Nanofibrous composite hemodiafiltration membrane: A facile approach towards tuning the barrier layer for enhanced performance

Applied Surface Science 465 (2019) 950–963

Contents lists available at ScienceDirect

Applied Surface Science journal homepage: www.elsevier.com/locate/apsusc

Full Length Article

Nanofibrous composite hemodiafiltration membrane: A facile approach towards tuning the barrier layer for enhanced performance Yadong Zhu, Xufeng Yu, Tonghui Zhang, Weikang Hua, Xuefen Wang

T

⁎

State Key Lab for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, PR China

A R T I C LE I N FO

A B S T R A C T

Keywords: Sulfonated poly(vinyl alcohol) Thin film nanofibrous composite Hemodiafiltration Antifouling Biocompatibility

In order to develop advanced hemodiafiltration membrane with favorable biocompatibility and efficient dialysis performance, novel thin film nanofibrous composite (TFNC) ultrafiltration (UF) membranes consisting of sulfonated poly(vinyl alcohol) (s-PVA) blended PVA hydrogel barrier layer and electrospun polyacrlonitrile (PAN) nanofibrous supporting layer were designed and fabricated by combining electrospinning and conventional surface coating techniques. The mesh sizes of hydrogel network of s-PVA/PVA barrier layer could be tuned by varying the blending content of s-PVA. The optimized s-PVA/PVA TFNC UF membrane (S-P-TFNC-1-3) possessed high pure water flux up to 380 L m−2 h−1 bar−1 with high bovine serum albumin (BSA) rejection (> 90%). Besides, the introduction of s-PVA into the hydrogel barrier layer endowed the TFNC membranes with enhanced hydrophilicity, antifouling property and biocompatibility (decreased protein adsorption, prolonged clotting time, suppressed platelet adhesion, lower hemolysis ratio and more benefits for cell proliferation) due to the presence of sulfonic groups. The dialysis simulation experiment results of S-P-TFNC-1-3 showed that 84.2% of urea and 60.9% of lysozyme were cleaned and over 95% of BSA was retained after 4 h dialysis process. Especially, the removal of middle-molecule uremic toxin was more efficient than conventional hemodialysis membranes reported so far, and high retention of big proteins was achieved simultaneously. This work exposes a window of opportunity for modified PVA TFNC membranes in blood purification applications.

1. Introduction With the number of patients suffering from chronic renal failure disease increasing, hemodiafiltration, one of the most popular clinical therapies [1–5] is highly desirable and critically important for these patients. When chronic renal failure steps in the end-stage period, it becomes uremia [6], which is a serious threat to the patient’s life. Hence, it is extremely important to remove the uremic toxins in the body of uremia patients to the greatest degree. Uremic toxins are a large group of metabolites, which have significantly higher levels in body fluids of renal failure patients, and are related with toxins metabolic disorders and clinical manifestations closely [7]. How to remove middle-molecule toxins effectively is a challenge to dialysis membranes, in that accumulation of such substances can promote the occurrence of uremic cardiovascular disease development, suppression of immune function and malnutrition [8–10]. Consequently, efficient removal of middle-molecule uremic toxins can bring a better quality of life of patients and long-term survival benefit [11]. Up to now, conventional dialysis membranes are normally prepared by non-solvent induced phase separation (NIPS) from nondegradable

⁎

synthetic polymers such as polyethersulfone (PES) [12], polysulfone (PSF) [13,14], polyvinylidene difluoride (PVDF) [15] and some degradable polymers such as chitosan [16] and poly (lactic acid) (PLA) [17–20]. Pollutants (proteins, microorganism, etc) tended to be adsorbed and deposited onto poor hydrophilic membrane surface via hydrophobic and electrostatic interaction, which can cause serious biofouling, contributing to the thrombus formation and responses of immune system [21–23], which is harmful and even fatal to patients during dialysis process. Most of work focused on the membrane modification to improve the fouling resistance and hemocompatibility by various techniques such as physical blending [15,23], surface chemical grafting [14,16], self-assemly [17,22]. However, current hemodialysis membrane always suffer from a typical tradeoff between high clearance of middle-molecular toxins and high retention of big proteins [24]. It is paradoxical to achieve efficient removal of small/middle molecule uremic toxins without sacrificing the retention of good proteins. Zhu et al. [23] blended PLA-PHEMA with PLA to prepared PLA/PLAPHEMA membranes via NIPS method. The pore size and porosity significantly increased upon addition of PLA-PHEMA, significantly improving the middle-molecule clearance but with the loss of big albumin.

Corresponding author. E-mail address: [email protected] (X. Wang).

https://doi.org/10.1016/j.apsusc.2018.09.201 Received 20 March 2018; Received in revised form 7 September 2018; Accepted 24 September 2018 Available online 28 September 2018 0169-4332/ © 2018 Elsevier B.V. All rights reserved.

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

It is a tough challenge that how to execute the fine regulation of the membrane pore size achieves the balance between high clearance of middle-molecular toxins and high retention of big proteins. Recently, we demonstrated a new type of PVA thin film nanofibrous composite (TFNC) ultrafiltration membrane with two-tier structure for hemodialysis [24]. The TFNC dialysis membrane consists of a highly porous PAN nanofibrous supporting layer and an ultrathin PVA hydrogel barrier layer, exhibiting good hemodialysis performance. For the key of the barrier layer, hydrogels own a three-dimensional (3D) network of macromolecular chains connected through crosslinked points, defining an effective mesh size allowing the water to permeate [25,26]. Moreover, hydrogels can swell and reserve some water inside their structures and exhibit soft tissue-like mechanical properties as a result of the hydrophilic 3D networks, resulting in excellent biocompatibility [27–29]. Additionally, the controllable mesh size of hydrogel made it an ideal material for size-selective transport through the 3D networks. For two-tier PVA/PAN TFNC hemodialysis membrane, it exhibited excellent size selectivity with more than 98% good protein retention and more than 45% lysozyme clearance simultaneously, which were obviously more effective than conventional hemodialysis membranes reported so far [24]. However, the hydrophilicity of PVA hydrogel barrier layer should be improved to enhance the antifouling property and biocompatibilty of the pristine PVA TFNC membrane was also improved to close in the clinical demands. On the other hand, the mesh size of the pure PVA hydrogel was tuned difficultly due to its very narrow casting window for preparing hydrogel barrier layer. Aiming to enhance its comprehensive performances especially for middle-molecule toxin removal and biocompatibilty, modified PVA TFNC membranes with controlled mesh sizes were fabricated by coating the PVA hydrogel blended with negatively charged sulfonated PVA (sPVA) onto the PAN nanofibrous substrate. The anionic s-PVA molecules possessed functional groups such as sulfonic and hydroxy groups similar to heparin and should have similar biology properties such as anticoagulant and antithrombotic activities besides strong hydrophilicity, which can be regarded as heparin-mimetic macromolecules for the surface modification of biomaterials. In addition, electrospun fibers have been applied in many biomedical fields [24,30–33]. Herein, the combining schematic of the s-PVA/PVA TFNC membrane

