An elastomer with in situ generated pure zwitterionic surfaces for fibrosis-resistant implants.

Polymeric elastomers are widely utilized in implantable biomedical devices. Nevertheless, the implantation of these elastomers can provoke a robust foreign body response (FBR), leading to the rejection of foreign implants and consequently reducing their effectiveness in vivo. Building effective anti-FBR coatings on those implants remains challenging. Herein, we introduce a coating-free elastomer with superior immunocompatibility. A super-hydrophilic anti-fouling zwitterionic layer can be generated in situ on the surface of the elastomer through a simple chemical trigger. This elastomer can repel the adsorption of proteins, as well as the adhesion of cells, platelets, and diverse microbes. The elastomer elicited negligible inflammatory responses after subcutaneous implantation in rodents for 2 weeks. No apparent fibrotic capsule formation was observed surrounding the elastomer after 6 months in rodents. Continuous subcutaneous insulin infusion (CSII) catheters constructed from the elastomer demonstrated prolonged longevity and performance compared to commercial catheters, indicating its great potential for enhancing and extending the performance of various implantable biomedical devices by effectively attenuating local immune responses. STATEMENT OF SIGNIFICANCE: The foreign body response remains a significant challenge for implants. Complicated coating procedures are usually needed to construct anti-fibrotic coatings on implantable elastomers. Herein, a coating-free elastomer with superior immunocompatibility was achieved using a zwitterionic monomer derivative. A pure zwitterionic layer can be generated on the elastomer surface through a simple chemical trigger. This elastomer significantly reduces protein adsorption, cell and bacterial adhesion, and platelet activation, leading to minimal fibrotic capsule formation even after six months of subcutaneous implantation in rodents. CSII catheters constructed from the PQCBE-H elastomer demonstrated prolonged longevity and performance compared to commercial catheters, highlighting the significant potential of PQCBE-H elastomers for enhancing and extending the performance of various implantable biomedical devices.

Molecular interaction mechanism for humic acids fouling resistance on charged, zwitterion-like and zwitterionic surfaces.

Humic acids (HA) are ubiquitous in surface waters, leading to significant fouling challenges. While zwitterion-like and zwitterionic surfaces have emerged as promising candidates for antifouling, a quantitative understanding of molecular interaction mechanism, particularly at the nanoscale, still remains elusive. In this work, the intermolecular forces between HA and charged, zwitterion-like or zwitterionic monolayers in aqueous environments were quantified using atomic force microscope. Compared to cationic MTAC ([2-(methacryloyloxy)ethyl]trimethylammonium chloride), which exhibited an adhesion energy of âˆ¼1.342 mJ/m2 with HA due to the synergistic effect of electrostatic attraction and possible cation-π interaction, anionic SPMA (3-sulfopropyl methacrylate) showed a weaker adhesion energy (∼0.258 mJ/m2) attributed to the electrostatic repulsion. Zwitterion-like MTAC/SPMA mixture, driven by electrostatic attraction between opposite charges, formed a hydration layer that prevented the interaction with HA, thereby considerably reducing adhesion energy to âˆ¼0.123 mJ/m2. In contrast, zwitterionic MPC (2-methacryloyloxyethyl phosphorylcholine) and DMAPS ([2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide) displayed ultralow adhesion energy (0.06-0.07 mJ/m2) with HA, arising from their strong dipole moments which could induce a tight hydration layer that effectively inhibited HA fouling. The pH-mediated electrostatic interaction resulted in the increased adhesion energy for MTAC but decreased adhesion energy for SPMA with elevated pH, while the adhesion energy for zwitterion-like and zwitterionic surfaces was independent of environmental pH. Density functional theory (DFT) simulation confirmed the strong binding capability of MPC and DMAPS with water molecules (∼-12 kcal mol-1). This work provides valuable insights into the molecular interaction mechanisms underlying humic-substance-fouling resistance of charged, zwitterion-like and zwitterionic materials at the nanoscale, shedding light on developing more effective strategy for HA antifouling in water treatment.

