Design of Carrageenan-Based Heparin-Mimetic Gel Beads as Self-Anticoagulant Hemoperfusion Adsorbents.

The currently used hemoperfusion adsorbents such as activated carbon and ion-exchange resin show dissatisfactory hemocompatibility, and a large dose of injected heparin leads to the increasing cost and the risk of systematic bleeding. Natural polysaccharide adsorbents commonly have good biocompatibility, but their application is restricted by the poor mechanical strength and low content of functional groups. Herein, we developed an efficient, self-anticoagulant and blood compatible hemoperfusion adsorbent by imitating the structure and functional groups of heparin. Carrageenan and poly(acrylic acid) (PAA) cross-linked networks were built up by the combination of phase inversion of carrageenan and post-cross-linking of AA, and the formed dual-network structure endowed the beads with improved mechanical properties and controlled swelling ratios. The beads exhibited low protein adsorption amounts, low hemolysis ratios, low cytotoxicity, and suppressed complement activation and contact activation levels. Especially, the activated partial thromboplastin time, prothrombin time, and thrombin time of the gel beads were prolonged over 13, 18, and 4 times than those of the control. The self-anticoagulant and biocompatible beads showed good adsorption capacities toward exogenous toxins (560.34 mg/g for heavy metal ions) and endogenous toxins (14.83 mg/g for creatinine, 228.16 mg/g for bilirubin, and 18.15 mg/g for low density lipoprotein (LDL)), thus, highlighting their potential usage for safe and efficient blood purification.

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.

Multifunctionalized polyethersulfone membranes with networked submicrogels to improve antifouling property, antibacterial adhesion and blood compatibility.

Intensive efforts have been employed in modifying biomedical membranes. Among them, blending is recognized as a simple method. However, the conventional blending materials commonly lead to an insufficient modification, which is mainly caused by the poor miscibility between the blending materials and the matrixes, the elution of the hydrophilic materials from the matrixes during the use and storage, and the insufficient surface enrichment of the blending materials. Aiming to solve the abovementioned disadvantages, we developed novel polyethersulfone/poly(acrylic acid-co-N-vinyl-2-pyrrolidone) networked submicrogels (PES/P(AA-VP) NSs), which were blended with PES to enhance the antifouling properties, antibacterial adhesion and haemocompatible properties of PES membranes. As results, the PES/P(AA-VP) NSs showed good miscibility with the PES matrix, and hydrophilic submicrogels would enrich onto the membrane surface during the phase inversion process due to the surface segregation. The entanglement between the PES matrix and the networked submicrogels would effectively limit the elution of the submicrogels. In conclusion, the modified PES membranes prepared by blending with the PES/P(AA-VP) NSs might draw great attention for the application in haemodialysis fields.

Engineering of hemocompatible and antifouling polyethersulfone membranes by blending with heparin-mimicking microgels.

To improve the hemocompatibility and antifouling property of polyethersulfone (PES) membranes, heparin-mimicking microgels of poly(acrylic acid-co-N-vinyl-2-pyrrolidone) (P(AA-VP)) and poly(2-acrylamido-2-methylpropanesulfonic acid-co-acrylamide) (P(AMPS-AM)) were synthesized by conventional free radical copolymerization, and then incorporated into a PES matrix by blending. The results of Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and scanning electron microscopy (SEM) confirmed that heparin-mimicking microgels were successfully synthesized. The presence of the microgels in the membrane matrix was also confirmed by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), thermogravimetric analysis (TGA), and SEM. Compared with pristine PES membranes, the improvement of the antifouling property of the heparin-mimicking microgel modified membranes was demonstrated by the increased flux recovery ratio and improved anti-bacterial adhesion, while the enhancement of hemocompatibility for the modified membranes was proved by the decreased plasma protein adsorption, suppressed platelet adhesion, prolonged clotting times, as well as depressed blood-related complement activation. Additionally, after introducing the heparin-mimicking microgels, the membranes showed enhanced cell adhesion and proliferation properties. These results indicated that the heparin-mimicking microgel modified membranes had great potential to be used as blood contacting materials.

A facile approach toward multi-functional polyurethane/polyethersulfone composite membranes for versatile applications.

The complex synthesis through multistep reactions and tedious purifications based on different monomers or macromolecules limits the practical applications of functional polymers. Herein, a facile approach toward a series of functional polyurethanes (PUs) is designed for versatile biological applications within fewer step reactions under mild conditions. The tertiary amino groups in the PU are converted into zwitterions or quaternary ammonium salt via simple one-step synthesis, and then used to prepare PU/polyethersulfone composite membranes. The composite membrane with tertiary amine groups exhibits significant adsorption capability to anionic dye Congo red (CR) and toxin bilirubin. The membrane bearing zwitterionic PU displays excellent blood compatibility; while which with quaternary ammonium salts has antibacterial property. Furthermore, carboxybetaine-functional composite membrane is exploited to bear Ag nanoparticles to endow with dual functions of antibacterial and antifouling properties. This work demonstrates the potential of PUs as readily available, multi-functional, and easy-to-use materials for biological 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.

Host-Guest Self-Assembly Toward Reversible Thermoresponsive Switching for Bacteria Killing and Detachment.

A facile method to construct reversible thermoresponsive switching for bacteria killing and detachment was currently developed by host-guest self-assembly of ß-cyclodextrin (ß-CD) and adamantane (Ad). Ad-terminated poly(N-isopropylacrylamide) (Ad-PNIPAM) and Ad-terminated poly[2-(methacryloyloxy)ethyl]trimethylammonium chloride (Ad-PMT) were synthesized via atom transfer radical polymerization, and then assembled onto the surface of ß-CD grafted silicon wafer (SW-CD) by simply immersing SW-CD into a mixed solution of Ad-PNIPAM and Ad-PMT, thus forming a thermoresponsive surface (SW-PNIPAM/PMT). Atomic force microscopy (AFM), X-ray photoelectron spectrometry (XPS), and water contact angle (WCA) analysis were used to characterize the surface of SW-PNIPAM/PMT. The thermoresponsive bacteria killing and detachment switch of the SW-PNIPAM/PMT was investigated against Staphyloccocus aureus. The microbiological experiments confirmed the efficient bacteria killing and detachment switch across the lower critical solution temperature (LCST) of PNIPAM. Above the LCST, the Ad-PNIPAM chains on the SW-PNIPAM/PMT surface were collapsed to expose Ad-PMT chains, and then the exposed Ad-PMT would kill the attached bacteria. While below the LCST, the previously collapsed Ad-PNIPAM chains became more hydrophilic and swelled to cover the Ad-PMT chains, leading to the detachment of bacterial debris. Besides, the proposed method to fabricate stimuli-responsive surfaces with reversible switches for bacteria killing and detachment is facile and efficient, which creates a new route to extend the application of such smart surfaces in the fields requiring long-term antimicrobial treatment.