fabrication process was shown in Scheme 1. The sulfonated PVA was synthesized via a facile nucleophilic substitution and blended with pure PVA to form the blending hydrogel barrier layer after crosslinking. The mesh size of s-PVA/PVA hydrogel barrier layer could be tuned finely by varying the blended content of s-PVA. Thus, the incorporation of s-PVA into the barrier layer could not only tune the barrier layer to ameliorate the permeability, but also could promote antifouling performance and biocompatibility of hydrogel top layer markedly. In order to further improve the dialysis performances of TFNC membranes, the mesh sizes of the hydrogel barrier of s-PVA/PVA TFNC membranes could be optimized to achieve the high-efficiency removal of middle-molecule toxins and retaining big proteins simultaneously. The chemistry, morphology, hydrophilicity, antifouling, biocompatibility and dialysis performance of the prepared s-PVA/PVA TFNC membranes were investigated in detail. 2. Experimental 2.1. Materials Poly(vinyl alcohol) powder (PVA, Mw = 146,000–186,000, 87–89% hydrolyzed), polyacrylonitrile (PAN, Mw = 120,000), dimethylformamide (DMF), glutaraldehyde (GA, 25% aqueous solution), hydrochloric acid (HCl, 36.5% aqueous solution), boric acid, ethanol (EtOH), immunoglobulin G (IgG, Mw = 150,000 Da), bovine serum albumin (BSA, Mw = 67,000 Da), egg albumin (Mw = 45,000 Da), pepsin (Mw = 35,000 Da), α-chymotrypsin (Mw = 24,500 Da), cytochrome C (Mw = 13,000 Da) and deionized water (DI water, HPLC grade) were all purchased from Aldrich. Sodium hydride, propane sultone were obtained from TCI, Tokyo, Japan. Lysozyme and p-dimethylaminobenzaldehyde (PDAB) was purchased from Aladdin. 3-(4,5-dimethyl-2thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), fluorescein diacetate (FDA), propidium iodide (PI), Phalloidin (FITC) and 4′,6diamidino-2-phenylindole (DAPI) were purchased from Shanghai Shanran Bio Technologies Co., Ltd. Urea was obtained from Sino pharm of China. Healthy human fresh blood was obtained from a 26 years old healthy volunteer, containing heparin sodium as anticoagulant (anticoagulant to blood ratio, 1:9), and the blood used in all the blood tests

Incorporated s-PVA

Scheme 1. Schematic illustration for the preparation of the PVA/s-PVA TFNC hemodialysis membrane. 951

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

were from the same donor. Micro BCATM protein assay reagent kits were the products of PIERCE. All chemicals were used as received without further purification unless noted.

Platelet-poor plasma (PPP) was obtained by centrifuging fresh blood at 3000 rpm for 15 min, and the supernatant was utilized to measure PRT. Platelet rich plasma (PRP) was acquired by centrifuging fresh blood at 1000 rpm for 10 min, and the supernatant was used to study the platelet adhesion considered as key triggers of thrombus formation, and platelet adhesion on s-PVA/PVA composite membrane was observed by SEM. Human vein endothelial cells (HUVECs) culture and growth and morphology were used to evaluate the cytocompatibility of the membranes including MTT assay for the viability of HUVECs and live/dead cell staining observed by a confocal laser scanning microscopy (CLSM, Leica). The detailed processes of above biocompatible experiments are described in the Supporting Information.

2.2. Preparation of thin film nanofibrous composite (TFNC) membranes containing s-PVA/PVA coating and PAN nanofibrous substrate Sulfonated PVA (s-PVA) was synthesized by nucleophilic substitution reaction [34] and the detailed synthesis methods of s-PVA was described in the Supporting Information. s-PVA/PVA TFNC membranes were prepared combining electrospinning and coating technology based on our previous reports [24]. For PAN nanofibrous supporting scaffold fabrication, a homogeneous solution (8 wt%) of PAN was prepared by dissolving dried PAN powder in DMF at 60 °C for 12 h for electrospinning using a laboratory setup. The applied voltage was 20 kV and the solution feed rate was set at 16 μL/min with a syringe pump, and the distance between the spinneret and collector was 15 cm. The asprepared electrospun PAN nanofibrous mat was cold-pressed at 6 MPa for 60 s to improve its mechanical strength and achieve smooth surface for the following preparation of top coating layer. For coating solution preparation, s-PVA/PVA powders with the different mass ratios were dissolved in pure water to obtain a 2 wt% concentration with gentle stirring at 80 °C for 4 h. Before the coating process, the PAN supporting layer was soaked with 0.8 M boric acid solution and then fixed and sealed on a flat glass plate. The aqueous s-PVA/PVA solution was adjusted its pH to 2 by adding 1.5 M HCl, then an appropriate amount of GA solution ([eOH]/[GA] = 4:1 in mol) was added into the solution to initiate the cross-linking reaction and the gelling time was monitored before coating process. Until an optimal pre-crosslinking time came (about 20 min) under the temperature of 25 °C in order to prevent the solution penetrating through the PAN scaffold, pre-crosslinking solution was coated on the PAN nanofibrous substrate by an automatic film applicator. The photographic image of coated TFNC membranes was similar and a typical photographic image of s-PVA/PVA TFNC membranes was shown in Fig. S1. To achieve a complete crosslinking, the composite membranes were kept in a humid chamber for 12 h and then thoroughly rinsed with phosphate buffered saline (PBS, pH = 7.4) at 37 °C for a week to remove the residual HCl and GA, and finally kept in a water bath before use. In the above experiments, s-PVA/PVA TFNC membranes with the sPVA/PVA mass ratios of 0/2, 0.40/1.60 (1:4), 0.50/1.50 (1:3), 0.67/ 1.33 (1:2) and 1.00/1.00 (1:1) were denoted as P-TFNC, S-P-TFNC-1-4, S-P-TFNC-1-3, S-P-TFNC-1-2 and S-P-TFNC-1-1, respectively. The fixed total coating solution of 2 wt% concentration was used to control the top coating layer with similar thickness.

2.5. Filtration performance and fouling analysis All filtration experiments of the membranes were evaluated by a dead-end filtration apparatus. Especially protein antifouling property is foremost for hemodialysis membranes, so the filtration of BSA aqueous solution through the membranes was performed to study the antifouling property [37,38]. Normally, the test membrane was pre-compacted with pure water at 1.2 Bar for 30 min to get stable filtration. The pure water flux of the membrane was determined at 1 Bar by collecting and weighting the permeated solution for 30 min, and the flux was calculated by Eq. (1). After that, 1 g/L BSA aqueous solution became the filtrate replacing pure water, and the data were recorded for 60 min at 1 Bar. After the protein solution filtration, the membrane was washed with pure water, and the pure water flux was measured again. The 90 min’s flux was termed as a cycle. All the data were recorded every 5 min. The liquid fluxes of the cycles were termed as J1, J2, and J3 in file, which were registered at intervals until stable and calculated by (1)

J = V /(S × P × T ) −2

−1

−1

where J (L m h bar ) is the flux, V (L) is the volume of the permeated solution, S (13.8 cm2) is the effective filtration area, T (h) is the operation time, P (Bar) is the pressure applied to the membrane. The antifouling performances of the membranes were evaluated by the flux recovery ratio (FRR = (J3/J1) × 100%), total fouling (Ft = (J1 − J2)/J1), reversible fouling (Fr = (J3 − J2)/J1) and irreversible fouling (Fir = (J1 − J3)/J1). In addition, the rejection for various proteins (100 mg/L) of different TFNC membranes were valued by using immunoglobulin G (IgG, Mw = 150,000 Da), bovine serum albumin (BSA, Mw = 67,000 Da), egg albumin (Mw = 45,000 Da), pepsin (Mw = 35,000 Da), α-chymotrypsin (Mw = 24,500 Da) and cytochrome C (Mw = 13,000 Da) in several as the feeding solution. When the rejection was 90%, the molecular weight of protein was considered as molecular weight cutoff (MWCO) [39]. The rejection ratio (R) for different proteins aqueous solution was defined as follow:

2.3. Characterizations The structure of s-PVA powder was confirmed by Fourier trans-form infrared spectroscopy (NEXUS-870, Nicolet Instrument Co. USA). The morphologies of the cross-section views for the membranes were characterized by a scanning electron microscope (SEM, Hitachi S-4800, Japan), and the surface composition of the thin film nanofibrous composite membrane was investigated with attenuated total reflection fourier transform infrared spectra (ATR-FTIR, Thermo-Nicolet 6700, US). The hydrophilicity of the membrane was determined by a contact angle goniometer (OCA20, Dataphysics, Germany).

