Additive-free preparation of hemodialysis membranes from
silibinin-modified polysulfone polymer with enhanced performance in anti-oxidative stress and hemocompatibility
Gan Wang
a, Ning Yang
a,c,*, Ying Luo
b, Yiping Zhao
a,caState Key Laboratory of Separation Membranes and Membrane Processes, National Center for International Joint Research on Separation Membranes, School of Materials Science and Engineering, Tiangong University, Tianjin, 300387, China
bTianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Institute of Hepatobiliary Disease, Nankai University Affiliated Third Centre Hospital, China
cCangzhou Institute of Tiangong University, Cangzhou, 061000, China
A R T I C L E I N F O Keywords:
Polysulfone grafted silibinin Porogen-additive-free Anti-oxidative stress Blood purification membrane
A B S T R A C T
Oxidative stress is highly prevalent in maintenance hemodialysis patients and increases the risk of cardiovascular morbidity and mortality. Silibinin (SLB) is a plant extract with excellent antioxidant effects. The polymer of polysulfone (PSF) grafted SLB (PSF-g-SLB) was synthesized using a two-step approach, and the PSF-g-SLB membrane, a porogen-additive-free blood purification membranes made up of simply the polymer and solvent, was fabricated via the nonsolvent induced phase separation method. The results showed that, with increasing the grafting rate of PSF-g-SLB, the hydrophilicity, antioxidant properties, and the stability of free radical scavenging rate of the PSF-g-SLB membranes were improved. Furthermore, platelet-erythrocyte adhesion and hemolysis rate were decreased, and coagulation time was prolonged. The PSF-g-SLB membrane exhibits significant potential for being compatible with hemocompatibility, biocompatibility, and antioxidant properties. Therefore, the appli- cation of PSF-g-SLB membranes could alleviate oxidative stress in patients during hemodialysis.
1. Introduction
Chronic kidney disease (CKD) poses a significant worldwide public health issue [1–4]. Hemodialysis (HD) is an efficacious and promising technique for managing chronic or acute kidney diseases and is gaining prominence in the contemporary medical domain [5,6]. The progression of blood purification membranes evolved from cellulose and its de- rivatives, which are natural polymeric materials, to synthetic dialysis membranes that exhibit improved performance and reduced occurrence of complement activation [7]. The polysulfone (PSF) family of materials has emerged as a prevailing choice for blood purification membranes due to its exceptional membrane-forming properties, superior temper- ature resistance, excellent acid and alkali resistance, and remarkable mechanical properties [8]. Nevertheless, PSF polymer has obvious hy- drophobicity and poor biocompatibility, which is prone to erythrocyte adhesion, platelet adhesion, and deformation; these conditions could lead to thrombosis, coagulation [9], inflammation [10], oxidative stress [11], and other dialysis complications. Modifying the PSF blood puri- fication membrane has become one of the research hotspots.
Typically, researchers would alter the physicochemical properties of the membrane surface or regulate the membrane pore structure through blending and membrane surface functionalization and membrane ma- terial chemical modification to improve the hydrophilicity and biocompatibility of PSF blood purification membranes [12–14]. Mem- brane surface functionalization is often conducted by coating or plasma treatment or by grafting on the surface to make the hydrophobic membrane surface change into a hydrophilic surface. For example, Liu et al. [15] successfully constructed an electrically neutral hydrophilic surface by grafting natural amphiphilic trimethylamine N-oxide on the surface of the PSF membrane using the Michael addition reaction and subsequent crosslinking with glycidyl ether oxypropyl trimethoxysilane, which significantly improved the hydrophilicity of the PSF membrane.
Then, it enhanced its blood compatibility, coagulation time, and anti- microbial properties. The chemical modification of membrane polymer could not only endow membrane polymer with unique functional properties but also retain the original beneficial properties of the membrane polymer. Most chemically modified membrane polymers typically require blending with unmodified membrane polymers for
* Corresponding author. School of Materials Science and Engineering, TianGong University, Tianjin, 300387, China.
E-mail address: [email protected](N. Yang).
Contents lists available at ScienceDirect
Journal of Membrane Science
journal homepage: www.elsevier.com/locate/memsci
https://doi.org/10.1016/j.memsci.2024.123345
Received 2 July 2024; Received in revised form 13 September 2024; Accepted 16 September 2024 Journal of Membrane Science 713 (2025) 123345
Available online 18 September 2024
0376-7388/© 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
practical application. For instance, Zhao et al. [16] initially synthesized amphiphilic ionic block copolymers PDMAEMA-b-PSF-b-PDMAEMA by combining PSF and poly(N, N-dimethylamino-2-methacrylic acid ethyl ester) (PDMAEMA) through condensation polymerization and atom transfer radical polymerization. The PDMAEMA-b-PSF-b-PDMAEMA copolymer was then combined with PSF to fabricate a membrane.
Subsequently, the PDMAEMA on the surface of membranes was con- verted into amphoteric poly(carboxymethyl methacrylic acid) betaine through quaternization. This process significantly enhanced the hydro- philicity, fouling resistance, and blood compatibility of the PSF mem- branes. The ternary blending of solvent, membrane-based material, and pore-forming agent prepared traditional blood purification membranes [17–19]. However, in practical application, the structure and perfor- mance of the membrane might be impacted by the leaching of the porogen-additive. For example, during HD, the part enriched with pol- yvinylpyrrolidone (PVP) has less adsorption of platelets and proteins. In contrast, the part exposed to PSF is more likely to adsorb proteins and platelets. That is due to PVP was rich in hydroxyl groups and has a greater affinity for water molecules. When blood comes into contact with the membrane surface, it reduces the adsorption of platelets and proteins due to the “buffering effect.” Therefore, when the porogen-additive is leached out, it increases membrane hardness (af- finity less water molecules), leading to easier adsorption of proteins and decreasing the biocompatibility of the membranes [20,21]. Further- more, leached porogen-additive such as PVP might permanently accu- mulate in the kidneys, liver, and other organs, which could lead to the failure of these vital organs [22]. Thus, blend modification has stability issues, and leached porogen-additive might lead to complications from dialysis.
Hence, developing a membrane polymer with membrane-forming properties and hydrophilicity through simple chemical modification would effectively address the limitations associated with traditional approaches. Research by Ren and colleagues [23] synthesized a block copolymer methoxy polyethylene glycol-polyethersulfone block-- methoxy polyethylene glycol (mPEG-b-PES-b-mPEG) that possessed membrane-forming, pore-forming, and hydrophilic properties. Then, it was used to prepare membranes. They found that the membranes exhibited significant enhancements for removing mid-molecular toxins and hemocompatibility. They were nearly impossible to elute in HD due to the chemically bonded hydrophilic segments included. Also, as Zhong et al. [24] studied, PSF-b-PEG block copolymers showed excellent hy- drophilicity and hemocompatibility and enhanced screening of small and medium molecular toxins when prepared as membranes without additional additives.
