Lang Ma

Biopolymer functionalized reduced graphene oxide with enhanced biocompatibility via mussel inspired coatings/anchors

A green and facile method for preparing biopolymer functionalized reduced graphene oxide (RGO) by using mussel inspired dopamine (DA) as the reducing reagent and the functionalized molecule is proposed. In the study, GO is reduced by DA and DA is adhered to RGO by one-step pH-induced polymerization of DA (polydopamine, PDA), and then heparin or protein is grafted onto the PDA adhered RGO (pRGO) through catechol chemistry. The obtained pRGO, heparin grafted pRGO (Hep-g-pRGO), and BSA grafted pRGO (BSA-g-pRGO) exhibit fine 2D morphology and excellent stability in water and PBS solution. Furthermore, the biocompatibility of the biopolymer functionalized RGO are investigated using human blood cells and human umbilical vein endothelial cells (HUVECs). The biopolymer functionalized RGO exhibits an ultralow hemolysis ratio (lower than 1.8%), and the cellular toxicity assay suggests that the biopolymer functionalized RGO has good cytocompatibility for HUVEC cells, even at a high concentration of 100 μg mL-1. Moreover, the high anticoagulant ability of Hep-g-pRGO indicates that the grafted biopolymer could maintain its biological activity after immobilization onto the surface of pRGO. Therefore, the proposed safe and green biomimetic method confers the biopolymer functionalized RGO with great potential for various biological and biomedical applications.

Mussel-inspired self-coating at macro-interface with improved biocompatibility and bioactivity via dopamine grafted heparin-like polymers and heparin

In this study, multifunctional mussel-inspired self-coated membranes with remarkable blood and cell compatibilities are prepared by a facile and green approach. A highly sulfonated linear heparin-like polymer (HepLP, poly(sodium 4-vinylbenzenesulfonate)-co-poly(sodium methacrylate)) and heparin are chosen for the mussel-inspired heparin-mimicking coating, respectively. Firstly, DA is grafted onto the backbone of HepLP or heparin to obtain DA grafted HepLP (DA-g-HepLP) or DA grafted heparin (DA-g-Hep) by means of the carbodiimide chemistry method. Then, the DA-g-HepLP and DA-g-Hep are used to prepare surface coated heparin-mimicking substrates; the polyethersulfone (PES) dialysis membrane is chosen as the model substrate. The coated surface composition, surface morphology, water contact angle, surface zeta-potential, blood compatibility and cell compatibility are systematically investigated. The results of surface spectra, scanning electron microscopy (SEM) and atomic force microscopy (AFM) indicated that the DA-g-HepLP and DA-g-Hep were successfully coated onto the membranes. The coated membranes showed increased hydrophilicity and electronegativity, decreased plasma protein adsorption, and suppressed platelet adhesion compared to the pristine membrane. The cell morphology observation and cytotoxicity assays demonstrated that the surface coated heparin-mimicking membranes showed superior performance in endothelial cell proliferation and morphology differentiation. In addition, the excellent anticoagulant bioactivities indicated that the adhered DA-g-HepLP (or DA-g-Hep) could function or maintain its biological activity after the immobilization. In general, the mussel-inspired protocol of surface self-coating conferred the modified membranes with integrated blood compatibility, cell proliferation and biological activity for multi-biomedical applications, like hemodialysis, blood purification, organ implantation, and cell and tissue cultures.

Toward 3D graphene oxide gels based adsorbents for high-efficient water treatment via the promotion of biopolymers.

Recent studies showed that graphene oxide (GO) presented high adsorption capacities to various water contaminants. However, the needed centrifugation after adsorption and the potential biological toxicity of GO restricted its applications in wastewater treatment. In this study, a facile method is provided by using biopolymers to mediate and synthesize 3D GO based gels. The obtained hybrid gels present well-defined and interconnected 3D porous network, which allows the adsorbate molecules to diffuse easily into the adsorbent. The adsorption experiments indicate that the obtained porous GO-biopolymer gels can efficiently remove cationic dyes and heavy metal ions from wastewater. Methylene blue (MB) and methyl violet (MV), two cationic dyes, are chosen as model adsorbates to investigate the adsorption capability and desorption ratio; meanwhile, the influence of contacting time, initial concentration, and pH value on the adsorption capacity of the prepared GO-biopolymer gels are also studied. The GO-biopolymer gels displayed an adsorption capacity as high as 1100 mg/g for MB dye and 1350 mg/g for MV dye, respectively. Furthermore, the adsorption kinetics and isotherms of the MB were studied in details. The experimental data of MB adsorption fitted well with the pseudo-second-order kinetic model and the Langmuir isotherm, and the results indicated that the adsorption process was controlled by the intraparticle diffusion. Moreover, the adsorption data revealed that the porous GO-biopolymer gels showed good selective adsorbability to cationic dyes and metal ions.