One pot synthesis of zwitteronic 99mTc doped ultrasmall iron oxide nanoparticles for SPECT/T1-weighted MR dual-modality tumor imaging.

In this study, we have synthesized 99mTc intrinsically labeled ultrasmall magnetic iron oxide nanoparticles with zwitterionic surface coating (99mTc-ZW-USIONPs) via one pot synthesis using sulfobetains functionalized poly (acrylic acid) as stabilizer and Na99mTcO4 and SnCl2 as additives. The commercialization of single photon emission computed tomography (SPECT)/magnetic resonance imaging (MRI) scanner made the combination use of 99mTc and iron oxide nanoparticles attracting much attention. Direct doping radioisotope into nanoparticles has the advantages of excellent radiochemical stability and no restriction on the surface functionalization. The complex Technetium chemistry made it challenging to direct dope 99mTc into IONPs, especially those ultrasmall ones without precipitation. We proved that it is possible to prepare 99mTc doped USIONPs with excellent water solubility and favorable T1 signal by controlling the radioactivity and reducing agent amount. With no need of chelator, the zwitterionic surface resists the protein corona formation, resulting in a reduced RES uptake and higher tumor contrast. The 99mTc-ZW-USIONPs demonstrated excellent performance of tumor SPECT and T1-weighted MR imaging capability in 4T1 tumor bearing mice. Together with their ease of preparation and superior biocompatibility, we believe these 99mTc-ZW-USIONPs represent a type of promising dual contrast agent for SPECT/T1 MRI.

Engineering Antifouling and Antibacterial Stainless Steel for Orthodontic Appliances through Layer-by-Layer Deposition of Nanocomposite Coatings.

In this study, a nanocomposite coating composed of polydopamine, functionalized poly(3,4-ethylenedioxythiophene) (PEDOT), and silver nanoparticles (AgNPs) was synthesized through layer-by-layer deposition. Biomimitic polydopamine and hydroxyl-functionalized PEDOT were used to enhance the adhesion strength. The deposition of PEDOT functionalized with zwitterionic phosphorylcholine can contribute to the antifouling property. After immersion in the AgNO3 solution, Ag+ ions were adsorbed on PEDOT films and further reduced to form AgNPs spontaneously, which conferred antibacterial properties on these nanocomposite films. Escherichia coli and Streptococcus mutans were chosen to represent two common Gram-negative and Gram-positive oral pathogens. We further conducted inductively coupled plasma mass spectrometry to confirm that the Ag+ ions released from these nanocomposite films did not exert adverse effects on the human body. These results suggested that, when applied to stainless steel orthodontic appliances, these durable antifouling and antibacterial coatings may be useful for avoiding bacterial infection.

Tailored elasticity combined with biomimetic surface promotes nanoparticle transcytosis to overcome mucosal epithelial barrier.

Overcoming epithelial barriers to enhance drug absorption is a major challenge for nanoparticle (NP)-based mucosal delivery systems. With adequate physicochemical properties, the transepithelial delivery of NPs may be efficiently enhanced. However, little is known about the role of elasticity on the transport of NPs across the polarized epithelium, especially the processes and mechanisms of endocytosis, intracellular trafficking and exocytosis. In this study, we discovered that zwitterionic hydrogel NPs with varied elasticity displayed considerably different oral insulin absorption on diabetic rats. It was found that NP elasticity strongly shaped the transepithelial behaviors of NPs, and the increase of elasticity boosted the transcytosis by improving both endocytosis and exocytosis. Elasticity also showed a profound effect on the intracellular trafficking routes of NPs, which was closely related to distribution of NPs in exocytosis pathway and their intra-endosome sphere-to-ellipsoid shape transformation. Importantly, NPs with zwitterionic surface experienced more efficient basolateral exocytosis than apical exocytosis, while the elasticity-related exocytosis enhancement appeared to be non-selective. Therefore, tailored elasticity could promote mucosal transcytosis of NPs, which was able to be further improved with biomimetic zwitterionic surface. This study may provide important knowledge for the design of functional nanovehicles to efficiently overcome mucosal epithelial barriers in the future.