Oxidative stress (OS) was another serial problem in HD; it could dramatically influence the progression of renal impairment. OS state was an imbalance between the overproduction of oxidants in the body and the inadequate degradation of these oxidants by the antioxidant system. It was an essential biochemical indicator of cardiovascular dis- eases (CVDs) [25,26]. Excessive OS promotes the development of CKD and renal failure, which were crucial factors contributing to increased CVDs and mortality in patients with CKD [27]. For example, it was found by the research of Dursun [28] that in the early stage of patients with CKD, antioxidant enzyme disorder would begin to appear in their bodies, and they were prone to OS during HD treatment, which might cause atherosclerosis in patients with uremia and other long-term dial- ysis complications. Nevertheless, in the study of Miroslav [29], the phenomenon of OS could be effectively inhibited by vitamin E-coated hemodialyzer in clinical practice. Therefore, HD membranes with OS-inhibiting capability effectively enhanced the survival time and quality of life for CKD patients. Our previous study [30] found that Silibinin (SLB) as a natural antioxidant for modifying PSF membranes by blending method could improve hemodialysis-induced OS. Also, Chen and colleagues [31], for example, assembled tannic acid (TA) with poly (N-acryloyl morpholine) (PACMO) on the surface of PES hollow fiber membranes through layer-by-layer hydrogen bonding. The PACMO
substantially improved the hydrophilicity and blood compatibility of PES hollow fiber membranes, and the TA conferred antioxidant prop- erties on the PES hollow fiber membranes. However, the addition of porogenic agents was also needed in this process.
Thus, inspired by previous research, the PSF-g-SLB membrane poly- mer was first prepared by chloromethylation of PSF and then by a nucleophilic substitution reaction with SLB. HD membranes consist only of solvent and membrane polymer without porogen-additive. The HD membrane was prepared using the nonsolvent-induced phase separation method, and the membrane-forming property was controlled by adjusting the grafting rate of PSF-g-SLB. Since SLB is a natural flavonoid lignan [32,33], it forms a hydrated layer on the surface of the membrane by hydrogen bonding. As a result, the membrane exhibits significant potential for being compatible with hemocompatibility, hydrophilicity, and antioxidant properties. The morphology, clearance properties, and membrane permeability were further investigated.
2. Experimental 2.1. Materials
Polysulfone (PSF, P1700) was obtained from Guangzhou Jiushun New Material Co., Ltd. Silibinin (SLB, purity ≥98.0 %) was purchased from Xi AnZelong Biotechnology Co. Ltd. N, N
′
-Dimethylformamide (DMF), methanol, ethanol absolute were purchased from Tianjin Kemiou Chemical Reagent Co., Ltd. Hydrochloric acid (HCl), tri- chloromethan were purchased from Tianjin Fengchuan Chemical Re- agent Co., Ltd. Chlorotrimethylsilane, sodium hydride (NaH), tin (IV) chloride (SnCl4) were purchased from Shanghai Macklin Biochemical Co., Ltd. 2, 2′
-Azinobis-(3-ethylbenzthiazoline-6-sulfonate) (ABTS+) and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) were provided by Solarbio.2.2. Synthesis of PSF-g-SLB polymer 2.2.1. Chloromethylation of PSF
According to reports [34], chloromethyl methyl ether (CME) or chloromethyl zinc ether (CMOE) are chloromethylation agents in chloromethylation reactions. However, these agents had been restricted due to the carcinogenicity and danger of CME and CMOE. Therefore, the chloromethylation used in this study was prepared with reference to the research of Shinichi Itsuno et al. [35] and Ecaterina Avram et al. [36]. In chloroform, paraformaldehyde and trimethylchlorosilane react in the presence of tin chloride. The reaction of paraformaldehyde and chlor- otrimethylsilane in the presence of tin chloride produces chloropropyl trimethylsilane, which has a similar structure to chloromethyl methyl ether. After a complete reaction, the excess chloromethylation agent was easily broken down during hydrolysis, making this method safer. 10 g of PSF was entirely dispersed in 500 mL of trichloromethane. Subse- quently, the reaction solution was supplemented with 226 mmol of paraformaldehyde and trimethylsilyl chloride, which served as the chlorinating agent, and 2.26 mmol of tin tetrachloride, which acted as the catalyst. The experiment was conducted at 65 ◦C for 72 h. The chloromethyl polysulfone (CMPSF) was acquired through several pro- cedures, including methanol precipitation, water washing, and drying after the reaction.
2.2.2. Synthesis of PSF-g-SLB
The synthetic route of PSF-g-SLB was according to the nucleophilic substitution reaction approach of Liu et al. [37,38] and modified. First, dissolve 5 g of CMPSF in 250 mL of DMF. Dissolve different proportions of SLB in DMF. Subsequently, a homogeneous dispersion of NaH in DMF was added to a slowly stirring SLB solution at 0 ◦C for 1 h. The reacted sodium salt was added to the stirring CMPSF solution and reacted at 60 ◦C for 24 h. Upon completion of the reaction, the reaction solution underwent precipitation through a mixture of dilute HCl, deionized water, and methanol. Subsequently, the product was subjected to water
washing and drying procedures, producing PSF-g-SLB with varying de- grees of grafting. Since flavonoids are photodegradable [39], Silibinin, a flavonoid lignan, also has a certain degree of photodegradation.
Therefore, the above reactions were carried out in the dark to avoid the photodegradation of Silibinin. The synthetic strategy for the preparation of the PSF-g-SLB was shown in Scheme 1.
Scheme. 1. Synthesis strategy of CMPSF and PSF-g-SLB. (i and (ii The chloromethylation reaction of PSF. (iii Grafting reaction of SLB with CMPSF by nucleophilic substitution reaction.(iv The antioxidant principle of SLB.
Scheme. 2.Schematic illustration for the process of preparing the PSF-g-SLB membranes.
G. Wang et al. Journal of Membrane Science 713 (2025) 123345
2.2.3. Characterization of the PSF-g-SLB polymer
Nuclear magnetic resonance spectroscopy (AVANCE AV 400 MHz, Bruker, Germany) was utilized to characterize the 1HMNR spectrum of PSF, CMPSF, and PSF-g-SLB using chloroform - d6 as solvent. Measure- ments were performed using attenuated total reflection Fourier trans- form infrared spectroscopy (ATR-FTIR, Nicolet iS50, Thermo Scientific, USA) between 4000 cm−1 and 400 cm−1 to characterize the PSF, CMPSF, and PSF-g-SLB.
2.3. Preparation of the PSF-g-SLB membrane
The PSF-g-SLB membranes with different grafting rates were pre- pared by the nonsolvent induce phase separation method shown in Scheme 2. The process was briefly concluded that the PSF-g-SLB was homogeneously dispersed in DMF through agitation at 60 ◦C for 8 h to obtain the casting solution. The casting solution was defoamed under a vacuum at 60 ◦C for 6 h. The defoamed casting solution was poured onto
the glass plate, scraped into a membrane with a 200 μm scraper, and put into a coagulation bath in deionized water. The above process was all conducted in the dark. Table 1displays the components of the casting solution.
2.4. Characterization of the PSF-g-SLB membranes
X-ray photoelectron spectroscopy (XPS, Thermo Fisher, USA) to characterize the composition of the membrane surface. The surface and cross-sectional morphology of the membranes were visualized by field emission scanning electron microscopy (FESEM, Hitachi S-4800, Japan) at an accelerating voltage of 10 kV. The membrane samples required dried and gold-sprayed treatment. The surface topography and rough- ness of the membranes were investigated by atomic force microscopy (AFM, Agilent-S5500, USA).
Usually, the water contact angle (WCA) is critical to evaluate the hydrophilic and hydrophobicity properties of the membrane. Dried membranes were fixed on a flat glass sheet to test the WCA by drop shape analysis (DSA, KRUSS GmbH, Germany). Then, the WCA values were recorded for 120 s using a video measurement technique. Experi- mental data requires at least three experiments to ensure consistency and accuracy.