Surface-engineered nanogel assemblies with integrated blood compatibility, cell proliferation and antibacterial property: towards multifunctional biomedical membranes

In this study, novel 3D multifunctional nanolayers are fabricated on biomedical membrane surfaces via layer-by-layer (LBL) self-assembly of nanogels and heparin-like polymers. To integrate long-term antibacterial activity, Ag nanoparticles embedded in nanogels were first prepared. Then, the Ag nanogels were assembled onto membrane surfaces by electrostatic interaction. To obtain a heparin-mimicking surface, the as-prepared nanogel-coated membranes were further assembled with heparin-like polymers by two different processes. The results indicated that the obtained nanogel and heparin-mimicking polymer assembled membranes exhibited 3D surface morphologies. Systematical blood compatibility and antithrombotic evaluations revealed that the functionalized membranes showed increased hydrophilicity, decreased protein adsorption, and prolonged clotting times and greatly suppressed platelet adhesion compared to pristine membrane. The cell culture observations demonstrated that the pristine, nanogel-assembled, and heparin-mimicking membranes showed different performances in terms of endothelial cell proliferation and adhesion morphology. The results of the antibacterial study indicated that the functionalized membranes exhibited significant inhibition capability for Escherichia coli and Staphylococcus aureus. In general, the surface coassembly of nanogels and heparin-mimicking polymers produced functionalized membranes with integrated blood compatibility, cell proliferation and antibacterial properties for multiple applications, which may advance the fabrication of biomedical devices by surface assembly of functional nanogels.

Heparin-Mimicking Multilayer Coating on Polymeric Membrane via LbL Assembly of Cyclodextrin-Based Supramolecules

In this study, multifunctional and heparin-mimicking star-shaped supramolecules-deposited 3D porous multilayer films with improved biocompatibility were fabricated via a layer-by-layer (LbL) self-assembly method on polymeric membrane substrates. Star-shaped heparin-mimicking polyanions (including poly(styrenesulfonate-co-sodium acrylate; Star-PSS-AANa) and poly(styrenesulfonate-co-poly(ethylene glycol)methyl ether methacrylate; Star-PSS-EGMA)) and polycations (poly(methyl chloride-quaternized 2-(dimethylamino)ethyl methacrylate; Star-PMeDMA) were first synthesized by atom transfer radical polymerization (ATRP) from β-cyclodextrin (β-CD) based cores. Then assembly of 3D porous multilayers onto polymeric membrane surfaces was carried out by alternating deposition of the polyanions and polycations via electrostatic interaction. The surface morphology and composition, water contact angle, blood activation, and thrombotic potential as well as cell viability for the coated heparin-mimicking films were systematically investigated. The results of surface ATR-FTIR spectra and XPS spectra verified successful deposition of the star-shaped supramolecules onto the biomedical membrane surfaces; scanning electron microscopy (SEM) and atomic force microscopy (AFM) observations revealed that the modified substrate had 3D porous surface morphology, which might have a great biological influence on the biointerface. Furthermore, systematic in vitro investigation of protein adsorption, platelet adhesion, human platelet factor 4 (PF4, indicates platelet activation), activate partial thromboplastin time (APTT), thrombin time (TT), coagulation activation (thrombin-antithrombin III complex (TAT, indicates blood coagulant)), and blood-related complement activation (C3a and C5a, indicates inflammation potential) confirmed that the heparin-mimicking multilayer coated membranes exhibited ultralow blood component activations and excellent hemocompatibility. Meanwhile, after surface coating, endothelial cell viability was also promoted, which indicated that the heparin-mimicking multilayer coating might extend the application fields of polymeric membranes in biomedical fields.

