Heparin-Like Chitosan Hydrogels with Tunable Swelling Behavior, Prolonged Clotting Times, and Prevented Contact Activation and Complement Activation.

The aim of this study was to create heparin-like chitosan hydrogels (HLCHs) for blood purification. Herein, we prepared two heparin-like chitosans (HLCSs) with various carboxymethyl and sulfate groups, followed by a cross-linking reaction with glutaraldehyde. The synthetic chitosan derivatives were characterized by X-ray photoelectron spectroscopy, gel permeation chromatography, FTIR and NMR. The average sulfonation degrees of two HLCSs were 0.69 and 0.94 per sugar unit, respectively. The swelling ratio of the HLCH could reach up to 4800%, and the HLCHs remained a well-defined shape and stable below 170 °C. Moreover, the activated partial thromboplastin time and thrombin time results indicated that both of the HLCSs and their hydrogels exhibited excellent thrombus inhibition property. Furthermore, the contact activation and complement activation results also proved that the hydrogels possessed good blood compatibility and had the potential to be used as blood-contacting materials.

Functional polyethersulfone particles for the removal of bilirubin.

In this study, polyethersulfone/poly (glycidyl methacrylate) particles are prepared via in situ cross-linked polymerization coupled with a phase inversion technique. The surfaces of these particles are then further modified by grafting amino groups using tetraethylenepentamine, dethylenetriamine, ethylenediamine, or 1,6-hexanediamine for the removal of bilirubin. The particles are characterized by Flourier transform infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. Batch adsorption experiments are performed to verify the adsorption capability, and the effect of bilirubin initial concentration, bovine serum albumin concentration, and solution ionic strength on the adsorption is also investigated. In addition, both adsorption kinetic and isotherm models are applied to analyze the adsorption process of bilirubin, and a particle column is used to further study the bilirubin removal ability.To prove that the method was a universal portal to prepare functional particles, polysulfone, polystyrene, and poly(vinylidene fluoride) based functional particles were also prepared and used for the removal of bilirubin. This study and the results indicated that the particles had a great potential to be used in hemoperfusion treatment for hyperbilirubinemia.

Surface modification of poly(ether sulfone) membrane with a synthesized negatively charged copolymer.

In this study, we provide a new method to modify poly(ether sulfone) (PES) membrane with good biocompatibility, for which diazotized PES (PES-N2(+)) membrane is covalently coated by a negatively charged copolymer of sodium sulfonated poly(styrene-alt-maleic anhydride) (NaSPS-MA). First, aminated PES (PES-NH2) is synthesized by nitro reduction reaction of nitro-PES (PES-NO2), and then blends with pristine PES to prepare PES/PES-NH2 membrane; then the membrane is treated with NaNO2 aqueous solution at acid condition; after surface diazo reaction, surface positively charged PES/PES-N2(+) membrane is prepared. Second, poly(styrene-alt-maleic anhydride) (PS-alt-MA) is synthesized, then sulfonated and treated by sodium hydroxide solution to obtain sodium sulfonated (PS-alt-MA) (NaSPS-MA). Finally, the negatively charged NaSPS-MA copolymer is coated onto the surface positively charged PES/PES-N2(+) membrane via electrostatic interaction; after UV-cross-linking, the linkage between the PES-N2(+) and NaSPS-MA changes to a covalent bond. The surface-modified PES membrane is characterized by FT-IR spectroscopy, X-ray photoelectron spectroscopy (XPS) analyses, and surface zeta potential analyses. The modified membrane exhibits good hemocompatibility and cytocompatibility, and the improved biocompatibility might have resulted from the existence of the hydrophilic groups (sodium carboxylate (-COONa) and sodium sulfonate (-SO3Na)). Moreover, the stability of the modified membrane is also investigated. The results indicated that the modified PES membrane using negatively charged copolymers had a lot of potential in blood purification fields and bioartificial liver supports for a long time.

Covalent deposition of zwitterionic polymer and citric acid by click chemistry-enabled layer-by-layer assembly for improving the blood compatibility of polysulfone membrane.