Based on the previously reported method, the PEG solution was selected as the experimental model to test the molecular weight cut-off (MWCO) [40]. The molecular weights selected were 1000, 2000, 4000, 6000, 10 000, 20 000, and 40 000 Da. The MWCO measurement method was identical to the membrane separation capability measurement method. When the rejection rate was 90 %, which corresponded to the MWCO of the membrane.
Table 1
Components of the casting solution for the PSF membrane and the PSF-g-SLB membrane.
Membranes PSF (wt %)
PSF-g- SLB60 %
(wt%)
PSF-g- SLB65 %
(wt%)
PSF-g- SLB70 %
(wt%)
PSF-g- SLB75 %
(wt%)
DMF (wt%)
M0 20 0 0 0 0 80
M60 0 20 0 0 0 80
M65 0 0 20 0 0 80
M70 0 0 0 20 0 80
M75 0 0 0 0 20 80
Fig. 1.A) 1H NMR spectra of PSF, CMPSF, and PSF-g-SLB; B) 1H NMR spectra of PSF-g-SLB with different grafting degrees.
2.5. Cell viability assay
According to a previous report [41], the L929 cells were digested by trypsinized and suspended in a fresh DMEM medium, and 2 ×104 cells were inoculated on its surface after sterilization of membrane samples.
The L929 cells were incubated at 37 ◦C with a CO2 concentration of 5 %, while the culture medium was replaced every 2 days. Cell proliferation was visualized and recorded by fluorescence microscopy (BX63, Japan).
Cell proliferation at the desired time was measured by CCK-8 assay.
2.6. Dialysis simulation experiment in vitro
Uremic toxins removed during HD were differentiated according to molecular weight. For example, urea and creatinine represent low mo- lecular weight toxins, whereas β2-microglobulin represents medium molecular weight toxins. In contrast, large molecular-weight proteins must be retained. According to previous reports [42], the dialysis per- formance of modified membranes was evaluated by simulating dialysis.
Urea was used for small molecule toxins. β2-microglobulin was replaced with lysozyme of similar molecular weight due to its high price and the need to be dispensed in whole blood or plasma. BSA of similar molecular weight was used as a substitute for essential albumin. The laboratory-scale monolayer dialysis experimental installation utilized was illustrated in Scheme S1. The flow was circulated staggered, with different flow rates between the dialysate and the simulated fluid on opposite sides of the dialysis membrane and with a maximum concen- tration difference to confirm complete solute transport. The simulation
solution mainly consisted of low-molecule urea (1.5 mg/mL, 60 Da), mid-molecule lysozyme (0.04 mg/mL, 14 000 Da), and large-molecule BSA (1 mg/mL, 68 000 Da), and a PBS solution (pH =7.4) was used as the solvent to prepare the simulation solution. Dialysis was simulated at 37 ◦C for 4 h, in which the flow rates of the simulation solution and dialysis solution were maintained at 120 mL/min and 300 mL/min, respectively. 4 mL of solution was taken from both sides every 1 h and repeated for 3 times. The color development reaction of urea with p-dimethylamino benzaldehyde determined urea concentration. By UV–visible spectrophotometer, the concentrations of BSA and lysozyme were both determined at 280 nm. The urea and lysozyme clearance (CL
%) were determined by Eq. (1):
CL%=C0-Ct
C0 ×100% (1)
Where C0 and Ct (mg/mL) represent the concentration of the simulated solution (urea or lysozyme) at the initial and each hour, respectively.
Calculate the percentage of BSA retention (Re%) from Eq. (2):
Re%=Ct
C0×100% (2)
Where C0 and Ct (mg/mL) represent the concentration of BSA in the simulation solution at initial and each hour, respectively.
Fig. 2. A) FTIR spectra of SLB, PSF, CMPSF, and PSF-g-SLB; B) FTIR spectra of PSF-g-SLB with different grafting degrees.
G. Wang et al. Journal of Membrane Science 713 (2025) 123345
2.7. Statistical analysis
SPSS R26.0 statistically analyzed all experimental data. x ± s expressed values, and comparisons between groups were analyzed by t- test and variance. When the probability of difference between any two groups of data was p <0.05, it was judged as a significant difference and was expressed by *; when the probability of difference between any two groups of data was p <0.01, it was judged as a highly significant dif- ference and was expressed by **.
3. Results and discussion
3.1. Characterization of the CMPSF and PSF-g-SLB
A comparison of Figs. 1 and 2with other papers using 1H NMR and ATR-FTIR spectra confirmed that the synthesis was successful [43,44].
As shown in Fig. 1A, for CMPSF (black) spectra, the chemical shifts with
peaks at δ of 6.93, 7.85 ppm, and 1.70 ppm were Ar–H and CH3 for bisphenol A (BPA), respectively, and the peak at δ of 4.53 ppm with the new –CH2Cl peak proves the successful chloromethylation of PSF. The percentage of chloromethylation (DS, degree of substitution) on each repeating unit was determined by the 1H NMR spectrum with a proton peak at δ of 4.53 ppm relative to six isopropyl protons at δ of 1.70 ppm as reference peaks. The results expressed that the DS value of ~0.8 Cl per repeat unit for the CMPSF. While the peak in the PSF-g-SLB (red) spec- trum at δ 4.53 ppm was chemically shifted to –CH2Cl at δ 4.63 ppm, indicating the formation of a chemical bond. The phenolic hydroxyl peak at δ 9.47 ppm appeared, demonstrating successful grafting of SLB with PSF. As shown in Fig. 1B, M60 to M75 degrees of substitution was determined by the phenolic hydroxyl peak at δ of 9.47 ppm in the 1H NMR spectrum with six isopropyl protons at δ of 1.70 ppm as reference peaks. The results indicated that the degrees of substitution of M60, M65, M70, and M75 were 60 %, 65 %, 70 %, and 75 %, respectively.
As shown in Fig. 2A, SLB showed an aryl ring conjugated ketone absorption peak at 1640 cm−1 and a strong –OH absorption peak at 3442 cm−1, which were the characteristic absorption peaks of SLB, while PSF and CMPSF were without peaks at these wavelengths. PSF-g- SLB showed an aryl ring conjugated ketone peak of SLB at 1667 cm−1 and a strong –OH absorption peak at 2928 cm−1. Moreover, there were asymmetric absorption peaks of aryl sulfone group (–SO2–) at 1323 cm−1 and 1294 cm−1, stretching vibration peak of ether bond (-O-) at 1241 cm−1, C–S–C absorption peak at 716 cm−1 and symmetric stretching vibration absorption peak of –SO2- at 1082 cm−1. As a result, the PSF-g-SLB contains all the primary peaks of PSF and the character- istic peaks of the SLB. As shown in Fig. 2B, the intensity of the charac- teristic peaks of PSF-g-SLB at 1667 cm−1 and 2928 cm−1, which were the characteristic absorption peaks of SLB, was gradually increasing with the increase of grafting degree, proving that SLB content was gradually increasing. Thus, PSF-g-SLB with different grafting degrees were suc- cessfully prepared.
3.2. Characterization of the membranes
The X-ray photoelectron spectroscopy (XPS) demonstrated an enhanced content of migrated SLB on the surface of the PSF-g-SLB membrane. As shown in the full XPS spectra in Fig. 3A, O1s, C1s, and S2p peaks appeared on the surface of the M0 membrane near the binding energies of 532.80 eV, 285.25 eV, and 168.21 eV, respectively, while the modified membrane had a new Cl2p peak near the binding energy of 199.03 eV.
