by introducingeither synthetic biomolecules and/ornatural ligandshas become a serious component in view to the overall fate of the NPsystem. Currently, maghemite (Fe2O3), carbon nanotubes (CNT) and

other NPs are available in a number of applications related to thehuman body, including hemodialysis but the current scenario of usingNPs in biomedical application is highly motivated towards the usageof modied carbon nanotubes due to ease of modication methodsand its surface modication were versatile and achievable. Modiedand functionalized CNT have low toxicity compared to pristine CNTand now days are largely used in bone scaffolds and tissue engineering.Thus its application as an additive for hemodialysis membrane is anattractive idea, however, the stability and the toxicity of NPs in PESdialysis membrane should be taken into consideration. Nanoparticleshave a high surface area to contact ratio and they are usually agglomer-ates in polymer matrix. The main challenges for manufacturing andusing Nps are its homogeneous dispersion. Different factors like thesurface chemistry, PH, surface charge and morphology inuence the

stability and dispersion of Nps in polymer matrix. Generally, electrostaticrepulsion is created between Nps by different surfactants like SDS, PVPetc. Change in pH effects stability and the dispersion of Nps but it'sextend depends upon the chemical structure of Nps.

At present the evaluation criteria of biocompatibility for NPs are notyet available and standardized. Therefore, safety guidelines for usage ofNPs on human health with clear endpoint are required. However, it isessential to completely evaluate the biocompatibility of NPs in vitroand vivo experiments prior to clinical applications.

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