R(%) = (1−Cp/ Cb) × 100%

(2)

where Cp and Cb (g/L) were the protein concentrations in the permeated and bulk solution, respectively. The protein concentrations were measured by a UV–vis spectrophotometer (UV-1750, Shimadzu Co. Ltd., Japan) at their specific wavelength. 2.6. Hemodiafiltration simulation experiment The simulated dialysis performance of the membranes (P-TFNC, S-PTFNC-1-3) was estimated using a mixed solution of urea (1.5 g/L), lysozyme (0.04 g/L) and BSA (1.0 g/L) in PBS solution as simulative blood (flow rate = 200 ml/min), and 1.5 g/L dextrose solution acted as simulative dialysate (flow rate = 500 ml/min) as described in our previous work [24]. The home-made testing scheme was shown in Fig. 1. The overall effective area of each membrane is 30 cm2. The experiment was constantly operated for 4 h and 10 ml test solution was drawn out every 1 h from the simulative blood. The change of urea

2.4. Biocompatibility The biocompatibility of dialysis membranes was usually evaluated by protein adsorption [23,24], plasma recalcification time (PRT) [17], platelet adhesion [21], hemolysis ratio (HR) [24] and cytocompatibility [35,36]. Protein adsorption is considered as the key factor when materials contact with the blood, and the proteins adsorption tests were measured by using the Micro BCATM Protein Assay Reagent Kit. 952

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

Fig. 1. Schematic diagram of single membrane dialysis system.

hydrogen bond forces made the stretching CeH reduced and CH2 vibration peak occurred in a blue shift from 1432 cm−1 to 1470 cm−1 [42], which also resulted from eOH replacing by eO(CH2)3SO3H. As the sulfonated modification was conducted under acidic conditions, poly(vinyl acetate) in PVA would be hydrolyzed and resulted in a significant decrease of the peak intensity from ester C]O group, indicating that only very few acetate groups were remained in PVA [43]. New peaks at 1065 cm−1 and 1200 cm−1 were assigned to the symmetric and asymmetric stretching vibration of O]S]O [44], respectively, indicating the successful sulfonated modification of PVA (sPVA). In addition, the sulfonic acid group content of s-PVA was 2.75 mmol/g which was in agreed with the fractional degree of sulfonic substitution of 12.1% measured by the acid-base titration test. For preparation of modified PVA/PAN TFNC membranes, the synthesized s-PVA was blended into PVA solution with various mass ratio at a fixed total weight concentration 2.0 wt%, then the blending solution was pre-crosslinked with a proper amount of crosslinking agent GA with an optimal time before the coating process in order to prevent the solution penetrating through the PAN nanofibrous supporting layer. All the coating layers were ultrathin with similar smooth surface thickness due to the fixed total concentration. The typical cross-section SEM image for the s-PVA/PVA TFNC membrane was shown in Fig. 3A. As can be seen from it, the blended s-PVA/PVA hydrogel top barrier layer was ultrathin with thickness of about 600 nm on porous PAN nanofibrous supporting layer. Although it was undulated along the contour of the underlying nanofibers, the surface was relatively smooth. The smooth and ultrathin surface might have positive effect on decreasing protein absorption [45]. The TFNC membranes with the s-PVA/PVA mass ratios of 1:4, 1:3, 1:2, 1:1 were denoted as P-TFNC, S-P-TFNC-1-4, S-P-TFNC-1-3, S-P-TFNC-1-2 and S-P-TFNC-1-1, respectively. The change of surface chemical compositions of the modified TFNC membranes with different mass ratios of s-PVA were investigated by ATRFTIR shown in Fig. 3B. The new peak appeared at approximately 1126 cm−1, which was the evidence for the existence of sulfonic acid group [46] on the surface of s-PVA/PVA thin film nanofibrous composite membranes. Besides, the intensity values of the peak at 1720 cm−1 ascribed to C]O stretching vibration decreased whilst the intensity of the peak at 1126 cm−1 was increased with the increase of mass ratio of s-PVA and PVA from 1:4 to 1:1, which also indicated the more content of sulfonic acid group was introduced into top barrier layer. The introduction of sulfonic groups could be beneficial to improve the hydrophilicity of hydrogel barrier layer, and the mesh size of 3D hydrogel network also could be tuned by adjusting the blending

solution concentration was detected with Ultraviolet spectrophotometer at 410 nm via the color reaction between urea and PDAB. Besides, the detections of BSA and lysozyme solution concentration were also utilized with Ultraviolet spectrophotometer at 278 nm and 280 nm, respectively. The urea clearance is calculated by the following equation:

Urea clearance percentage = (1−At / A0 ) × 100%

(3)

where A0 and At are the urea concentrations in the testing solution reservoir at time t = 0 and t = 1, 2, 3, 4 h, respectively. The lysozyme clearance is calculated by the following equation:

Lysozyme clearance percentage = (A0 −At )/ A0 × 100%

(4)

where A0 and At are the lysozyme concentrations in the testing solution reservoir at time t = 0 and t = 1, 2, 3, 4 h, respectively. The BSA retention is calculated by the following equation:

BSA retention percentage = At / A0 × 100%

(5)

where A0 and At are the BSA absorption value in the testing solution reservoir at time t = 0 and t = 1, 2, 3, 4 h, respectively. 3. Results and discussion 3.1. Preparation of modified PVA/PAN TFNC membranes The sulfonic groups were introduced into PVA through nucleophilic substitution reaction of PVA with propane sultone as shown in Fig. 2A, and could be confirmed by FTIR spectrum. PVA is generally an atactic copolymer in that it is made by the hydrolysis of poly(vinyl acetate) and the hydrolysis reaction doesn't go to completion in alkaline medium [40]. FTIR spectrum in Fig. 2C clearly revealed the major peaks associated with PVA. The large bands between 3200 cm−1 and 3550 cm−1 was assigned to typical OeH stretching vibration from the intermolecular and intramolecular hydrogen bonds, the vibration band observed between 2850 cm−1and 3000 cm−1 referred to stretching CeH from alkyl groups, and stretching vibration peaks between 1710 cm−1and 1770 cm−1 were due to C]O and CeO from poly(vinyl acetate) and acetate group remaining in PVA, the band at 1432 cm−1 was attributed to CH2 vibration peak, all of which were in agreement with the reported literature data for PVA [40,41]. Due to the some conversion of eOH to eO(CH2)3SO3H after sulfonated modification, the intensity of the characteristic OeH stretching peaks of PVA decreased and the intensity of CH2 was increased on the opposite. Besides, weaker 953

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

A OH

OH

OH

OH

+

O

O S O

NaH, H+ 80 °C, 24h HO 3S

O

OH

O

OH SO 3H

B

C

Fig. 2. (A) The synthetic route of s-PVA. (B) Photographic images of pure PVA and s-PVA powder. (C) FTIR spectra of pure PVA and s-PVA powders.

uniformly on the surfaces and inner pore channels of hydrogel barrier layer and the wettability of modified membranes was strengthened with the increase of s-PVA content. Thus, this facile blending modification provided a highly effective means for the design and tune of functional barrier layer. The improved hydrophilicity could also reduce the adsorption of organic pollutant and transmembrane resistance, expecting to endow the membrane with good anti-fouling property and blood compatibility. Normally, the blood compatibility of the hemodialysis membrane is evaluated mainly by the protein adsorption, PRT, platelet adhesion and hemolysis ratio. The protein adsorption amount of membrane surfaces should be confirmed firstly since it is the pivotal premonition of blood compatibility. Commonly, hydrophobic surface adsorbs more proteins on membrane surfaces, the more pores will be blocked resulting in the decrease of the membrane permeation performance. And conversely,

mass ratio of s-PVA and PVA as shown in Scheme 1. 3.2. Hydrophilicity and hemocompatibility Water contact angle (WCA) is widely used to evaluate the hydrophilicity property of membrane surfaces. For membranes possessing similar structures, the better hydrophilicity is equal to smaller WCA commonly. As shown in Fig. 4A, the initial contact angle of pure PVA TFNC membrane (P-TFNC) was 67°, and it almost remained stable when the drop age exceeded 40 s, corresponding to its some hydrophobility. After the introduction of s-PVA in the barrier layer, the initial contact angles of the modified TFNC membranes decreased from 64° to 47° with the s-PVA/PVA mass ratio increased from 1:4 to 1:1, and the decaying rate was enhanced markedly with the increasing blended s-PVA. It could be attributed to that, the superhydrophilic s-PVA were distributed 954

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

A

non-hemolytic with prominent blood compatibility and cut down the harm to erythrocyte. Platelet adhesion and platelet morphology on membrane surfaces are considered as key triggers of thrombus formation [51]. Here, the morphology of the adherent platelets and the adhered platelet amount were further investigated to evaluate the blood compatibility. Fig. 5 presented the SEM micrographs of platelets adhering onto pure PVA TFNC and modified PVA TFNC membranes. As can be seen from that, the surface of pristine PVA TFNC membrane (P-TFNC) was prone to induce the activation and transmutation of platelets due to its weak hydrophilicity, the number of the adhered and aggregated platelets outspread in irregular shapes was clearly higher than that from the modified PVA TFNC membranes with more blended s-PVA (such as S-PTFNC-1-3, the observed individual adherent platelets exhibited spherical morphologies with nearly no pseudopodia shape and deformation). With the s-PVA/PVA blending mass ratio increased, platelet adhesion was obviously suppressed and almost no platelets adhered on the S-P-TFNC-1-1. The platelet adhesion result was consistent with the previous protein adsorption, and indicated the introduction of hydrophilic of s-PVA into TFNC barrier layer was favor to form a good hemocompatible barrier in preventing platelet adhesion.