As shown in Fig. 3B for the C1s spectrum after Gaussian fitting treatment, M0 showed two peaks at 284.6 eV (C–H) and 286.4 eV (C–O–C) while the Cls spectra of M60-M75, the characteristic absorption peak at 288 eV (C––O) was added, and the characteristic absorption peak area gradually increased with the grafting rate of SLB in PSF-g-SLB.
The C––O on the surface of the M0 membrane was calculated and increased from 0 to 2.55 % after modification in Table S1. It demon- strated that the SLB migrating content on the surface of the PSF-g-SLB membranes was gradually enhanced with the increase of grafting degree.
Fig. 4 shows the surface and cross-sectional morphology of the membrane by SEM. The SEM images revealed that the M0 membrane surface exhibited a smooth topography. However, the PSF-g-SLB mem- branes exhibited a progressively rougher surface as the degree of grafting increased. The surface topography and roughness of the mem- branes were observed in the AFM images of Fig. 5. The M0 surface topography demonstrated relatively smoothness. In contrast, the surface topography of the modified membranes exhibited an increase in roughness with the enhancement of the grafting degree, consistent with the phenomenon observed in the surface SEM diagram of the mem- branes in Fig. 4. The surface roughness of the membranes increased from 2.02 ±0.45 nm to 7.47 ±1.06 nm, which may be due to the increase in pore size and porosity of the membrane surface caused by the Fig. 3. The membranes of A) XPS survey spectrum and B) high-resolution C1s
XPS spectra.
enrichment and segregation of SLB at the hydrophilic component to the membrane surface, resulting in an impaved and uneven surface. All membranes had typical asymmetric structures observed from the cross- sectional images of the membranes in Fig. 4. The M0 membrane has a dense separation skin layer and a finger pore structure. In contrast, the PSF-g-SLB membrane has a dense, thin separation skin layer and a dense, sponge-like pore structure. Because of the strong hydrophilicity of the SLB in the PSF-g-SLB membrane, the phase separation on the membrane surface was accelerated during the membrane formation process, resulting in the formation of a dense skin layer, which slowed down the relative diffusion rate between the solvent DMF and the solidification bath water inside the skin layer, thus forming a dense sponge-like pore structure. Meanwhile, the porosity increases as the degree of grafting increases. The findings indicated that the porosity of the membrane exhibited a positive correlation with the degree of grafting of the modified membranes, as depicted in Fig. S1. This observation was consistent with the cross-sectional structure of the modified membranes, as illustrated in Fig. 4.
The surface roughness of the membrane positively influences the
hydrophilicity [45]. Table 2showed the water contact angles (WCAs) of the membranes. The original WCAs exhibited by the membranes fol- lowed the order of M0>M60>M65>M70>M75. M0 exhibited the inherent hydrophobicity of PSF membranes with the initial WCAs as high as 88◦, while the WCAs of M0 decreased by only 3◦within 120 s, further demonstrating the poor wettability of PSF membranes. By contrast, the original WCAs of the PSF-g-SLB membranes were decreased to 73◦(M60), 72◦(M65), 68◦(M70), and 67◦(M75), respectively. The WCAs exhibited by M75 experienced a reduction of approximately 8◦ within 120 s, the lowest WCAs among the modified membranes since it possesses the highest degree of SLB grafting. The findings demonstrated an enhancement in the hydrophilicity of the modified membranes, which was anticipated to inhibit protein adsorption and mitigate com- plement activation in the dialysis process.
3.3. Basic performance of membrane
The methods of pure water flux and BSA rejection of the membranes cloud be found in SI, and the results were showed in Table 2. M0 Fig. 4. Morphology structure of the membrane. Surface SEM magnification: a1-a5, ×60K. Cross-section SEM magnification: b1-b5, ×600, c1-c5, ×5.0k, d1- d4, 20.0k
G. Wang et al. Journal of Membrane Science 713 (2025) 123345
exhibited a water flux of only 6 L/m2h, while the BSA rejection rate was 99 %, related to its compact skin layer. The pure water flux of the modified membrane remarkably increased with the enlargement of the grafting degree, especially the pure water flux of M75 reached 222 L/
m2h and the BSA rejection rate was 96 %. Combined with the cross- sectional electron microscopy of the membranes in Fig. 4 and the membrane porosity in Fig. S1, the porosity and pore diameter of the membranes increased with the grafting rate of SLB, the membrane pore diameter became larger in a gradient, and the membrane skin was quite dense. Consequently, the modified membrane exhibited a noteworthy increase in pure water flux while maintaining a BSA rejection rate of over 95 %.
HD was required to replace the kidneys to remove low-molecule toxins like urea (60 Da) and mid-molecule toxins like β2-microglobulin (14 000 Da) and to avoid hypoalbuminemia during HD, which requires the retention of large-molecule proteins like albumin (68 000 Da).
Table 2 shows that the MWCO of M0 is 10 700 Da. Meanwhile, the MWCO of the modified membrane gradually enlarges as β2 (14 000 Da)
<M60 (18 100 Da) <M65 (19 900 Da) <M70 (30 300 Da) <M75 (34 200 Da) <BSA (68 000 Da), consequently the MWCO of the modified membrane satisfied the requirement of HD removal of low and mid-
molecule toxins and retention of large-molecule proteins. The data presented in Fig. 6indicates a positive correlation between the degree of grafting and the pore size of the membranes.
3.4. Antioxidant of membrane
Antioxidant properties of the membrane were characterized by DPPH and ABTS+free radical scavenging and lipid peroxidation inhi- bition experiments, and these methods could be found in the SI.
The DPPH radical scavenging method has been extensively utilized Fig. 5. The surface topography morphology and roughness of the membranes.
Table 2
The basic performance of the investigated membranes in this work.
Membrane Pure water flux (L/
m2h)
BSA rejection (%)
0s Water contact angles (◦)
120s Water contact angles (◦)
MWCO
（Da）
M0 6 99 88 85 10 700
M60 115 99 73 62 18 100
M65 145 99 72 60 19 900
M70 180 98 68 59 30 300
M75 222 96 67 59 34 200
Fig. 6. Pore size distribution of the pristine PSF and PSF-g-SLB membranes.
to evaluate compounds free radical scavenging ability due to its rapidity, simplicity, and cheapness [46]. The ABTS+radical scavenging method was convenient and prevalent for evaluating the total antioxidant ca- pacity of biological samples and applied to hydrophilic and lipophilic antioxidants [47]. Advanced lipid peroxidation end products are stable polymerization products derived from the reaction of proteins or amino acid residues, which interfere with cellular and organism functions closely associated with diseases like diabetes and CVDs [48].
Fig. 7illustrated the evaluation of the antioxidant performance of the membrane. The M0 exhibited weak free radical scavenging activity and inhibition of lipid peroxidation. It was observed in Fig. 7A and B that the modified membrane alters the color of the DPPH/ABTS+solution from deep to shallow. From Fig. 7A, the modified membranes significantly enhanced DPPH radical scavenging activity compared to M0 (0.041 μmol/cm2). Especially, the scavenging activity of M75 for DPPH radicals was up to 0.441 μmol/cm2. From Fig. 7B, the modified membranes displayed a remarkable enhancement in ABTS+radical scavenging ac- tivity compared to M0 (0.059 μmol/cm2). Notably, the ABTS+radical scavenging activity of M75 was up to 0.700 μmol/cm2. As shown in Fig. 7C, M0 (8.8 %) had a weak lipid peroxidation inhibition capacity.