Development of blood compatible membranes is critical for biomedical applications. Zwitterionic polymers have been proved to be resistant to nonspecific protein adsorption and platelet adhesion. In this work, two kinds of zwitterionic copolymers bearing alkynyl and azide groups are synthesized by atom transfer radical polymerization (ATRP) and subsequent reactions, namely alkynyl-poly(sulfobetaine methacrylate) (alkynyl-PSBMA) and azide-poly(sulfobetaine methacrylate) (azide-PSBMA). The copolymers are directly used to modify azido-functionalized polysulfone (PSf-N3) membrane via click chemistry-enabled layer-by-layer (LBL) assembly. Alkynyl-citric acid is then clicked onto the membrane when the outermost layer was azide-PSBMA. The chemical compositions, surface morphologies, and hydrophilicity of the zwitterionic polymer and citric acid multilayer modified membranes are characterized. The composite multilayer is resistant to protein adsorption and platelet adhesion and also prolongs clotting times, indicating that the blood compatibility is improved. Moreover, after clicking the small molecule anticoagulant alkynyl-citric acid onto the outermost of the zwitterionic multilayer, the membrane shows further improved anticoagulant property. The deposition of zwitterionic polymer and citric acid via click chemistry-enabled LBL assembly can improve the blood compatibility of the PSf membrane.

Immobilization of carbonic anhydrase on modified PES membranes for artificial lungs.

The introduction of carbonic anhydrase (CA) onto an extracorporeal membrane oxygenation (ECMO) membrane can improve the permeability of carbon dioxide (CO2). However, existing CA-grafting methods have limitations, and the hemocompatibility of current substrate membranes of commercial ECMO is not satisfactory. In this study, a 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)/N-hydroxy succinimide (NHS) activation method is adopted to graft CA with CO2-catalyzed conversion activity onto a polyethersulfone (PES) membrane, which is prepared by a phase inversion technique after in situ crosslinking polymerization of 1-vinyl-2-pyrrolidone (VP) and acrylic acid (AA) in PES solution. The characterization results reveal that CA has been grafted onto the modified PES membrane successfully and exhibits catalytic activity. The kinetic parameters of esterase activity verify that the grafted amount of active CA increases with an increase in the concentration of the CA incubation solution. The CA-grafted membrane (CA-M) can accelerate the conversion of bicarbonate to CO2 in water and blood, which demonstrates the special catalytic activity towards bicarbonate of CA. Finally, blood compatibility tests prove that the CA-M does not lead to hemolysis, shows suppressed protein adsorption and increased coagulation time, and is suitable for application in ECMO. This work demonstrates a green and efficient method for preparing bioactive materials and has practical guiding significance for subsequent pulmonary membrane research and ECMO applications.

Photoresponsive surface molecularly imprinted poly(ether sulfone) microfibers.

In the present study, photoresponsive surface molecularly imprinted poly(ether sulfone) microfibers are prepared via nitration reaction, the wet-spinning technique, surface nitro reduction reaction, and surface diazotation reaction for the selectively photoregulated uptake and release of 4-hydrobenzoic acid. The prepared molecularly imprinted microfibers show selective binding to 4-HA under irradiation at 450 nm and release under irradiation at 365 nm. The simple, convenient, effective, and productive method for the preparation of azo-containing photoresponsive material is also applied to the modification of polysulfone and poly(ether ether ketone). All three benzene-ring-containing polymers show significant photoresponsibility after the azo modification.

General and biomimetic approach to biopolymer-functionalized graphene oxide nanosheet through adhesive dopamine.

Graphene oxide (GO), reduced graphene oxide (rGO), and their derivatives are investigated for various biomedical applications explosively. However, the defective biocompatibility was also recognized, which restricted their potential applications as biomaterials. In this study, a facile biomimetic approach for preparation of biopolymer adhered GO (rGO) with controllable 2D morphology and excellent biocompatibility was proposed. Mussel-inspired adhesive molecule dopamine (DA) was grafted onto heparin backbone to obtain DA grafted heparin (DA-g-Hep) by carbodiimide chemistry method; then, DA-g-Hep was used to prepare heparin-adhered GO (Hep-a-GO) and heparin-adhered rGO (Hep-a-rGO). The obtained heparin-adhered GO (rGO) showed controllable 2D morphology, ultrastable property in aqueous solution, and high drug and dye loading capacity. Furthermore, the biocompatibility of the heparin-adhered GO (rGO) was investigated using human blood cells and human umbilical vein endothelial cells, which indicated that the as-prepared heparin-adhered GO (rGO) exhibited ultralow hemolysis ratio (lower than 1.2%) and high cell viability. Moreover, the highly anticoagulant bioactivity indicated that the adhered heparin could maintain its biological activity after immobilization onto the surface of GO (rGO). The excellent biocompatibility and high bioactivity of the heparin-adhered GO (rGO) might confer its great potentials for various biomedical applications.