Integration of photo-induced biocidal and hydrophilic antifouling functions on nanofibrous membranes with demonstrated reduction of biofilm formation.

Survival and pathogenic microbial adhesions on surfaces of materials followed by the formation of biofilms with robust resistance to antibiotics constitute the forefront of disease transmissions. Conventional strategies responding to this challenge are rather limited due to the biofouling effect of microorganisms or the irreversible consumption of antimicrobial agents embedded into the materials. Herein, we report an approach of combining photo-induced rechargeable biocidal properties with microbial resisting and releasing zwitterionic hydrophilic functions on surfaces of materials to improve antifouling performances. Poly(vinyl alcohol-co-ethylene) (EVOH) nanofibrous membranes (NFMs) were chemically incorporated with both 3,3',4,4'-benzophenonetetracarboxylic dianhydride (BPTCD), a photoactive chemical, and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA), a zwitterionic monomer. Both functional agents work independently and construct concerted microbial resisting, killing, and releasing functions to reduce microbial contamination and biofilm formation. The resulted SBMA@EVOH NFMs exhibited integrated features of large ROS production capacity, ease of photoactive rechargeability and controllability, long-term stability, high biocidal efficacy (>99.9999% via contact killing), and promising antifouling performance, which enable the SBMA@EVOH NFMs to serve as a biocidal material for food safety and medical applications.

Rechargeable Antibacterial N-Halamine Films with Antifouling Function for Food Packaging Applications.

Pathogenic microbial contamination from microbial adhesion and subsequent formation of the biofilm on surfaces of plastic food packaging materials, especially with robust resistance to antimicrobial agents, is a major reason for the outbreak of foodborne infections. Conventional strategies in controlling the contaminations are significantly limited either by biofouling or by the irreversible consumption of antimicrobial agents. Herein, we report a robust methodology to create rechargeable biocidal poly(vinyl alcohol- co-ethylene) films (SBMA@HAF films) with antifouling function via chemically incorporating both N-halamine (HAF) and zwitterionic moieties [[2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA)]. The promise of the design exhibits three features to defeat bacterial contaminations: (i) zwitterionic moieties can effectively reduce bacterial attachment onto the films, (ii) N-halamine with robust rechargeable biocidal activity can rapidly kill any attached bacteria, and (iii) any inactivated bacterial debris can be easily released to avoid biofilm formation due to the superhydrophilicity of the zwitterions. The resulting SBMA@HAF films exhibit integrated properties of high transparency, robust mechanical property, great hydrophilicity, ease of chlorine recharging (>250 ppm), long-term stability, high biocidal efficacy (>99.9999% via contact killing), and promising antifouling functions, which enable the SBMA@HAF films to serve as a biocidal material in food packaging applications.

Self-Generating and Self-Renewing Zwitterionic Polymer Surfaces for Marine Anti-Biofouling.

Regeneration of antifouling polymer surfaces after contamination or damage is an important issue, especially in complex marine environments. Here, inspired by the self-renewal of silyl acrylate polymers and the protein resistance of zwitterionic polymers, we prepared a novel hydrolysis-induced zwitterionic monomer, tertiary carboxybetaine triisopropylsilyl ester ethyl acrylate (TCBSA), and copolymerized it with methyl methacrylate (MMA). Such a copolymer rapidly self-generates a zwitterionic surface and provides fouling resistance in marine environments. Furthermore, TCBSA was copolymerized with MMA and 2-methylene-1,3-dioxepane (MDO), where MDO causes degradation of the polymers. Our study demonstrates that the degradation of the polymer is controlled, and the degradation rate increases with the external enzyme concentration in the seawater, leading to a self-renewing dynamic surface. Quartz crystal microbalance with dissipation measurements show that the polymeric coating with self-generating zwitterions has excellent protein resistance in seawater. Bioassays demonstrate that the coating can effectively inhibit the adhesion of marine bacteria (Pseudomonas sp.) and diatoms (Navicula incerta). The coating with a self-generating and self-renewing zwitterionic surface is potential to find applications in marine anti-biofouling.