Whereas the lipid peroxidation inhibition ability of the modified mem- branes intensified with the enhancement of the grafting degree, the lipid peroxidation inhibition ratio of the modified membranes was over 90 %.
Compared with the study of Jia [30] and Xiao [49], PSF-g-SLB mem- branes were more capable of DPPH and ABTS+radicals scavenging, and PSF-g-SLB membranes demonstrated a stronger ability to inhibit lipid peroxidation compared with the study of Fu and his colleagues [50].
The OS induced by the HD process was commonly recognized as a biochemical marker that impacts the severity of CKD [25,26]. Therefore it was worthwhile and important for HD membranes to have the ability to inhibit OS. In summary, the scavenging activity of modified mem- branes for DPPH and ABTS+free radicals and the inhibition rate of lipid peroxidation were remarkably enhanced compared to M0. The modified membranes exhibited excellent antioxidant properties.
The radical scavenging rate of M0 and the PSF-g-SLB membranes stored for 60 days were tested, and the results are plotted in Fig. S2. The membranes maintained the same stable radical scavenging activities during a certain period(1–60 d). For M75, the DPPH free radical scav- enging rates were 87.8 %, 86.4 %, 87.7 %, and 81.1 % for 1, 7, 30, and 60 days. Meanwhile, for the PSF-g-SLB membrane, the ABTS+radical scavenging rate was nearly undiminished within 60 days.
Under the simulated HD conditions (Fig. S3), M60, M65, M70, and M75 had no difference after shaking in 37 ◦C PBS for 4 h, while the free radical scavenging efficiency remained relatively high (46.7 % (M60), 83.2 % (M65), 84.4 % (M70) and 85.3 % (M75)). These results indicated that the PSF-g-SLB membranes maintained their antioxidant activities during the typical HD process.
3.5. Membrane hemocompatibility
The hemocompatibility of the membranes were evaluated by an anti- protein adsorption test, hemolysis ratio, platelet and erythrocyte adhe- sion, and clotting time; these methods could be found in the SI.
3.5.1. Membrane anti-protein adsorption
The anti-protein adsorption of the membranes could be seen in Fig. 9A. It exhibited high BSA adsorption on M0 of 81.32 μg/cm2. The modified membranes performed superior anti-protein adsorption, reducing BSA adsorption from 44.56 μg/cm2 to 15.39 μg/cm2. As shown in the surface topography of the membranes in Fig. 5and the WCAs test of the membranes in Table 2, the membrane surface had enhanced hy- drophilicity, which consequently caused the formation of a hydrated layer on the membrane surface more conveniently, thereby reducing the adsorption of BSA protein on the membrane surface.
Fig. 7. A) DPPH, B) ABTS+free radical scavenging activity, and C) Lipid per- oxidation inhibition ratio of the pristine PSF and PSF-g-SLB membranes.
G. Wang et al. Journal of Membrane Science 713 (2025) 123345
3.5.2. Hemolysis ratio
The hemolysis ratio tests erythrocyte damage and is an essential indicator of membrane hemocompatibility [51]. According to the data in Fig. 9B, the hemolysis ratio observed for the PSF-g-SLB membranes were significantly lower than that of M0, with values of 2.3 %, 1.6 %, 1.3
%, and 1.2 %, respectively. Thus, it was demonstrated that the PSF-g-SLB membrane had superior hemocompatibility.
3.5.3. Platelet and erythrocyte adhesion
Hemocompatibility is evaluated more visually by observing the adhesion of erythrocytes and platelets to membranes than by anti- protein adsorption.
As shown in Fig. 8A, platelet clustering on M0 and the formation of root-like pseudopods were extended and deformed. It means platelet activation. In contrast, the number of platelets adhering to the modified membrane was depressed because of the heightened hydrophilicity of the surface. As shown in the adhesion of erythrocytes in Fig. 8B, the M0 surface presented a massive aggregation of erythrocytes with deforma- tion and breakage. The adhesion and deformation of the erythrocyte on the modified membrane were significantly inhibited. Owing to the segregation and enrichment of hydrophilic chain segments of SLB to the membrane surface, the hydrophilicity of the membrane surface was enhanced, and a hydration layer was constructed. It significantly in- hibits the adhesion, aggregation, and activation of platelets and
erythrocytes.
3.5.4. Clotting time
The present study employed APTT, PT, and TT as measures to assess the anticoagulant efficacy of the dialysis membrane.
The clotting times APTT, PT, and TT for the membranes were illus- trated in Fig. 9C. The clotting times of commercial PSF membranes were nearly undifferentiated from the PPP (APTT, 38 s; PT, 11.5 s; TT, 17 s).
By contrast, the clotting times of the modified membranes M70 and M75 were prolonged with increasing grafting degrees. Noticeably, M75 had the longest clotting time, with APTT extending from 38 s to 44.5 s. While the extension of PT and TT from 11.5 s to 12.2 s and from 17 s to 18.5 s, respectively, was inconspicuous. The results were coherent with the results of hemolysis and anti-protein adsorption tests. Due to the heightened hydrophilicity formed a hydrated layer on the membrane surface, inhibiting plasma protein adhesion and erythrocyte breakage.
As a result, the duration of plasma coagulation factors activated by the modified membrane in contact with blood was prolonged. Coagulation pathway activation was effectively delayed [52].
3.6. Cytotoxicity assay
In order to conduct a more comprehensive analysis of the biocom- patibility of the innovative HD membrane, an assessment was performed Fig. 8. SEM images of A) platelet adhesion and B) erythrocyte adhesion of the pristine PSF and PSF-g-SLB membranes.
to determine the cytotoxicity of the PSF-g-SLB membranes. The L929 cells were inoculated on the membrane surface at the identical original density. The process of cell proliferation was visualized through the utilization of a fluorescence microscope (BX63, Japan) (Fig. 10A). The L929 cells proliferated favorably on the PSF-g-SLB modified membrane by visualizing the proliferation of L929 cells at 1, 3, and 5 days. The CCK-8 assay was conducted to further assess the cytocompatibility of the membranes (Fig. 10B). The CCK-8 results showed no discrepancy be- tween the membranes (*p >0.05), indicating that the materials had no adverse effects on cell growth.
3.7. Membrane sieving performance
The capacity of the membranes to solute-sieving solutes was evalu- ated by measuring the clearance of low-molecular urea (60 Da), mid- molecular lysozyme (14 600 Da), and retention of large-molecular bovine serum albumin (68 000 Da). As shown by the simulated Fig. 9. A) Anti-protein adsorption, B) Hemolysis ratio, and C) Clotting time of
the pristine PSF and PSF-g-SLB membranes.
Fig. 10.A) Fluorescence microscope ( ×200) and B) L929 cells proliferation on the surfaces of the membranes.