Multi-functional nanofilms capable of angiogenesis, near-infrared-triggered anti-bacterial activity and inflammatory regulation for infected wound healing.

Chronic infected wound healing is a critical challenge in clinical practice owing to the involvement of multiple physiological processes, including bacteria-related, inflammatory regulation and angiogenesis. Therefore, a multi-functional strategy with synergistic anti-bacterial, anti-inflammatory and pro-angiogenic effects should be developed. Owing to their biomimetic structural features and controlled delivery of active agents, electrospun nanofilms are promising biomaterials for the treatment of skin defects. In this study, we fabricated multi-functional nanofilms with pro-angiogenic, anti-bacterial and anti-inflammatory capacities. First, strontium (Sr) ions were incorporated into poly(L-lactic-co-caprolactone) (PLCL) nanofilms. Subsequently, polydopamine (PDA) and zinc oxide (ZnO) were decorated onto the surface of Sr-loaded PLCL nanofilms to prepare ZnO/PDA@PLCL@Sr nanofilms. In vitro results showed that ZnO/PDA@PLCL@Sr nanofilms were biocompatible, exhibited angiogenic activity and significantly inhibited the growth of Staphylococcus aureus and Escherichia coli upon near-infrared -light irradiation. Furthermore, ZnO/PDA@PLCL@Sr nanofilms were found to drive the transformation of macrophages into the M2 phenotype. In vivo results further validated that ZnO/PDA@PLCL@Sr nanofilms exhibited pro-angiogenic and anti-bacterial activities and regulated inflammation to accelerate wound -healing in a rat model of bacteria-infected skin defects. In conclusion, we successfully developed a multi-functional biomaterial with pro-angiogenic, anti-bacterial and anti-inflammatory capacities to treat chronic infected wounds.

Amides and Heparin-Like Polymer Co-Functionalized Graphene Oxide Based Core @ Polyethersulfone Based Shell Beads for Bilirubin Adsorption.

Excessive bilirubin in the body of patient with liver dysfunction or metabolic obstruction may cause jaundice with irreversible brain damage, and new type of adsorbent for bilirubin is under frequent investigation. Herein, graphene oxide based core @ polyethersulfone-based shell beads are fabricated by phase inversion method, amides and heparin-like polymer are introduced to functionalize the core-shell beads. The beads are successfully prepared with obvious core-shell structure, adequate thermostability and porous shell. Clotting times and protein adsorption are investigated to inspect the hemocompatibility property of the beads. The adsorption of bilirubin is systematically investigated by evaluating the effects of contacting time, initial concentration and temperature on the adsorption, which exhibits improved bilirubin adsorption amount for the beads with amides contained cores or/and shells. It is worth believing that the amides and heparin-like polymer co-functionalized core-shell beads may be utilized in the field of hemoperfusion for bilirubin adsorption.

Positively-charged polyethersulfone nanofibrous membranes for bacteria and anionic dyes removal.

Given the complexity of pollutants in wastewater, development of facile and effective multifunctional materials, which can not only kill bacteria but also remove dyes from wastewater, is in high demand. Herein, a facile strategy for the preparation of positively-charged nanofibrous membranes (NFMs) is reported via the combination of electrospinning and in-situ cross-linked polymerization of poly ([2-(methacryloyloxy)-ethyl] trimethyl ammonium chloride) (PMETAC) in poly (ether sulfone) (PES) solution. The quaternary ammonium salt polymer of PMETAC enabled the NFMs with positive charge to kill bacteria and remove anionic dyes. The antibacterial tests including agar plate counting and live/dead staining indicate that the NFMs show strong antibacterial ability with bacterial killing ratios of nearly 99% for both Escherichia coli and Staphylococcus aureus, as well as remarkable recyclability towards killing bacteria. The dyes adsorption experiments show that the NFMs exhibit high adsorption capacity for anionic dyes up to 208 mg g-1 for Congo Red (CR) and good reusability toward CR. Impressively, the membrane adsorption column test indicates that the CR dye removal ratio is up to 100% for the first time, and that is still as high as 96.5% for the third time with a fresh dye solution. Given the above advantages, such fascinating NFMs may provide new perspectives in the exploitation of multifunctional membrane materials for complex water remediation.