Intracellular Enzyme-Triggered Assembly of Amino Acid-Modified Gold Nanoparticles for Accurate Cancer Therapy with Multimode.

Multiple amino acid (glutamine and lysine)-modified gold nanoparticles a with pH-switchable zwitterionic surface were fabricated through coordination bonds using ferrous iron (Fe2+) as bridge ions, which are able to spontaneously and selectively assemble in tumor cells for accurate tumor therapy combining enzyme-triggered photothermal therapy and H2O2-dependent catalytic medicine. These gold nanoparticles showed electric neutrality at pH 7.4 (hematological system) to prevent endocytosis of normal cells, which could be positively charged at pH 6.8 (tumor microenvironment) to promote the endocytosis of tumor cells to these nanoparticles, performing great tumor selectivity. After cell uptake, the specific enzyme (transglutaminase) in tumor cells would catalyze the polymerization of glutamine and lysine to cause the intracellular assembly of these gold nanoparticles, resulting in an excellent photothermal property for accurate tumor therapy. Moreover, the Fe2+ ion could decompose excess hydrogen peroxide (H2O2) in tumor cells via the Fenton reaction, resulting in a large amount of hydroxyl radicals (·OH). These radicals would also cause tumor cell damage. This synergetic therapy associating with high tumor selectivity generated an 8-fold in vitro cytotoxicity against tumor cells compared with normal cells under 48 h incubation with 10 min NIR irradiation. Moreover, in vivo data from tumor-bearing nude mice models showed that tumors can be completely inhibited and gradually eliminated after multimode treatment combining catalytic medicine and photothermal therapy for 3 weeks. This system takes advantage of three tumor microenvironment conditions (low pH, enzyme, and H2O2) to trigger the therapeutic actions, which is a promising platform for cancer therapy that achieved prolonged circulation time in the blood system, selective cellular uptake, and accurate tumor therapy in multiple models.

Mixed-charge pseudo-zwitterionic mesoporous silica nanoparticles with low-fouling and reduced cell uptake properties.

The design of drug delivery systems needs to consider biocompatibility and host body recognition for an adequate actuation. In this work, mesoporous silica nanoparticles (MSNs) surfaces were successfully modified with two silane molecules to provide mixed-charge brushes (-NH3⊕/-PO3⊝) and well evaluated in terms of surface properties, low-fouling capability and cell uptake in comparison to PEGylated MSNs. The modification process consists in the simultaneous direct-grafting of hydrolysable short chain amino (aminopropyl silanetriol, APST) and phosphonate-based (trihydroxy-silyl-propyl-methyl-phosphonate, THSPMP) silane molecules able to provide a pseudo-zwitterionic nature under physiological pH conditions. Results confirmed that both mixed-charge pseudo-zwitterionic MSNs (ZMSN) and PEG-MSN display a significant reduction of serum protein adhesion and macrophages uptake with respect to pristine MSNs. In the case of ZMSNs, this reduction is up to a 70-90% for protein adsorption and c.a. 60% for cellular uptake. This pseudo-zwitterionic modification has been focused on the aim of local treatment of bacterial infections through the synergistic effect between the inherent antimicrobial effect of mixed-charge system and the levofloxacin antibiotic release profile. These findings open promising future expectations for the effective treatment of bacterial infections through the use of mixed-charge pseudo-zwitterionic MSNs furtive to macrophages and with antimicrobial properties. STATEMENT OF SIGNIFICANCE: Herein a novel antimicrobial mixed-charge pseudo-zwitterionic MSNs based system with low-fouling and reduced cell uptake behavior has been developed. This chemical modification has been performed by the simultaneous grafting of short chain organosilanes, containing amino and phosphonate groups, respectively. This nanocarrier has been tested for local infection treatment through the synergy between the antimicrobial effect of mixed-charge brushes and the levofloxacin antibiotic release profile.