Graphene oxide based heparin-mimicking and hemocompatible polymeric hydrogels for versatile biomedical applications

Studies on the design of heparin and heparin-mimicking polymer based hydrogels are of tremendous interest and are fuelled by diverse emerging biomedical applications, such as antithrombogenic materials, growth factor carriers, and scaffolds for tissue engineering and regeneration medicine. In this study, inspired by the recent developments of heparin-based hydrogels, graphene oxide (GO) based heparin-mimicking hydrogels with hemocompatibility and versatile properties were prepared via free radical copolymerization, and poly(ethylene glycol) methyl ether methacrylate (PEGMA) and 2-hydroxyethyl methacrylate (HEMA) hydrogels were used as the control samples. The GO based heparin-mimicking polymeric hydrogels exhibited interconnected structures with thin pore walls and high porosity. Because of the increased ionization and electrostatic repulsion of sodium styrene sulfonate (SSNa) segments, the swelling ratios of the SSNa added hydrogels were dramatically increased; after incorporating flexible GO nanosheets, as the 3D skeleton of the hydrogels, the swelling ability was further increased. In addition, the GO based heparin-mimicking hydrogels showed superior red blood cell compatibility, anti-platelet adhesion ability and anticoagulant ability. Furthermore, drug release data indicated that the GO based heparin-mimicking hydrogels had high drug loading ability and prolonged drug releasing ability; the antibacterial tests showed coincident results with large inhibition zones and long effective periods. Due to the integration of blood compatibility, drug loading and releasing abilities, as well as an excellent ability for the removal of toxic molecules, the GO based heparin-mimicking hydrogels can be used for versatile biomedical applications.

Substrate-Independent Robust and Heparin-Mimetic Hydrogel Thin Film Coating via Combined LbL Self-Assembly and Mussel-Inspired Post-Cross-linking.

In this work, we designed a robust and heparin-mimetic hydrogel thin film coating via combined layer-by-layer (LbL) self-assembly and mussel-inspired post-cross-linking. Dopamine-grafted heparin-like/-mimetic polymers (DA-g-HepLP) with abundant carboxylic and sulfonic groups were synthesized by the conjugation of adhesive molecule, DA, which exhibited substrate-independent adhesive affinity to various solid surfaces because of the formation of irreversible covalent bonds. The hydrogel thin film coated substrates were prepared by a three-step reaction: First, the substrates were coated with DA-g-HepLP to generate negatively charged surfaces. Then, multilayers were obtained via LbL coating of chitosan and the DA-g-HepLP. Finally, the noncovalent multilayers were oxidatively cross-linked by NaIO4. Surface ATR-FTIR and XPS spectra confirmed the successful fabrication of the hydrogel thin film coatings onto membrane substrates; SEM images revealed that the substrate-independent coatings owned 3D porous morphology. The soaking tests in highly alkaline, acid, and concentrated salt solutions indicated that the cross-linked hydrogel thin film coatings owned high chemical resistance. In comparison, the soaking tests in physiological solution indicated that the cross-linked hydrogel coatings owned excellent long-term stability. The live/dead cell staining and morphology observations of the adhered cells revealed that the heparin-mimetic hydrogel thin film coated substrates had low cell toxicity and high promotion ability for cell proliferation. Furthermore, systematic in vitro investigations of protein adsorption, platelet adhesion, blood clotting, and blood-related complement activation confirmed that the hydrogel film coated substrates showed excellent hemocompatibility. Both the results of inhibition zone and bactericidal activity indicated that the gentamycin sulfate loaded hydrogel thin films had significant inhibition capability toward both Escherichia coli and Staphylococcus aureus bacteria. Combined the above advantages, it is believed that the designed heparin-mimetic hydrogel thin films may show high potential for applications in various biological and clinical fields, such as long-term hemocompatible and drug-loading materials for implants.

Layer by layer assembly of sulfonic poly(ether sulfone) as heparin-mimicking coatings: scalable fabrication of super-hemocompatible and antibacterial membranes

In this study, to approach the scalable fabrication of super-hemocompatible and antibacterial membranes, surface engineered 3D heparin-mimicking coatings were designed by layer by layer (LBL) assembly of water-soluble heparin-mimicking polymer (WHP) and quaternized chitosan (QC). The low cost and scalable WHP was synthesized by a combination of polycondensation and post-carboxylation method, and the antibacterial QC was prepared by a two-step quaternization reaction. Then, the as-prepared negatively charged WHP and positively charged QC were used to conduct the LBL assembly on the widely used poly(ether sulfone) (PES) membrane surface to prepare heparin-mimicking modified membrane. The results indicated that the assembled heparin-mimicking coating nanofilms exhibited 3D porous morphology. The systematic blood compatibility and antithrombotic evaluation revealed that the functionalized membrane owned prolonged clotting times and greatly suppressed platelet adhesion and activation; further contacting activation detection (TAT and PF-4) and complement activation (C3a and C5a) experiments indicated that the heparin-mimicking membranes had lower blood activation compared to the pristine membrane. The cell observations demonstrated that the surface assembled heparin-mimicking nanofilms showed superior performances in endothelial cells adhesion and growth than the pure PES membrane. The results of the antibacterial study indicated that the QC contained coating exhibited significant inhibition ability for both Escherichia coli and Staphlococcus aureus. In general, the LBL assembled heparin-mimicking coatings conferred the functionalized PES membranes with integrated blood compatibility, cytocompatibility and antibacterial property for multi-applications, which may forward the fabrication and application of heparin-mimicking biomedical devices.