~600nm

5ȝm

B

3.3. Cytocompatibility The cytocompatibility of the various membranes was assessed by observing HUVECs viability, morphology and MTT assay. Earlier papers [35,36] had reported that heparin and heparin-mimicking surface was favorable for cell proliferation. Sulfonated PVA possessing sulfonic acid and hydroxy groups could be regarded as a kind of heparin-mimetic polymer. Herefore, the s-PVA blended PVA TFNC membranes were anticipated to improve the cell adhesion ability and favor for cell proliferation. To explore the HUVECs viability and morphology onto the pristine and modified membrane surfaces, fluorescence images of live/deadstained cell cultured for 5 days on various membranes were shown in Fig. 6 (top). It could been seen that lager amounts of live cells were observed (in green) and negligible dead cells (in red) were observed on all TFNC membrane surfaces, which implied that all TFNC membranes had low toxicity toward HUVECs. And the larger number of live cells existed on s-PVA/PVA TFNC membranes surfaces also implies that the introduction of s-PVA into the hydrogel coatings were able to improve the attachment of HUVECs. The enhancement of cell attachment should be resulted from the 3D hydrogel network structure and heparin-mimetic functionality, which could improve the affinity of HUVECs to the substrates. Besides, to get a better view of the HUVEC structures, we conducted CLSM observation using a double staining of cytoplasm and nuclei. The CLSM images of HUVECs cultured on various TFNC membranes were shown in Fig. 6 (bottom). The HUVECs seeded on heparinmimetic s-PVA/PVA TFNC membrane surfaces exhibited distinct regional aggregations, and the adhered cells could spread on the hydrogel surface. A dense intercellular network of HUVECs cytoplasm was observed and this phenomenon was more and more obvious with the increase of s-PVA. The results of cell morphology observation indicated that sulfonated hydrogel coating could effectively promote cell attachment and growth because the sulfonic groups of s-PVA/PVA TFNC membrane surfaces might provide more bioactive receptor binding sites for the attachment and growth of the HUVECs. The results were also consistent with the results displayed in Fig. 6 (top). To further evaluate the cytotoxicity, cell proliferation and activation in vitro of the membranes, MTT assay was employed. As shown in Fig. 7, the viability of the cells on each membrane increased continuously with the increase of culture time, indicating that the hydrogel coatings were nontoxic and could support cell proliferation. Additionally, the absorbance of the modified membranes were higher than that of P-TFNC after incubating cell for 1, 3, 5 days, especially when the s-PVA/PVA mass ratio was 1:3 or larger, the MTT values of s-PVA/PVA

Fig. 3. (A) SEM image of the cross-section views for TFNC membranes. (B) ATR-FTIR spectra for the various membranes: (a) P-TFNC, (b) S-P-TFNC-1-4, (c) S-P-TFNC-1-3, (d) S-P-TFNC-1-2, (e) S-P-TFNC-1-1.

hydrophilic surface has less protein adsorption due to an ultrathin water film formed on the hydrophilic membrane surface impeding the deposition of proteins. As shown in Fig. 4B, the highest BSA adsorbed amounts (30 μg/cm2) existed on the P-TFNC membrane, whereas the protein adsorption of s-PVA/PVA TFNC membranes (s-PVA/PVA mass ratio from 1:4 to 1:1 with the corresponding protein adsorption of 26, 22, 17, 12 μg/cm2) exhibited about 13–60% decrease. The tendency of protein adsorption for s-PVA/PVA TFNC membranes was negatively correlated with the hydrophilicity, which should be attributed to that the incorporation of more sulfonic acid groups in the ultrathin hydrogel top layer resulted in s-PVA/PVA TFNC membrane surface excellent hydrophilicity with lower protein adsorption capacity[47]. Accordingly, the decreased protein adsorption on the s-PVA/PVA hydrogel TFNC membrane surfaces might imply better blood compatibility. As confirmed by the PRT results shown in Fig. 4C, the PRT of modified TFNC membranes significantly increased from 260 s of P-TFNC membrane to 550 s of S-P-TFNC-1-1 (s-PVA/PVA mass ratio = 1:1). The prolonged PRT after the incorporation of s-PVA indicated the better anti-coagulation behavior, which could be ascribed to the increased sulfonic acid groups of barrier layer stemming the transition of the fibrinogen to fibrin [48–50]. Additionally, the intensified anti-coagulant property also corresponded with the increased hydrophilicity and decreased protein adsorption as mentioned above. For the evaluation of hemocompatibility, hemolysis ratio (HR) of the membrane was performed to investigate the hemolytic potential caused by extraneous materials. As shown in Fig. 4D, HRs of S-P-TFNC1-4, S-P-TFNC-1-3, S-P-TFNC-1-2 and S-P-TFNC-1-1 were 1.17%, 0.92%, 0.67% and 0.50%, respectively, which were all lower than that of P-TFNC (1.36%), indicating that s-PVA/PVA TFNC membranes were 955

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

Fig. 4. (A) Water contact angle of different membranes versus drop age. (B) The amount of absorbed BSA on the various membranes. (C) Plasma recalcification time of different membranes. (D) Hemolysis ratio of different membrane samples.

of blending hydrogel layer. The enlarged mesh size was caused by less crosslinks and the enhanced hydrophilicity after the substitution of eSO3H for eOH, schematic illustration for which was shown in Fig. 9. Moreover, the more hydrophilic s-PVA/PVA barrier layer would absorb more water when contacting with water molecule resulting in slight volume expansion and s-PVA/PVA molecule chain stacking more loosely, also enlarging mesh sizes of hydrogels. The control of mesh size of hydrogels correlated strongly with the mass ratio of s-PVA and PVA. Interestingly, when mass ratio of sulfated PVA and PVA of hydrogel coating solution was beyond 1:3, the pure water flux value just went up slightly. The pure water flux of S-P-TFNC-1-3 membrane could get to 380 L m−2h−1 bar−1 increasing about 31% based on that of pristine PTFNC membrane (290 L m−2h−1 bar−1), while the BSA rejection of S-PTFNC-1-3 membrane was slightly decreased by 4% (to 90.5%) compared to that of pure P-TFNC membrane (94.6%). The 90.5% of BSA rejection could meet the good selectivity requirement of normal ultrafiltration membranes [22] (above 90%) for hemodialysis, which implied that S-P-TFNC-1-3 membrane may have the proper bigger mesh size, promoting the permeability-selectivity anti-trade-off behavior of TFNC ultrafiltration membranes. To further demonstrate the abovementioned bigger mesh size, the molecular weight cutoffs (MWCOs) of different TFNC membranes were used to evaluate the mesh size indirectly, since it is difficult to directly determine the pore diameters of the ultrafiltration membrane. Mesh size could be predictive of retention of relatively large proteins and release of relatively small proteins, because the proteins had the globoid structure and the size scale was similar to the actual mesh size of PVA TFNC barrier layer. The rejection results of several proteins with different molecular weight for various