G. Wang et al. Journal of Membrane Science 713 (2025) 123345
dialysis for 4 h in Fig. 11. The results indicated that the M70 and M75 performed better removal of low-molecular urea with 72 % and 83 %, respectively (Fig. 11A). The removal of lysozyme was 45 % and 52 % for M70 and M75, respectively (Fig. 11B). All membranes exhibited a BSA rejection rate of over 91 % (as shown in Fig. 11C) concurrently, thereby preventing the loss of crucial proteins during dialysis. Typically, low- molecules exhibit a higher rate of mass transfer compared to mid- molecules, which is why the rate of removal increase of urea is more than that of lysozyme. Owing to the enlarged pore diameter (Fig. 6, M0 (2.6 nm) <M60(3.4 nm) <M65(3.3 nm) <M70(4.5 nm) <M75(4.6 nm)) and high porosity (Fig. S1, M0(25 %) <M60(64 %) <M65(73 %)
<M70(81 %) <M75(83 %)) of the PSF-g-SLB membrane, causes the PSF-g-SLB membrane has a more robust ability to remove low and mid- sized molecules of toxins.
These results indicated that the PSF-g-SLB membrane could accom- modate dialysis demands and effectively inhibit OS during HD. In contrast, the overall performance of the PSF-g-SLB membrane is superior to most dialysis membranes reported in the academic literature. In Table 3, we present a comprehensive overview of the overall perfor- mance of the membranes, including pure water flux, DPPH, ABTS+ radical scavenging capacity, and solute screening performance.
Compared to the membranes with antioxidant properties in the table, PSF-g-SLB not only does not only required no additives but also has superior antioxidant properties, higher pure water flux, and superior solute separation properties. It had comparable pure water flux with additive-free HD membranes such as mPEG-b-PES-b-mPEG-based membranes. Although the solute separation performance was slightly lower, the PSF-g-SLB membrane had antioxidant properties, which could effectively inhibit OS during HD. The pure water flux was comparable to commercial HD membranes, with a slightly weaker ability to remove small and medium molecular toxins. These results showed that the PSF- g-SLB antioxidant HD membrane was promising for HD membranes.
4. Conclusion
This study successfully synthesized PSF-g-SLB membrane polymer using chloromethylated PSF and nucleophilic substitution reaction. By regulating the extent of grafting, the membrane-forming property, hy- drophilicity, antioxidant property, and blood compatibility of PSF-g-SLB were optimally balanced. A nonsolvent induce phase separation method prepared additive-free blood purification membranes M60, M65, M70, and M75. The natural flavonoid lignan SLB improved the hydrophilicity, hemocompatibility, permeability, and sieving properties of the PSF-g- SLB membranes and conferred significant radical scavenging ability.
The membrane exhibited strong hydrophilicity and hemocompatibility (effective inhibition of platelet-erythrocyte adhesion, low hemolysis Fig. 11. A) urea clearance ratio; B) lysozyme clearance ratio; C) BSA retention
ratio of the pristine PSF and PSF-g-SLB membranes.
Table 3
Comparisons of the comprehensive capacity of PSF-g-SLB membranes with those reported in the literature.
Membranes Flux
(L/ m2h)
Clearance rate (%) Scavenging free radicals (μmol/
cm2) Urea
(60 Da) Lysozyme (14
000 Da) DPPH ABTS+
PSF/SLB [30] 102 53 41 0.350 0.700
PSF/RES [53] 106 90 75 0.240 0.690
TA-PACMO
Functionalized [31] – 75 60 0.181 0.516
mPEG-b-PES-b-mPEG-
based [23] 248 96 60 – –
Linoleic acid-modified
PSF [54] – – – 0.03 –
PCL-grafted lignin/
PCL nanofiber [55] – – – 0.054 –
FX 60 210 91 76 – –
This study 222 83 52 0.441 0.700
rate; M75 extends APTT time by 6.5 s) and remarkable and stable antioxidant properties (Scavenging capacity for DPPH (0.441 μmol/cm2 for M75) and ABTS+(0.700 μmol/cm2 for M75) free radicals, which were also maintained at a high level after 60 d). In conclusion, a porogen-additive-free PSF-g-SLB blood purification membrane has excellent permeability separation performance and blood compatibility, which could effectively inhibit OS and reduce the occurrence of dialysis- related complications. It has a promising application in the field of blood purification.
CRediT authorship contribution statement
Gan Wang: Writing – original draft. Ning Yang: Writing – review &
editing, Conceptualization. Ying Luo: Writing – original draft, Conceptualization. Yiping Zhao: Writing – review & editing.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
Data will be made available on request.
Acknowledgements
This research is supported by Key Research & Development projects in Cangzhou (No. 222104005), Cangzhou Institute of Tiangong Uni- versity (No. TGCYY-F-0206). We would like to thank the Analytical &
Testing Center of Tiangong University.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.memsci.2024.123345.
References
[1] P. Cockwell, L.-A. Fisher, The global burden of chronic kidney disease, Lancet 395 (10225) (2020) 662–664, https://doi.org/10.1016/s0140-6736(19)32977-0.
[2] K. Kalantar-Zadeh, T.H. Jafar, D. Nitsch, B.L. Neuen, V. Perkovic, Chronic kidney disease, Lancet 398 (10302) (2021) 786–802, https://doi.org/10.1016/s0140- 6736(21)00519-5.
[3] J.A. Kellum, P. Romagnani, G. Ashuntantang, C. Ronco, A. Zarbock, H.J. Anders, Acute kidney injury, Nat. Rev. Dis. Prim. 7 (1) (2021) 52, https://doi.org/10.1038/
s41572-021-00284-z.
[4] K.A. Barraclough, J.W.M. Agar, Green nephrology, Nat. Rev. Nephrol. 16 (5) (2020) 257–268, https://doi.org/10.1038/s41581-019-0245-1.
[5] N. Said, W.J. Lau, Y.C. Ho, S.K. Lim, M.N. Zainol Abidin, A.F. Ismail, A review of commercial developments and recent laboratory research of dialyzers and membranes for hemodialysis application, Membranes 11 (10) (2021), https://doi.
org/10.3390/membranes11100767.
[6] Y.S. Tang, Y.C. Tsai, T.W. Chen, S.Y. Li, Artificial kidney engineering: the development of dialysis membranes for blood purification, Membranes 12 (2) (2022) 177–193, https://doi.org/10.3390/membranes12020177.
[7] P.G. Kerr, L. Huang, Review: membranes for haemodialysis, Nephrology 15 (4) (2010) 381–385, https://doi.org/10.1111/j.1440-1797.2010.01331.x.
[8] E.R. Radu, S.I. Voicu, V.K. Thakur, Polymeric membranes for biomedical applications, Polymers 15 (3) (2023), https://doi.org/10.3390/polym15030619.
[9] F. Poppelaars, B. Faria, M. Gaya da Costa, C.F.M. Franssen, W.J. van Son, S.
P. Berger, M.R. Daha, M.A. Seelen, The complement system in dialysis: a forgotten story? Front. Immunol. 9 (2018) 71–83, https://doi.org/10.3389/
fimmu.2018.00071.
[10] De la F. Monica, M. Jaime, An update of the oxidation-inflammation theory of aging the involvement of the immune system in Oxi-Inflamm-Aging, Curr.
Pharmaceut. Des. 15 (26) (2009) 3003–3026, https://doi.org/10.2174/
138161209789058110.
[11] S. Verma, P. Singh, S. Khurana, N.K. Ganguly, R. Kukreti, L. Saso, D.S. Rana, V. Taneja, V. Bhargava, Implications of oxidative stress in chronic kidney disease: a review on current concepts and therapies, Kidney Res, Clin. Pract. 40 (2) (2021) 183–193, https://doi.org/10.23876/j.krcp.20.163.