N-Propyl-N'-2-pyridylurea-modified silica as mixed-mode stationary phase with moderate weak anion exchange capacity and pH-dependent surface charge reversal.

Herein, we present a novel silica-based stationary phase modified with N-propyl-N'-2-pyridylurea selector. Due to the weakly basic properties of the pyridine selector and the presence of residual silanols after selector immobilization, a zwitterionic surface with a pI observed at approximately pH 5.5 was measured by electrophoretic light scattering in pH-dependent ζ-potential determinations. The capability of the new N-propyl-N'-2-pyridylurea-modified silica to serve as mixed-mode stationary phase was investigated. For this purpose, it was characterized under RP and HILIC conditions using test mixtures. Subsequent classification of this stationary phase in comparison to in-house and commercial benchmarks was carried by principal component analysis of resultant retention factors from chromatographic tests. The results show a relatively unique mixed-mode character amongst the tested stationary phases. The chromatographic retention characteristics of acidic compounds matched well the ζ-potential determinations. The application of anion-exchange at low pH values (e.g. pH 5) and ion exclusion chromatography at pH 7 for the separation of uridine 5'-mono-, di- and triphosphate demonstrated a pH-dependent umpolung of the stationary phase surface. The combination of these separation principles in a pH gradient from 5 to 7 gave rise to weak anion-exchange selectivity with a charge-inducted elution due to repulsive interactions at higher pH and resulted in a significant faster separation with improved peak shape under mild elution conditions.

Surface-anchored counterions on weak chiral anion-exchangers accelerate separations and improve their compatibility for mass-spectrometry-hyphenation.

In the present work we propose new variants of chiral stationary phases (CSP) with tert-butylcarbamoylquinine (tBuCQN) as chiral selector molecule. Four tBuCQN-CSPs with distinct bonding chemistries are compared in terms of their pH-dependent surface charge by ζ-potential determinations, by achiral and chiral liquid chromatographic tests and LC-ESI-MS hyphenation. In one embodiment tBuCQN was immobilized on 3-mercaptopropylmethylsilyl-modified silica by thiol-ene click reaction (brush type CSP with selector coverage of 0.38mmol/g). In another embodiment, poly-(3-mercaptopropyl)-methylsiloxane was coated onto vinylized silica particles in presence of tBuCQN and radical initiator. The tBuCQN selector was then immobilized onto the polysiloxane film which in turn was crosslinked to the vinyl-surface in a simultaneous double click reaction leading to a CSP with enhanced stability due to multiple linkages (0.29mmol/g tBuCQN). Aliquots of each of the two CSPs were further modified by oxidation of free residual thiol groups to sulfonic acid functionalities to obtain strongly acidic endcapping groups which act as immobilized counterions of the chiral WAX CSPs (0.2mmol/g sulfonic acid co-ligands for brush type CSP). This caused secondary repulsive interactions, hence balanced interactions of the target analytes (chiral acids) at the WAX site and decreased non-specific interactions. Furthermore, this rendered possible the use of milder elution conditions, i.e. lower ionic strength, for acidic compounds. Separation performance was maintained and slightly improved, respectively, when using polar organic or reversed-phase type elution mode in chiral separations which were significantly accelerated (isoeluotropic conditions could be achieved with ca. factor 40 lower counterion concentration in the mobile phase). Thus, LC-ESI-MS enantiomer separations could be readily performed at very low ionic strength conditions (10mM acetate) which is favorable due to less ion suppression. In addition to this the newly developed stationary phases showed complementary retention profiles in RP- and HILIC-mode which make these type of stationary phases also promising tools for achiral applications in pharmaceutical analysis, especially as orthogonal separation principle e.g. in 2D-LC and impurity profiling.

Prevention of bacterial adhesion to zwitterionic biocompatible mesoporous glasses.