TFNC membranes (S-P-TFNC-1-3, S-P-TFNC-1-2 and S-P-TFNC-1-1) were all higher than that of the control, which indicated that sulfonated hydrogel could simulate the biofunctionality of heparin and promoted the HUVECs growth remarkably. The results of MTT assay were also consistent with that of the above-mentioned cell viability and morphology. Accordingly, it can be concluded that the heparin-mimetic sPVA/PVA TFNC membranes not only increased the HUVECs attachment efficiently but also promoted the cell growth on the ultrathin hydrogel surfaces, the explanation for which was that heparin-mimicking s-PVA primarily interact with proteins through electrostatic interactions in the binding sites of the biomolecules between its sulfonated groups and the clusters of positively charged amino acid residues (such as lysine and arginine). 3.4. Membrane transport and antifouling properties Apart from the good biocompatibility, the incorporation of hydrophilic s-PVA may bring in some good effects on permeability and antifouling performance. The test of pure water permeation flux and BSA rejection for s-PVA/PVA TFNC membranes was evaluated using a home-made dead-end filtration apparatus, and the results were shown in Fig. 8. The pure water flux of pristine PVA TFNC membrane was 290 L m−2 h−1 bar−1 and the BSA rejection was 94.6%. With an increase of s-PVA in the s-PVA/PVA blending hydrogel layer, the pure water fluxes were increased markedly up to 380 L m−2 h−1 bar−1 and then slowly up to 395 L m−2 h−1 bar−1, on the contrary, the BSA rejection was decreased quite slowly down to 90% and then quickly drop to 70%, the turning point was at mainly ascribed to the larger mesh size 956

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

P-TFNC

S-P-TFNC-1-4 1ȝm

1ȝm

50ȝm

50ȝm S-P-TFNC-1-2

S-P-TFNC-1-3

1ȝm

1ȝm

50ȝm

50ȝm

S-P-TFNC-1-1 1ȝm

50ȝm Fig. 5. The typical SEM images of the adherent platelets on the P-TFNC, S-P-TFNC-1-4, S-P-TFNC-1-3, S-P-TFNC-1-2 and S-P-TFNC-1-1 membrane surfaces.

TFNC membranes were represented by simulating the logistic fitting curves shown in Fig. 10. It could be found that the MWCOs at the proteins' rejection (90%) of the P-TFNC, S-P-TFNC-1-4, S-P-TFNC-1-3, S-P-TFNC-1-2 and S-P-TFNC-1-1 were 47,838, 56,940, 63,212, 80,522 and 88,556 Da, respectively. It was evident that the MWCO got bigger

after the more introduction of s-PVA. On the basis of the relation between molecular weight of solutes commonly used in MWCO determination and the average pore size on ultrafiltration membrane reported by M. N. Sarbolouki [39], the predictive mesh sizes of P-TFNC, S-PTFNC-1-4, S-P-TFNC-1-3, S-P-TFNC-1-2 and S-P-TFNC-1-1 were 6.8,

P- TFNC

S-P-TFNC-1-4

S-P-TFNC-1-3

S-P-TFNC-1-2

S-P-TFNC-1-1

P-TFNC

S-P-TFNC-1-4

S-P-TFNC-1-3

S-P-TFNC-1-2

S-P-TFNC-1-1

Fig. 6. The live/dead-stained fluorescence (top) and CLSM (bottom) images of HUVECs cultured on the surfaces of different membranes after 5 days. 957

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

Fig. 7. Absorbance of HUVECs determined from MTT assay. (The values were expressed as mean ± SD, n = 3. HUVEC adhesion on bare TCPS was taken as the control sample.)

Fig. 8. The pure water flux and BSA rejection of various membranes. 958

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

Fig. 9. Schematic illustration of tuning the mesh size of s-PVA/PVA hydrogel barrier layer.

Fig. 10. MWCO of the P-TFNC, S-P-TFNC-1-4, S-P-TFNC-1-3, S-P-TFNC-1-2 and S-P-TFNC-1-1 membranes.

hydrogel layer quickly while the BSA macromolecule was retained effectively, which had been demonstrated by the above results of pure water flux and BSA rejection. Therefore, S-P-TFNC-1-3 may possess the optimized mesh size, achieving the balance between permeability and selectivity. In summary, the mesh size could be tuned finely and facilely by varying the s-PVA/PVA blending mass ratio. And the enlarged tunable mesh size was attributed to two main aspects: one was the crosslinking degree of the blending hydrogel was reduced with the

7.2, 7.5, 8.3, 8.7 nm. When the mass ratio of s-PVA and PVA was beyond 1:3, the TFNC membranes (S-P-TFNC-1-2 and S-P-TFNC-1-1) could not intercept BSA totally, which is attributed to the larger mesh size compared to the average diameter [52] of BSA (7.8 ± 1.0 nm). This result was consistent with that of the aforementioned BSA rejection. In addition, when the mass ratio of s-PVA and PVA was 1:3, the expanded mesh size of S-P-TFNC-1-3 (7.5 nm, close in the average diameter of BSA) could make water molecules pass through the 959

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

Table 1 The water flux recovery ratio (FRR) of pristine PVA and modified membranes. Sample

P-TFNC S-P-TFNC-1-4 S-P-TFNC-1-3 S-P-TFNC-1-2 S-P-TFNC-1-1

FRR First cycle

Second cycle

Third cycle

81.69 93.65 95.80 96.47 98.78

78.98 93.12 95.78 96.41 98.52

78.31 92.67 95.74 95.97 98.41

filtration tests. After three circles filtration fouling, there was almost no decline in the water flux of modified s-PVA/PVA membranes. As shown in Table 1, the water flux recovery ratio of P-TFNC membrane was 81.69% in the first cycle, and the value decreased to 78.98% in the second cycle, and reached 78.31% in the third cycle. While three-cycle flux recovery ratio of the optimized S-P-TFNC-1-3 (95.80%, 95.78% and 95.74%) exceeds that of P-TFNC membrane apparently. With s-PVA content increased above 1:3, the FRR slightly improved. These results were the evidence for that antifouling abilities of s-PVA/PVA TFNC membranes were improved significantly after the incorporation of sPVA into PVA hydrogel barrier. The long-standing fouling resistance was a special advantage of the s-PVA/PVA membranes prepared by fine tuning hydrogel barrier layer with interpenetrating network which was desired eagerly, normally foreign additives physically incorporated into the membranes continually suffered from leaching out during the test resulting in flux decay and loss of fouling resistance with time going by [53]. For the quantitative evaluation of the antifouling property of sPVA/PVA membranes, the total fouling ratio (Ft) could be divided into the reversible fouling ratio (Fr) and irreversible fouling ratio (Fir). The reversible fouling ratio caused by reversible protein adsorption or deposition could be eliminated by a strong shear force or backwashing through hydrodynamic method; while the irreversible fouling ratio caused by irreversible fouling could only be eliminated by chemical cleaning or enzymatic degradation [54]. The percentages of reversible fouling in total fouling (Fr/Ft) and irreversible fouling in total fouling (Fir/Ft) were presented in Fig. 11B. It was obviously observed that Fir/ Ft of the P-TFNC membrane was largest (20%) among all TFNC membranes, indicating that the pristine PVA TFNC membrane was relatively easy to be fouled by BSA protein and the partial deposited BSA could not be removed by hydraulic cleaning. With the more introduction of sPVA, Fir/Ft of s-PVA/PVA TFNC membranes decreased from 20% to 2% whereas reversible fouling in total fouling (Fr/Ft) were on the contrary (increase from 80% to 98%), which suggested that most of protein deposition on modified s-PVA/PVA TFNC membrane surfaces could be washed away, showing superior antifouling property. This phenomenon was ascribed to the enrichment of hydrophilic sulfonic groups on the membrane surfaces and inner mesh walls. That is to say, s-PVA chains were homogeneously tethered throughout the inner and outer surfaces of s-PVA/PVA TFNC membranes, leading to the comprehensive improvement of the hydrophilicity of barrier layer, which inhibited the permanent adsorption of proteins. Similarly, the extent of antifouling performance enlarged slightly in accordance with FRR and pure water flux while the BSA rejection was decreased sharply when the s-PVA mass ratio exceeds 1:3. Taking all above-mentioned experimental results into consideration, the mass ratio of s-PVA/PVA (1:3) was deemed to be the optimum blend load since the optimized S-P-TFNC-1-3 membrane integratedly possessed high permeability, good selectivity, super-antifouling and biocompatible properties. Therefore, S-P-TFNC-13 membrane was chosen as a most appropriate hemodiafiltration membrane among the s-PVA/PVA TFNC membranes for the further evaluation.