Engineering antimicrobial and biocompatible electrospun PLGA fibrous membranes by irradiation grafting polyvinylpyrrolidone and periodate.

Postoperative adhesion may form as the result of a complicated fibrosis and inflammatory response, thus leads to a series of complications or increases the risk of surgery failure. Herein, we prepared poly (lactic-co-glycolic acid)-graft-polyvinylpyrrolidone/polyiodide (PLGA-g-PVP/I) electrospun fibrous membranes to prevent postoperative adhesion and infection formation. Firstly, hydrophilic PVP molecules were grafted on the surface of PLGA powders by gamma ray, and then iodine ions were coordinated with the grafted PVP. Subsequently, PLGA-g-PVP/I fibrous membranes were prepared by electrospinning. The PLGA-g-PVP/I membranes were analyzed via UV-vis, FTIR, Raman, and XPS. The formed polyiodide endowed the membranes with sustained antibacterial activity. The antimicrobial property of PLGA-g-PVP/I membranes was ascribed to the synergistic effect of intracellular ROS production and glutathione oxidation. Furthermore, the prevention efficacy of postoperative abdominal adhesion from the PLGA-g-PVP/I composite membranes was characterized in a rat model of sidewall defect-cecum abrasion. The results demonstrated that the PLGA-g-PVP/I fibrous membranes could prevent the postoperative abdominal adhesion effectively. Therefore, to endow the PLGA-g-PVP/I electrospun fibrous membranes with durable antibacterial property may be a promising strategy towards an anti-bacterial and anti-adhesion system for commercial and clinical uses.

[Study on adsorption of methylene blue by sulfonated polyethersulfone I. The preparation of sulfonated polyethersulfone and its adsorption of methylene blue in water].

The evaluation of the adsorption of methylene blue (MB) in water by the sulfonated polyethersulfone (SPES) adsorbent column was carried out in this study after the SPES was prepared by gassy SO3 method. The polyethersulfone (PES) adsorbent column was used as control. The results indicated that the adsorption of MB by adsorbent column of SPES was more efficient than that of PES. In addition, the effect of the flow rate or ionic intensity on the adsorption and desorption of MB in water by SPES adsorbent column were also investigated. The results showed that the removal rate in water by SPES adsorbent column was larger than that in saline. However, the desorption experiment revealed that the desorption amount of the SPES adsorbent column in saline was larger than that in water.

[Study on adsorption of methylene blue by sulfonated polyethersulfone II. The adsorption of methylene blue by sulfonated polyethersulfone in plasma].

The evaluation of the adsorption of methylene blue (MB) in plasma by sulfonated polyethersulfone (SPES) adsorbent column was carried out in this study. The results indicated the adsorption of MB by SPES adsorbent column was more efficient than that by polyethersulfone (PES). In addition, the changes of the concentration of BSA solution passing through adsorbent column along with the time and the biochemical indices of plasma before and after adsorption treatment were also investigated. The results showed that the adsorption amount of BSA by PES adsorbent column was larger than that by SPES, and the biochemical parameters such as total protein, albumin, glucose, triglyceride and total cholesterol in plasma varied slightly before and after passing through the column, which were still within the clinical indices.

Integrating zwitterionic polymer and Ag nanoparticles on polymeric membrane surface to prepare antifouling and bactericidal surface via Schiff-based layer-by-layer assembly.