Catechol Chemistry Inspired Approach to Construct Self-Cross-Linked Polymer Nanolayers as Versatile Biointerfaces

In this study, we proposed a catechol chemistry inspired approach to construct surface self-cross-linked polymer nanolayers for the design of versatile biointerfaces. Several representative biofunctional polymers, P(SS-co-AA), P(SBMA-co-AA), P(EGMA-co-AA), P(VP-co-AA), and P(MTAC-co-AA), were first synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and then the catecholic molecules (dopamine, DA) were conjugated to the acrylic acid (AA) units by the facile carbodiimide chemistry. Then, the catechol (Cat) group conjugated biofunctional polymers, named PSS-Cat, PSBMA-Cat, PEGMA-Cat, PVP-Cat, and PMTAC-Cat, were applied for the construction of self-cross-linked nanolayers on polymeric substrates via the pH induced catechol cross-linking and immobilization. The XPS spectra, surface morphology, and wettability gave robust evidence that the catechol conjugated polymers were successfully coated, and the coated substrates possessed increased surface roughness and hydrophilicity. Furthermore, the systematic in vitro investigation of protein adsorption, platelet adhesion, activated partial thromboplastin time (APTT), thrombin time (TT), cell viability, and antibacterial ability confirmed that the coated nanolayers conferred the substrates with versatile biological performances. The PSS-Cat coated substrate had low blood component activation and excellent anticoagulant activity; while the PEGMA-Cat and PSBMA-Cat showed ideal resistance to protein fouling and inhibition of platelet activation. The PSS-Cat and PVP-Cat coated substrates exhibited promoted endothelial cell proliferation and viability. The PMTAC-Cat coated substrate showed an outstanding activity on bacterial inhibition. In conclusion, the catechol chemistry inspired approach allows the self-cross-linked nanolayers to be easily immobilized on polymeric substrates with the stable conformation and multiple biofunctionalities. It is expected that this low-cost and facile bioinspired coating system will present great potential in creating novel and versatile biointerfaces.

Nanofibrous Heparin and Heparin-Mimicking Multilayers as Highly Effective Endothelialization and Antithrombogenic Coatings

Combining the advantages of the fibrous nanostructure of carbon nanotubes (CNTs) and the bioactivities of heparin/heparin-mimicking polyanions, functional nanofibrous heparin or heparin-mimicking multilayers were constructed on PVDF membrane with highly promoted endothelialization and antithrombogenic activities. Oxidized CNT (oCNT) was first functionalized with water-soluble chitosan (polycation), then enwrapped with heparin or a typical sulfonated heparin-mimicking polymers (poly(sodium 4-styrenesulfonate-co-sodium methacrylate)) to construct the multilayers. Then, the surface-deposited multilayers were constructed via electrostatic layer-by-layer assembly of the functionalized oCNTs. The scanning electron microscope and atom force microscope images confirmed that the coated multilayers exhibited nanofibrous and porous structure. The live/dead cell staining and cell viability assay results indicated that the coated nanofibrous multilayers had excellent compatibility with endothelial cells. The cell morphology observation further confirmed the promotion ability of surface endothelialization due to the coated heparin/heparin-mimicking multilayers. Further systematical evaluation on blood compatibility revealed that the surface heparin/heparin-mimicking multilayer-coated membranes also had significantly improved blood compatibility including restrained platelet adhesion and activation, prolonged blood clotting times, and inhibited activation of coagulation and complement factors. In summary, the proposed nanofibrous multilayers integrated endothelialization and antithrombogenic properties; meanwhile, the heparin-mimicking coating validated comparable performances as heparin coating. Herein, it is expected that the surface coating of nanofibrous multilayers, especially the facilely constructed heparin-mimicking coating, may have great application potential in biomedical fields.