Fig. 11. (A) Time-dependent fluxes for the membranes during the process of three recycles of BSA ultrafiltration at room temperature. (B) The ratio of reversible fouling (Fr) and irreversible fouling (Fir) to the total fouling (Ft = Fr + Fir), respectively.

substitution of eSO3H for eOH resulting in the increased mesh size of hydrogel barrier; the other was the improved hydrophilicity after the introduction of sulfonic groups made the hydrogel layer get looser, which was equal to enlarge hydrogel network mesh size. The concept of tailoring mesh size through a combination of reduced crosslinks and hydrophilicity driven mesh expansion is of importance as it opens up a critical path for the tune of mesh size of various hydrogel barrier. The antifouling property of the TFNC membranes was measured by the flux recovery ratio (FRR) of deionized water (DI) before and after protein filtration [37,38]. The filtration results of BSA and DI solution for three-cycle filtrations were shown in Fig. 11A. It was apparently observed that the fluxes decreased promptly (from 290–400 L m−2 h−1 bar−1 to 70–100 L m−2 h−1 bar−1) when BSA aqueous solution replaced DI solution due to the fouling caused by the adsorption or deposition of BSA onto membrane surfaces and inner pores. When the deposition and propagation of BSA became saturated on the membrane surface, the water flux kept steady in a cycle. It could be found that all modified s-PVA/PVA TFNC membranes had the higher water fluxes than virgin P-TFNC membrane, indicating that they could inhibit the adsorption or deposition of BSA onto membrane surfaces and inner pores, which was due to the incorporation of s-PVA chains with hydrophilic sulfonic groups. Besides, the adhesive or deposited proteins generally not only blocked the mesh of hydrogel barrier layer but also made the s-PVA/PVA chains more hydrophobic, affecting the diffusive and convective ability of the membranes. Thus, the long-term fouling resistance of the TFNC membranes was also investigated to evaluate the durability of antifouling properties through three cycles of

960

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

(45.8%), which should be attributed to the enlarged mesh size (increase from 6.8 nm to 7.5 nm) and better antifouling (water flux recovery increased from 79.7% to 95.8%) of the barrier layer. The expanded transport channel made the middle-molecule uremic toxin pass easily and quickly throughout the hydrogel barrier layer, which was due to that the clearance of medium molecular toxins mainly depended on the effect of convection. The bigger the mesh size of the hydrogel top layer, the higher the clearance of middle-molecule uremic toxins. Besides, the hydrogel top layer of S-P-TFNC-1-3 was more hydrophilic and showed superior antifouling ability caused by the incorporation of s-PVA, which made three-dimensional network of the hydrogel be hardly fouled by contaminants (e.g. protein and bacteria), thus reducing the transfer resistance during the dialysis process lasting for 4 h. This was also the evidence for the high-efficiency clearance of middle-molecule uremic toxin. The 60.9% lysozyme clearance was extremely good and up to now no other dialysis membranes reported in recent years’ papers listed in table 2 have achieved this effect meanwhile remaining over 95% BSA rejection (95.6%), and the simultaneous high BSA rejection was ascribed to that the mesh size of S-P-TFNC-1-3 (7.5 nm) was close to the average diameter [52] of BSA (7.8 ± 1.0 nm). The 60.9% lysozyme clearance is a preeminent breakthrough for middle-molecule clearance regarded as a tough problem surrounding the dialysis membrane all the time. Hence, this facile and efficacious mesh size control of hydrogel barrier layer integrated with antifouling performance paved the way for new type of hemodiafiltration membrane with high-efficiency middlemolecule removal.

4. Conclusions The sulfonated PVA (s-PVA) was synthesized via a facile nucleophilic substitution and blended with pure PVA to form the blending hydrogel barrier layer after crosslinking onto PAN nanofibrous scaffold to fabricate s-PVA/PVA TFNC membranes. The mesh size of s-PVA/PVA hydrogel barrier layer could be tuned finely by varying the blended content of s-PVA. Also, the anionic s-PVA molecules possessed similar functional groups such as sulfonic and hydroxy groups with heparin and could be regarded as heparin-mimetic macromolecules for the surface modification of biomaterials. The incorporation of s-PVA into the barrier layer could ameliorate the permeability, antifouling performance and biocompatibility of hydrogel top layer. This combination offered a simple and efficacious modification method to improve the comprehensive properties of pristine PVA TFNC membrane. The s-PVA/PVA TFNC membranes displayed remarkable biocompatibility (decreased protein adsorption, prolonged clotting time, suppressed platelet adhesion, lower hemolysis ratio and more benefits for cell proliferation) due to the introduction of heparin-mimicking sulfonic groups. Meanwhile, filtration test demonstrated that larger mesh sizes of hydrogel barrier layer were obtained by incorporating s-PVA chain, thus resulting in improvement of the TFNC membrane permeability and sacrificing membrane selectivity. And also, the mesh size of the hydrogel barrier layer was tuned finely by changing the blending mass ratio of s-PVA and PVA to get an optimized TFNC membrane. The optimized s-PVA/ PVA TFNC (S-P-TFNC-1-3) membrane possessed high water flux and retained BSA well simultaneously, promoting the permeability-selectivity anti-trade-off behavior of TFNC ultrafiltration membranes. Most importantly, it could cleaned 84.2% urea and 60.9% lysozyme, retaining over 95% BSA at the same time in the hemodiafiltration simulation. No other dialysis membranes had achieved this efficient dialysis performance before, in that the trade-off between high middlemolecule toxin removal and high protein retention is always a tough obstacle for dialysis membranes. All above results demonstrate that there is an enormous potential of s-PVA/PVA TFNC membranes in the application of blood purification.

Fig. 12. Solute transmission efficiency of P-TFNC membrane and S-P-TFNC-1-3 membrane: (A) urea clearance percentage; (B) lysozyme clearance percentage; (C) BSA rejection percentage.

3.5. Dialysis performance In order to evaluate the dialysis performances of the P-TFNC and SP-TFNC-1-3 membranes, the urea and lysozyme clearance and BSA rejection for the two membranes were measured by a hemodiafiltration simulation test, and the dialysis results were shown in Fig. 12. It could be easily found that the S-P-TFNC-1-3 membrane cleaned 84.2% urea and retained 95.6% BSA contemporaneously, which were comparable to those of P-TFNC membrane after simulating dialysis for 4 h. Nevertheless, with respect to middle-molecule uremic toxin removal, the lysozyme clearance of the S-P-TFNC-1-3 membrane (60.9%) was increased remarkably in comparison to that of the P-TFNC membrane 961

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

Table 2 Permeation and dialysis performance of different recently reported membranes. Membranes

PVDF PVDF/PEG PLA Heparin immobilized PLA PES PES/PVP90/f-MWCNT PLLA/PEO PLA/PSf-g-PLA Optimized PLA/PLA-PHEMA PVA TFNC Hirudin immobilized PLA Optimized PVA/s-PVA TFNC

Year

2014 2014 2014 2014 2014 2014 2015 2015 2015 2017 2017 2018

Pure water flux (L m−2 h−1 bar−1)

5.1 27.5 120 109.5 7.1 68.5 224.5 54 236 290.5 / 380

Dialysis performance

Ref. no.

Urea clearance (%)

Lysozyme clearance (%)

BSA retention (%)

10 62 74.6 79 11.5 56.3 77 65 ∼75 82.6 ∼79 84.2

/ / 12.6 17.9 1.2 27.9 33 15 ∼50 45.8 ∼34 60.9

∼98 ∼94 93.7 90.8 ∼90 ∼90 90.9 95 ∼70 98.8 ∼90 95.6

Acknowledgments [15]

This work was supported by Program of Shanghai Science and Technology Innovation International Exchange and Cooperation (15230724700) and Program for Innovative Research Team in University of Ministry of Education of China (IRT_16R13).