[12] O.E.M. ter Beek, D. Pavlenko, D. Stamatialis, Hollow fiber membranes for long- term hemodialysis based on polyethersulfone-SlipSkin™ polymer blends, J. Membr. Sci. 604 (2020), https://doi.org/10.1016/j.memsci.2020.118068.
[13] M. Bonomini, L. Piscitani, L. Di Liberato, V. Sirolli, Biocompatibility of surface- modified membranes for chronic hemodialysis therapy, Biomedicines 10 (4) (2022), https://doi.org/10.3390/biomedicines10040844.
[14] J.Y. Park, M.H. Acar, A. Akthakul, W. Kuhlman, A.M. Mayes, Polysulfone-graft- poly(ethylene glycol) graft copolymers for surface modification of polysulfone membranes, Biomaterials 27 (6) (2006) 856–865, https://doi.org/10.1016/j.
biomaterials.2005.07.010.
[15] Y. Liu, G. Li, Q. Han, H. Lin, Q. Li, G. Deng, F. Liu, Construction of electro-neutral surface on dialysis membrane for improved toxin clearance and anti-coagulation/
inflammation through saltwater fish inspired trimethylamine N-oxide (TMAO), J. Membr. Sci. 641 (2022), https://doi.org/10.1016/j.memsci.2021.119900.
[16] Y.F. Zhao, L.P. Zhu, Z. Yi, B.K. Zhu, Y.Y. Xu, Improving the hydrophilicity and fouling-resistance of polysulfone ultrafiltration membranes via surface zwitterionicalization mediated by polysulfone-based triblock copolymer additive, J. Membr. Sci. 440 (2013) 40–47, https://doi.org/10.1016/j.memsci.2013.03.064.
[17] Y. Raharjo, M.N. Zainol Abidin, A.F. Ismail, M.Z. Fahmi, Saiful, M. Elma, D. Santoso, H. Haula, A.R. Habibi, Dialysis membranes for acute kidney injury, Membrane 12 (3) (2022), https://doi.org/10.3390/membranes12030325.
[18] C. Ronco, A. Brendolan, C. Crepaldi, M. R, Blood and dialysate flow distributions in hollow-fiber hemodialyzers analyzed by computerized helical scanning technique, J. Am. Soc. Nephrol. 13 (1) (2002) S53–S61, https://doi.org/10.1681/ASN.
V13suppl_1s53.
[19] L. Pieroni, S. Levi Mortera, V. Greco, V. Sirolli, M. Ronci, P. Felaco, G. Fucci, S. De Fulviis, R. Massoud, S. Condo, A. Capria, N. Di Daniele, S. Bernardini, A. Urbani, M. Bonomini, Biocompatibility assessment of haemodialysis membrane materials by proteomic investigations, Mol. Biosyst. 11 (6) (2015) 1633–1643, https://doi.
org/10.1039/c5mb00058k.
[20] K. Namekawa, M. Matsuda, M. Fukuda, A. Kaneko, K. Sakai, Poly(N-vinyl-2- pyrrolidone) elution from polysulfone dialysis membranes by varying solvent and wall shear stress, J. Artif. Organs 15 (2) (2012) 185–192, https://doi.org/10.1007/
s10047-012-0629-5.
[21] C. Neelakandan, T. Chang, T. Alexander, L. Define, M. Evancho-Chapman, T. Kyu, In vitro evaluation of antioxidant and anti-inflammatory properties of genistein- modified hemodialysis membranes, Biomacromolecules 12 (7) (2011) 2447–2455, https://doi.org/10.1021/bm200591q.
[22] K. Namekawa, A. Kaneko, K. Sakai, S. Kunikata, M. Matsuda, Longer storage of dialyzers increases elution of poly(N-vinyl-2-pyrrolidone) from polysulfone-group dialysis membranes, J. Artif. Organs 14 (1) (2011) 52–57, https://doi.org/
10.1007/s10047-011-0552-1.
[23] J. Ren, X. Yang, W. Yan, X. Feng, Y. Zhao, L. Chen, mPEG-b-PES-b-mPEG-based candidate hemodialysis membrane with enhanced performance in sieving, flux, and hemocompatibility, J. Membr. Sci. 657 (2022), https://doi.org/10.1016/j.
memsci.2022.120680.
[24] D. Zhong, Z. Wang, J. Zhou, Y. Wang, Additive-free preparation of hemodialysis membranes from block copolymers of polysulfone and polyethylene glycol, J. Membr. Sci. 618 (2021), https://doi.org/10.1016/j.memsci.2020.118690.
[25] K. Daenen, A. Andries, D. Mekahli, A. Van Schepdael, F. Jouret, B. Bammens, Oxidative stress in chronic kidney disease, Pediatr. Nephrol. 34 (6) (2019) 975–991, https://doi.org/10.1007/s00467-018-4005-4.
[26] A. Scholze, J. Jankowski, J. Pedraza-Chaverri, P. Evenepoel, Oxidative stress in chronic kidney disease, Oxid. Med. Cell. Longev. 2016 (2016) 8375186, https://
doi.org/10.1155/2016/8375186.
[27] C. Vida, C. Oliva, C. Yuste, N. Ceprian, P.J. Caro, G. Valera, I. Gonzalez de Pablos, E. Morales, J. Carracedo, Oxidative stress in patients with advanced CKD and renal replacement therapy: the Key role of peripheral blood leukocytes, Antioxidants 10 (7) (2021), https://doi.org/10.3390/antiox10071155.
[28] E. Dursun, T. Ozben, G. Süleymanlar, B. Dursun, G. Yakupoglu, Effect of hemodialysis on the oxidative stress and antioxidants, Clin. Chem. Lab. Med. 40 (10) (2002) 1009–1013, https://doi.org/10.1515/CCLM.2002.175.
[29] Miroslav Mydlík, K. Derzsiov´a, O. Racz, A. ´ Sipulovˇ ´a, E. Lov´asov´a, J. Petroviˇcov´a, A modified dialyzer with vitamin E and antioxidant defense parameters, Kidney Int. 59 (2001) S144–S147, https://doi.org/10.1046/j.1523-1755.2001.59780144.
[30] N. Yang, X. Jia, D. Wang, C. Wei, Y. He, L. Chen, Y. Zhao, Silibinin as a natural x.
antioxidant for modifying polysulfone membranes to suppress hemodialysis- induced oxidative stress, J. Membr. Sci. 574 (2019) 86–99, https://doi.org/
10.1016/j.memsci.2018.12.056.
[31] Q. Chen, Y. He, Y. Zhao, L. Chen, Tannic acid and Poly(N-acryloyl morpholine) layer-by-layer built hemodialysis membrane surface for intervening oxidative stress integrated with high biocompatibility and dialysis performance, J. Membr.
Sci. 621 (2021), https://doi.org/10.1016/j.memsci.2020.118896.
[32] J. Post-White, E.J. Ladas, K.M. Kelly, Advances in the use of milk thistle (Silybum marianum), Integr. Cancer Ther. 6 (2) (2007) 104–109, https://doi.org/10.1177/
1534735407301632.
[33] H.S. Tuli, S. Mittal, D. Aggarwal, G. Parashar, N.C. Parashar, S.K. Upadhyay, T.