Development of antibacterial membranes is strongly desired for biomedical applications. Herein, we integrated antifouling and bactericidal properties on polymeric membrane surface via Schiff-based layer-by-layer (LbL) assembly. Zwitterionic polymers bearing plentiful amino groups (based on polyethylenimine (PEI) and sulfobetaine methacrylate (SBMA), and termed as PEI-SBMA) were utilized to prepare an antifouling membrane surface; then robust wide-spectrum bactericidal Ag nanoparticles (Ag NPs) were in situ generated on the surface. The as-prepared zwitterionic polymer surface showed excellent resistance to protein adsorption and bacterial adhesion. The Ag NPs could be tightly and uniformly distributed on the membrane surface by the chelation of PEI-SBMA, and endowed the membrane with bactericidal activity. Meanwhile, the Ag NPs loaded membrane could effectively resist bacterial attachment for a long time, even though the bactericidal activity lost. The proposed bactericidal and antifouling membrane was flexible, versatile and could be large-scale preparation; and this strategy would have great potential to be widely used to avoid undesired bacterial contamination of biomedical implants or biological devices.

Heparin-mimetic polyurethane hydrogels with anticoagulant, tunable mechanical property and controllable drug releasing behavior.

In the present study, novel heparin-mimetic polyurethane hydrogels were prepared by introducing chemical crosslinked sulfated konjac glucomannan (SKGM). Scanning electron microscopy (SEM) results indicated that the introduction of SKGM and the increase of the molecular weight of diol segments could enlarge the pore sizes of the hydrogels. The swelling behavior corresponded with the SEM results, and the hydrogels could absorb more water after the modification. The modification also led to an improvement in the mechanical property. Meanwhile, the SKGM and the modified polyurethane hydrogels showed excellent hemocompatibility. The thromboplastin time of SKGM could reach up to 182.9s. Gentamycin sulfate (GS) was used as a model drug to be loaded into the hydrogels, and the loading amount was increased ca. 50% after the introduction of SKGM, thus resulting in high bactericidal efficiency. The results indicated that the introduction of SKGM and the alternation in the diol's molecular weight bestowed polyurethane hydrogels with promising properties of integrated blood-compatibility, mechanical properties and drug loading-releasing behavior. Therefore, the heparin-mimetic multifunctional polyurethane hydrogels have great potential to be used in biomedical applications.

A facile way to prepare anti-fouling and blood-compatible polyethersulfone membrane via blending with heparin-mimicking polyurethanes.

In this study, new kinds of heparin-mimicking polyurethanes (PUs) were fabricated conveniently in the mixed solution of dimethyl sulfoxide (DMSO) and water, reducing the usage of organic solvent. Functional groups of SO3H and/or COOH were introduced into PUs with various ratios of SO3H to COOH. The PUs were then blended with polyethersulfone (PES) to fabricate heparin-mimicking modified PES membranes by a phase inversion technique. Then, the microstructures, zeta potentials, water contact angles (WCA) and protein adsorptions of the membranes were characterized. Comparing with pristine PES membrane, the modified membranes showed changed cross-sectional morphology, lowered zeta potentials and decreased water contact angles, revealing that the hydrophilicity and anti-fouling properties were improved. The modified membranes also showed prolonged clotting tines (APTTs) and suppressed platelet adhesion, revealing that the anticoagulant properties increased. The results of complement activation, contact activation and platelet activation further implied that the modified membranes had good blood compatibility. In addition, the cells on the membranes showed good morphology with the introduction of the PUs. With the increase of the ratio of SO3H to COOH, the hydrophilicity, the blood compatibility as well as the cytocompatibility increased, implying that the SO3H groups could improve the hemocompatibility of the membranes more effectively than COOH groups. While the membranes containing more COOH groups had better antifouling properties of BSA and BFG. Therefore, the hemocompatibility for the heparin-mimicking membranes could be tuned by controlling the ratios of SO3H to COOH. The PES/PU composite membranes might have great potential to be used in the field of blood purification.

[Grafting and characterization of poly (ethylene glycol) on polysulfone sheets].

Grafting of poly (ethylene glycol) (PEG) on the surface of polysulfone (PSF) sheets by simultaneous or sequential UV irradiation with 4-azidobenzoic acid as the photocoupler was carried out. Water contact angle measurements showed that there was a great improvement of hydrophilicity on the grafted surface. X-ray photoelectron spectroscopy suggested that the area covered by PEG be 77.3% and 41.9% respectively after grafting by simultaneous and sequential pathways. With atomic force microscope (AFM), obvious difference in the shape and the phase mode was observed between surfaces of PEG-g-PSF sheets made by these two pathways. Evidences implied that simultaneous pathway would produce a branched PEG layer on the surface, while sequential pathway was coupled with a "pan-cake" PEG layer on it. This study provides the foundation for further advancement in tethering brush-like PEG on PSF hollow fiber membranes.