[16]

[17]

Appendix A. Supplementary material

[18]

Supplementary data to this article can be found online at https:// doi.org/10.1016/j.apsusc.2018.09.201.

[19]

References

[20]

[1] V. Forster, R.D. Signorell, M. Roveri, J.C. Leroux, Liposome-supported peritoneal dialysis for detoxification of drugs and endogenous metabolites, Sci. Transl. Med. 6 (2014) 258ra141. [2] E.F. Carney, Dialysis: optimal timing of arteriovenous fistula placement in elderly patients, Nat. Rev. Nephrol. 10 (2014) 613. [3] G.Y. Xiong, X.P. Chen, X.S. Li, D. Fang, L.X. Zhang, L. Yang, L. Zhang, L. Yao, Z.S. He, L.Q. Zhou, Prevalence and factors associated with baseline chronic kidney disease in China: a 10-year study of 785 upper urinary tract urothelial carcinoma patients, J. Formosan. Med. Assoc. 113 (2014) 521–526. [4] H. Sugiyama, H. Yokoyama, H. Sato, T. Saito, Y. Kohda, S. Nishi, K. Tsuruya, H. Kiyomoto, H. Iida, T. Sasaki, M. Higuchi, M. Hattori, K. Oka, S. Kagami, T. Kawamura, T. Takeda, H. Hataya, Y. Fukasawa, A. Fukatsu, K. Morozumi, N. Yoshikawa, A. Shimizu, H. Kitamura, Y. Yuzawa, S. Matsuo, Y. Kiyohara, K. Joh, M. Nagata, T. Taguchi, H. Makino, Japan renal biopsy registry and Japan kidney disease registry: committee report for 2009 and 2010, Clin. Exp. Nephrol. 17 (2013) 155–173. [5] C. Ahn, T.Y. Koo, J.C. Jeong, M. Kim, J. Yang, J. Lee, S.I. Min, J.E. Lee, M.S. Kim, O.J. Kwon, S.J. Kim, Y.H. Kim, Y.H. Kim, B.S. Choi, S.J. Choi, D.H. Lee, S.Y. Chung, W.H. Cho, Y.S. Kim, Initial report of the Korean organ transplant registry: the first report of national kidney transplantation data, Transplant. Proc. 46 (2014) 425–430. [6] H.H. Su, C.M. Kao, Y.C. Lin, Y.C. Lin, C.C. Kao, H.H. Chen, C.C. Hsu, K.C. Chen, C.C. Peng, M.S. Wu, Relationship between serum total bilirubin levels and mortality in uremia patients undergoing long-term hemodialysis: a nationwide cohort study, Atherosclerosis 265 (2017) 155–161. [7] A. Yavuz, C. Tetta, F.F. Ersoy, V. D’intini, R. Ratanarat, M. De Cal, M. Bonello, V. Bordoni, G. Salvatori, E. Andrikos, G. Yakupoglu, N.W. Levin, C. Ronco, Reviews: uremic toxins: a new focus on an old subject, Semin. Dial. 8 (2005) 203–211. [8] B.J.G. Pereira, L. Shapiro, A.J. King, M.E. Falagas, J.A. Strom, C.A. Dinarello, Plasma levels of IL-1β, TNFα and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients, Kidney Int. 45 (1994) 890–896. [9] T. Drüeke, The pathogenesis of parathyroid gland hyperplasia in chronic renal failure, Kidney Int. 48 (1995) 259–272. [10] Z. Makita, R. Bucala, E.J. Rayfield, H. Fuh, K. Manogue, A. Cerami, H. Viassara, E. Friedman, A. Kaufman, S. Korbet, Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure, Lancet 343 (1994) 1519–1522. [11] B. Gondouin, C.A. Hutchison, High cut-off dialysis membranes: current uses and future potential, Adv. Chronic Kidney Dis. 18 (2011) 180–187. [12] M. Irfan, A. Idris, N.M. Yusof, N.F.M. Khairuddin, H. Akhmal, Surface modification and performance enhancement of nano-hybrid f-MWCNT/PVP90/PES hemodialysis membranes, J. Membr. Sci. 467 (2014) 73–84. [13] T. Hasegawa, Y. Iwasaki, K. Ishihara, Preparation and performance of protein-adsorption-resistant asymmetric porous membrane composed of polysulfone/phospholipid polymer blend, Biomaterials 22 (2001) 243–251. [14] J.Y. Park, M.H. Acar, A. Akthakul, W. Kuhlman, A.M. Mayes, Polysulfone-graft-poly

[21]

[22]

[23]

[24]

[25]

[26]

[27] [28]

[29]

[30]

[31]

[32]

[33]

[34]

962

[15] [15] [17] [17] [12] [12] [18] [19] [23] [24] [20] This study

(ethylene glycol) graft copolymers for surface modification of polysulfone membranes, Biomaterials 27 (2006) 856–865. K.H. Chan, E.T. Wong, M.I. Khan, A. Idris, N.M. Yusof, Fabrication of polyvinylidene difluoride nano-hybrid dialysis membranes using functionalized multiwall carbon nanotube for polyethylene glycol (hydrophilic additive) retention, J. Ind. Eng. Chem. 20 (2014) 3744–3753. C. Radhakumary, P.D. Nair, C.P. Reghunadhan Nair, S. Mathew, Chitosan-graft-poly (vinyl acetate) for hemodialysis applications, J. Appl. Polym. Sci. 125 (2012) 2022–2033. A.L. Gao, F. Liu, L.X. Xue, Preparation and evaluation of heparin-immobilized poly (lactic acid) (PLA) membrane for hemodialysis, J. Membr. Sci. 452 (2014) 390–399. A.L. Gao, F. Liu, H.Y. Shi, L.X. Xue, Controllable transition from finger-like pores to inter-connected pores of PLLA membranes, J. Membr. Sci. 478 (2015) 96–104. X.M. Yu, F. Liu, L.H. Wang, Z. Xiong, Y.Z. Wang, Robust poly(lactic acid) membranes improved by polysulfone-g-poly(lactic acid) copolymers for hemodialysis, RSC Adv. 5 (2015) 78306–78314. J.L. Li, F. Liu, Y. Qin, J.D. He, Z. Xiong, G. Deng, Q. Li, A novel natural hirudin facilitated anti-clotting polylactide membrane via hydrogen bonding interaction, J. Membr. Sci. 523 (2017) 505–514. S.Q. Nie, M. Tang, C. Cheng, Z.H. Yin, L.R. Wang, S.D. Sun, C.S. Zhao, Biologically inspired membrane design with a heparin-like interface: prolonged blood coagulation, inhibited complement activation, and bio-artificial liver related cell proliferation, Biomater. Sci. 2 (2014) 98–109. L.J. Zhu, F. Liu, X.M. Yu, A.L. Gao, L.X. Xue, Surface zwitterionization of hemocompatible poly(lactic acid) membranes for hemodiafiltration, J. Membr. Sci. 475 (2015) 469–479. L.J. Zhu, F. Liu, X.M. Yu, L.X. Xue, Poly(lactic acid) hemodialysis membranes with poly(lactic acid)-block-poly(2-hydroxyethyl methacrylate) copolymer as additive: preparation, characterization, and performance, ACS Appl. Mater. Interf. 7 (2015) 17748–17755. X.F. Yu, L.D. Shen, Y.D. Zhu, X. Li, Y. Yang, X.F. Wang, M.F. Zhu, B.S. Hsiao, High performance thin-film nanofibrous composite hemodialysis membranes with efficient middle-molecule uremic toxin removal, J. Membr. Sci. 523 (2017) 173–184. X.F. Wang, D.F. Fang, K. Yoon, B.S. Hsiao, B. Chu, High performance ultrafiltration composite membranes based on poly(vinyl alcohol) hydrogel coating on crosslinked nanofibrous poly(vinyl alcohol) scaffold, J. Membr. Sci. 278 (2006) 261–268. I. Tokarev, S. Minko, Stimuli-responsive porous hydrogels at interfaces for molecular filtration, separation, controlled release, and gating in capsules and membranes, Adv. Mater. 22 (2010) 3446–3462. H.Y. Wang, S.C. Heilshorn, Adaptable hydrogel networks with reversible linkages for tissue engineering, Adv. Mater. 27 (2015) 3717–3736. Y. Ahn, H. Lee, D. Lee, Y. Lee, Highly conductive and flexible silver nanowire-based microelectrodes on biocompatible hydrogel, ACS Appl. Mater. Interf. 6 (2014) 18401–18407. D. Das, P. Ghosh, A. Ghosh, C. Haldar, S. Dhara, A.B. Panda, S. Pal, Stimulus-responsive, biodegradable, biocompatible, covalently cross-linked hydrogel based on dextrin and poly(N-isopropylacrylamide) for in vitro/in vivo controlled drug release, ACS Appl. Mater. Interf. 7 (2015) 14338–14351. L.Y. Cheng, X.M. Sun, X. Zhao, L. Wang, J. Yu, G.Q. Pan, B. Li, H.L. Yang, Y.G. Zhang, W.G. Cui, Surface biofunctional drug-loaded electrospun fibrous scaffolds for comprehensive repairing hypertrophic scars, Biomaterials 83 (2016) 169–181. X. Zhao, J.W. Zhao, Z.Y. Lin, G.Q. Pan, Y.Q. Zhu, Y.S. Cheng, W.G. Cui, Self-coated interfacial layer at organic/inorganic phase for temporally controlling dual-drug delivery from electrospun fibers, Colloids Surf. B Biointerf. 130 (2015) 1–9. S. Liu, J.W. Zhao, H.G. Ruan, W. Wang, T.Y. Wu, W.G. Cui, C.Y. Fan, Antibacterial and anti-adhesion effects of the silver nanoparticles-loaded poly(L-lactide) fibrous membrane, Mater. Sci. Eng. C 33 (2013) 1176–1182. Y.Q. Zhu, C.M. Hu, B. Li, H.L. Yang, Y.S. Cheng, W.G. Cui, A highly flexible paclitaxel-loaded poly(ε-caprolactone) electrospun fibrous-membrane-covered stent for benign cardia stricture, Acta Biomater. 9 (2013) 8328–8336. S.G. Yun, H. Im, Y. Heo, J. Kim, Crosslinked sulfonated poly(vinyl alcohol)/sulfonated multi-walled carbon nanotubes nanocomposite membranes for direct