S. Barwal, A. Jain, G. Kaur, R. Savla, K. Sak, M. Kumar, M. Varol, A. Iqubal, A.
K. Sharma, Path of Silibinin from diet to medicine: a dietary polyphenolic flavonoid having potential anti-cancer therapeutic significance, Semin. Cancer Biol. 73 (2021) 196–218, https://doi.org/10.1016/j.semcancer.2020.09.014.
[34] T. Li, X. Yan, J. Liu, X. Wu, X. Gong, D. Zhen, S. Sun, W. Chen, G. He, Friedel-Crafts alkylation route for preparation of pendent side chain imidazolium-functionalized polysulfone anion exchange membranes for fuel cells, J. Membr. Sci. 573 (2019) 157–166, https://doi.org/10.1016/j.memsci.2018.11.079.
G. Wang et al. Journal of Membrane Science 713 (2025) 123345
[35] S. Itsuno, K. Uchikoshi, K. Ito, Novel method for halomethylation of cross-linked polystyrenes, J. Am. Chem. Soc. 112 (1990) 8187–8188, https://doi.org/10.1021/
ja00178a064.
[36] E. Avram, E. Butuc, C. Luca, I. Druta, Polymers with pendant functional group. III.
Polysulfones containing viologen group, J. Macromol. Sci., Pure Appl. Chem. 34 (9) (1997) 1701–1714, https://doi.org/10.1080/10601329708010036.
[37] C.T. Bibeau, B.K. Hubbard, C.J. Abelt, A facile dialkyl ether cleavage and rearrangement under mildly basic conditions during the Williamson synthesis with ß-cyclodextrin, Chem. Commun. (5) (1997) 437–438, https://doi.org/10.1039/
a607829j.
[38] M.A. Siyad, G.S.V. Kumar, Synthesis and characterization of linear and cyclic endothelin peptides on PEGylated poly(O-benzyl ether) dendrimeric supports, Polymer 67 (2015) 80–91, https://doi.org/10.1016/j.polymer.2015.04.033.
[39] H. Chaaban, I. Ioannou, C. Paris, C. Charbonnel, M. Ghoul, The photostability of flavanones, flavonols and flavones and evolution of their antioxidant activity, J. Photochem. Photobiol., A 336 (2017) 131–139, https://doi.org/10.1016/j.
jphotochem.2016.12.027.
[40] A. Roy, P. Dadhich, S. Dhara, S. De, In vitro cytocompatibility and blood compatibility of polysulfone blend, surface-modified polysulfone and
polyacrylonitrile membranes for hemodialysis, RSC Adv. 5 (10) (2015) 7023–7034, https://doi.org/10.1039/c4ra13460e.
[41] J. Zheng, L. Wang, X. Zeng, X. Zheng, Y. Zhang, S. Liu, X. Shi, Y. Wang, X. Huang, L. Ren, Controlling the integration of polyvinylpyrrolidone onto substrate by quartz crystal microbalance with dissipation to achieve excellent protein resistance and detoxification, ACS Appl. Mater. Interfaces 8 (29) (2016) 18684–18692, https://doi.org/10.1021/acsami.6b04348.
[42] X. Yu, L. Shen, Y. Zhu, X. Li, Y. Yang, X. Wang, M. 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, https://doi.org/10.1016/j.memsci.2016.09.057.
[43] D. Pooja, D.J. Babu Bikkina, H. Kulhari, N. Nikhila, S. Chinde, Y.M. Raghavendra, B. Sreedhar, A.K. Tiwari, Fabrication, characterization and bioevaluation of silibinin loaded chitosan nanoparticles, Int. J. Biol. Macromol. 69 (2014) 267–273, https://doi.org/10.1016/j.ijbiomac.2014.05.035.
[44] H. Toiserkani, G. Yilmaz, Y. Yagci, L. Torun, Functionalization of polysulfones by click chemistry, Macromol. Chem. Phys. 211 (22) (2010) 2389–2395, https://doi.
org/10.1002/macp.201000245.
[45] X. Yan, L. Yang, Y. An, W. Jin, Y. Li, B. Li, Surface roughness and hydrophilicity enhancement of polyolefin-based membranes by three kinds of plasma methods, Surf. Interface Anal. 47 (4) (2015) 545–553, https://doi.org/10.1002/sia.5747.
[46] S. Baliyan, R. Mukherjee, A. Priyadarshini, A. Vibhuti, A. Gupta, R.P. Pandey, C.- M. Chang, Determination of antioxidants by DPPH radical scavenging activity and quantitative phytochemical analysis of Ficus religiosa, Molecules 27 (4) (2022), https://doi.org/10.3390/molecules27041326.
[47] A. Floegel, D.-O. Kim, S.-J. Chung, S.I. Koo, O.K. Chun, Comparison of ABTS/DPPH assays to measure antioxidant capacity in popular antioxidant-rich US foods, J. Food Compos. Anal. 24 (7) (2011) 1043–1048, https://doi.org/10.1016/j.
jfca.2011.01.008.
[48] G. Aldini, G. Vistoli, M. Stefek, N. Chondrogianni, T. Grune, J. Sereikaite, I. Sadowska-Bartosz, G. Bartosz, Molecular strategies to prevent, inhibit, and degrade advanced glycoxidation and advanced lipoxidation end products, Free Radic. Res. 47 (2013), https://doi.org/10.3109/10715762.2013.792926.
[49] T. Xiao, Y. Wang, H. Wang, Y. Zhang, J. Zhou, Q. Zhao, Anticoagulant and antioxidant properties of hemodialysis membranes modified by hydrogels incorporating carbon dots, J. Membr. Sci. 692 (2024) 122318.
[50] X. Fu, T. Lei, S. Song, L. Xia, Y. Xiao, G. Xiao, Preparation and hemocompatibility of novel antioxidant-modified polyethersulfone membranes as red blood cell thrombosis inhibitors, Macromol. Biosci. (2024), https://doi.org/10.1002/
mabi.202300496.
[51] J. Wang, M. Qiu, C. He, A zwitterionic polymer/PES membrane for enhanced antifouling performance and promoting hemocompatibility, J. Membr. Sci. 606 (2020), https://doi.org/10.1016/j.memsci.2020.118119.
[52] Y. Liu, G. Li, Q. Han, H. Lin, Q. Li, J. Hua, F. Liu, Anticoagulant dialyzer with enhanced Ca2+chelation and hydrophilicity for heparin free hemodialysis, J. Membr. Sci. 604 (2020), https://doi.org/10.1016/j.memsci.2020.118082.
[53] X. Qi, N. Yang, Y. Luo, X. Jia, J. Zhao, X. Feng, L. Chen, Y. Zhao, Resveratrol as a plant type antioxidant modifier for polysulfone membranes to improve hemodialysis-induced oxidative stress, Mater. Sci. Eng., C 123 (2021) 111953, https://doi.org/10.1016/j.msec.2021.111953.
[54] F.C. Kung, J.J. Chang, M.C. Yang, The reduction of oxidative stress, anticoagulation of platelets, and inhibition of lipopolysaccharide by conjugated linoleic acid bonded on a polysulfone membrane, Polym. Adv. Technol. 18 (4) (2007) 286–291, https://doi.org/10.1002/pat.863.
[55] R. Liang, J. Zhao, B. Li, P. Cai, X.J. Loh, C. Xu, P. Chen, D. Kai, L. Zheng, Implantable and degradable antioxidant poly(ε-caprolactone)-lignin nanofiber membrane for effective osteoarthritis treatment, Biomaterials 230 (2020), https://
doi.org/10.1016/j.biomaterials.2019.119601.