A recyclable and regenerable magnetic chitosan absorbent for dye uptake.

A recyclable and regenerable magnetic polysaccharide absorbent for methylene blue (MB) removal was prepared by coating magnetic polyethyleneimine nanoparticles (PEI@MNPs) with sulfonated chitosan (SCS) and further cross-linked with glutaraldehyde. The driving force for coating is the electrostactic interaction between positively charged PEI and negatively charged SCS. Infrared spectra, zeta potential, thermal gravimetric analysis and X-ray diffraction demonstrated the successful synthesis of magnetic polysaccharide absorbent. The self-assembly of polysaccharide with magnetic nanopartices did not alter the saturation magnetization value of the absorbent confirmed by vibrating sample magnetometer. The nanoparticles showed fast removal (about 30min reached equilibrium) of MB. In particular, the removal ability of MB after desorption did not reduce, demonstrating an excellent regeneration ability. Our study provides new insights into utilizing polysaccharides for environmental remediation and creating advanced magnetic materials for various promising applications.

Zwitterionic polymer functionalization of polysulfone membrane with improved antifouling property and blood compatibility by combination of ATRP and click chemistry.

The chemical compositions are very important for designing blood-contacting membranes with good antifouling property and blood compatibility. In this study, we propose a method combining ATRP and click chemistry to introduce zwitterionic polymer of poly(sulfobetaine methacrylate) (PSBMA), negatively charged polymers of poly(sodium methacrylate) (PNaMAA) and/or poly(sodium p-styrene sulfonate) (PNaSS), to improve the antifouling property and blood compatibility of polysulfone (PSf) membranes. Attenuated total reflectance-Fourier transform infrared spectra, X-ray photoelectron spectroscopy and water contact angle results confirmed the successful grafting of the functional polymers. The antifouling property and blood compatibility of the modified membranes were systematically investigated. The zwitterionic polymer (PSBMA) grafted membranes showed good resistance to protein adsorption and bacterial adhesion; the negatively charged polymer (PNaSS or PNaMAA) grafted membranes showed improved blood compatibility, especially the anticoagulant property. Moreover, the PSBMA/PNaMAA modified membrane showed both antifouling property and anticoagulant property, and exhibited a synergistic effect in inhibiting blood coagulation. The functionalization of membrane surfaces by a combination of ATRP and click chemistry is demonstrated as an effective route to improve the antifouling property and blood compatibility of membranes in blood-contact.

Graphene oxide and sulfonated polyanion co-doped hydrogel films for dual-layered membranes with superior hemocompatibility and antibacterial activity.

In this study, a new kind of hemocompatible and antibacterial dual-layered polymeric membrane was fabricated by coating a top layer of graphene oxide and a sulfonated polyanion co-doped hydrogel thin film (GO-SPHF) on a bottom membrane substrate. After a two-step spin-coating of casting solutions on glass plates, dual-layered membranes were obtained by a liquid-liquid phase inversion method. The GO-SPHF composite polyethersulfone (PES) membranes (PES/GO-SPHF) showed top layers with obviously large porous structures. The chemical composition tests indicated that there were abundant hydrophilic groups enriched on the membrane surface. The examination of membrane mechanical properties indicated that the composite membranes exhibited only slightly decreased performance compared to pristine PES membranes. Moreover, to validate the potential applications of this novel dual-layered membrane in diverse fields, we tested the hemocompatibility and antibacterial activity of the membranes, respectively. Notably, the PES/GO-SPHF membranes showed highly improved in vitro hemocompatibility, such as good anti-coagulant activity, suppressed platelet adhesion and activation, low inflammation potential, and good red blood cell compatibility. Furthermore, the dual-layered membranes exhibited robust antibacterial ability after in situ loading of Ag-nanoparticles with excellent bactericidal capability to both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Due to the integration of the porous membrane structure, good mechanical strength, excellent hemocompatibility, as well as robust bactericidal capability, the GO and sulfonated polyanion co-doped dual-layered membranes may open up a new protocol to greatly demonstrate the potential application of polymeric membranes for clinical hemodialysis and many other biomedical therapies.