Applied Surface Science 465 (2019) 950–963

Y. Zhu et al.

methanol fuel cells, J. Membr. Sci. 380 (2011) 208–215. [35] C. He, C. Cheng, S.Q. Nie, L.R. Wang, C.X. Nie, S.D. Sun, C.S. Zhao, Graphene oxide linked sulfonate-based polyanionic nanogels as biocompatible, robust and versatile modifiers of ultrafiltration membranes, J. Mater. Chem. B 4 (2016) 6143–6153. [36] R. Wang, Y. Xie, T. Xiang, S.D. Sun, C.S. Zhao, Direct catechol conjugation of mussel-inspired biomacromolecule coatings to polymeric membranes with antifouling, anticoagulant and cytocompatibility, J. Mater. Chem. B 5 (2017) 3035–3046. [37] H.M. Song, F. Ran, H.L. Fan, X.Q. Niu, L. Kang, C.S. Zhao, Hemocompatibility and ultrafiltration performance of surface-functionalized polyethersulfone membrane by blending comb-like amphiphilic block copolymer, J. Membr. Sci. 471 (2014) 319–327. [38] L.L. Li, Z.H. Yin, F.L. Li, T. Xiang, Y. Chen, C.S. Zhao, Preparation and characterization of poly(acrylonitrile-acrylic acid-N-vinyl pyrrolidinone) terpolymer blended polyethersulfone membranes, J. Membr. Sci. 349 (2010) 56–64. [39] M.N. Sarbolouki, A general diagram for estimating pore size of ultrafiltration and reverse osmosis membranes, Sep. Sci. Technol. 17 (2006) 381–386. [40] M.S. Selim, R. Seoudi, A.A. Shabaka, Polymer based films embedded with high content of ZnSe nanoparticles, Mater. Lett. 59 (2005) 2650–2654. [41] H.S. Mansur, C.M. Sadahira, A.N. Souza, A.A.P. Mansur, FTIR spectroscopy characterization of poly (vinyl alcohol) hydrogel with different hydrolysis degree and chemically crosslinked with glutaraldehyde, Mater. Sci. Eng., C 28 (2008) 539–548. [42] J. Joseph, E.D. Jemmis, Red-, blue-, or no-shift in hydrogen bonds: a unified explanation, J. Am. Chem. Soc. 129 (2007) 4620–4632. [43] G.I. Andrade, E.F. Barbosa-Stancioli, A.A.P. Mansur, W.L. Vasconcelos, H.S. Mansur, Small-angle X-ray scattering and FTIR characterization of nanostructured poly (vinyl alcohol)/silicate hybrids for immunoassay applications, J. Mater. Sci. 43 (2007) 450–463. [44] J.M. Xu, H.Z. Ni, S. Wang, Z. Wang, H.X. Zhang, Direct polymerization of a novel sulfonated poly(arylene ether ketone sulfone)/sulfonated poly(vinylalcohol)

[45] [46]

[47]

[48]

[49] [50]

[51]

[52]

[53] [54]

963

crosslinked membrane for direct methanol fuel cell applications, J. Membr. Sci. 492 (2015) 505–517. D. Rana, T. Matsuura, Surface modifications for antifouling membranes, Chem. Rev. 110 (2010) 2448–2471. Y. Xie, S.S. Li, X. Jiang, T. Xiang, R. Wang, C.S. Zhao, Zwitterionic glycosyl modified polyethersulfone membranes with enhanced anti-fouling property and blood compatibility, J. Colloid Interf. Sci. 443 (2015) 36–44. K. Ishihara, K. Fukumoto, Y. Iwasaki, N. Nakabayashi, Modification of polysulfone with phospholipid polymer for improvement of the blood compatibility. Part 2. Protein adsorption and platelet adhesion, Biomaterials 20 (1999) 1553–1559. F.Y. Tong, X.Q. Chen, L.B. Chen, P.Y. Zhu, J.F. Luan, C. Mao, J.C. Bao, J. Shen, Preparation, blood compatibility and anticoagulant effect of heparin-loaded polyurethane microspheres, J. Mater. Chem. B 1 (2013) 447–453. Y. Tamada, M. Murata, T. Hayashi, K. Goto, Anticoagulant mechanism of sulfonated polyisoprenes, Biomaterials 23 (2002) 1375–1382. R. Li, G.Z. Wu, Y. Ye, In vitro hemocompatibility of sulfonated polypropylene nonwoven fabric prepared via a facile γ-ray pre-irradiation grafting method, Appl. Surf. Sci. 356 (2015) 1221–1228. L. Ma, C. Cheng, C.X. Nie, C. He, J. Deng, L.R. Wang, Y. Xia, C.S. Zhao, Anticoagulant sodium alginate sulfates and their mussel-inspired heparin-mimetic coatings, J. Mater. Chem. B 4 (2016) 3203–3215. V. Valiño, M.F. San Román, R. Ibáñez, J.M. Benito, I. Escudero, I. Ortiz, Accurate determination of key surface properties that determine the efficient separation of bovine milk BSA and LF proteins, Sep. Purif. Technol. 135 (2014) 145–157. V. Kochkodan, N. Hilal, A comprehensive review on surface modified polymer membranes for biofouling mitigation, Desalination 356 (2015) 187–207. V. Vatanpour, S.S. Madaeni, L. Rajabi, S. Zinadini, A.A. Derakhshan, Boehmite nanoparticles as a new nanofiller for preparation of antifouling mixed matrix membranes, J. Membr. Sci. 401–402 (2012) 132–143.