Novel materials, based on Mesoporous Bioactive Glasses (MBGs) in the ternary system SiO2-CaO-P2O5, decorated with (3-aminopropyl)triethoxysilane (APTES) and subsequently with amino acid Lysine (Lys), by post-grafting method on the external surface of the glasses (named MBG-NH2 and MBG-Lys), are reported. The surface functionalization with organic groups did not damage the mesoporous network and their structural and textural properties were also preserved despite the high solubility of MBG matrices. The incorporation of Lys confers a zwitterionic nature to these MBG materials due to the presence of adjacent amine and carboxylic groups in the external surface. At physiologic pH, this coexistence of basic amine and carboxilic acid groups from anchored Lys provided zero surface charge named zwitterionic effect. This behaviour could give rise to potential applications of antibacterial adhesion. Therefore, in order to assess the influence of zwitterionic nature in in vitro bacterial adhesion, studies were carried out with Staphylococcus aureus. It was demonstrated that the efficient interaction of these zwitterionic pairs onto the MBG surfaces reduced bacterial adhesion up to 99.9% compared to bare MBGs. In order to test the suitability of zwitterionic MBGs materials as bone grafts, their cytocompatibility was investigated in vitro with MC3T3-E1 preosteoblasts. These findings suggested that the proposed surface functionalization strategy provided MBG materials with notable antibacterial adhesion properties, hence making these materials promising candidates for local bone infection therapy. STATEMENT OF SIGNIFICANCE: The present research work is focused in finding a preventive treatment of bone infection based on Mesoporous Bioactive Glasses (MBGs) with antibacterial adhesion properties obtained by zwitterionic surface modification. MBGs exhibit unique nanostructural, textural and bioactive characteristics. The novelty and originality of this manuscript is based on the design and optimization of a straightforward functionalization method capable of providing MBGs with zwitterionic surfaces that are able to inhibit bacterial adhesion without affecting their cytocompatibility. This new characteristic enhanced the MBG properties to avoid the bacterial adherence onto the implant surfaces for bone tissue engineering applications. Subsequently, it could help to decrease the infection rates after implantation surgery, which represents one of the most serious complications associated to surgical treatments of bone diseases and fractures.

Efficient Preparation of Super Antifouling PVDF Ultrafiltration Membrane with One Step Fabricated Zwitterionic Surface.

On the basis of the excellent fouling resistance of zwitterionic materials, the super antifouling polyvinylidene fluoride (PVDF) membrane was efficiently prepared though one-step sulfonation of PVDF and polyaniline blend membrane in situ. The self-doped sulfonated polyaniline (SPANI) was generated as a novel zwitterionic polymer to improve the antifouling property of PVDF ultrafiltration membrane used in sewage treatment. Surface attenuated total reflection Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, surface zeta potential, and water contact angle demonstrated the successful fabrication of zwitterionic interface by convenient sulfonation modification. The static adsorption fouling test showed the quantified adsorption mass of bovine serum albumin (BSA) pollutant on the PVDF/SPANI membrane surface decreases to 3(±2) µg/cm(2), and the water flux recovery ratio (FRR) values were no less than 95% for the three model pollutants of BSA, sodium alginate (SA), and humic acid (HA), which were corresponding hydrophobic, hydrophilic, and natural pollutants in sewage, respectively. This Research Article demonstrated the antifouling advantages of zwitterionic SPANI and aimed to provide a simple method for the large scale preparation of zwitterionic antifouling ultrafiltration membranes.

Cleaning of Oil Fouling with Water Enabled by Zwitterionic Polyelectrolyte Coatings: Overcoming the Imperative Challenge of Oil-Water Separation Membranes.

Herein we report a self-cleaning coating derived from zwitterionic poly(2-methacryloyloxylethyl phosphorylcholine) (PMPC) brushes grafted on a solid substrate. The PMPC surface not only exhibits complete oil repellency in a water-wetted state (i.e., underwater superoleophobicity), but also allows effective cleaning of oil fouled on dry surfaces by water alone. The PMPC surface was compared with typical underwater superoleophobic surfaces realized with the aid of surface roughening by applying hydrophilic nanostructures and those realized by applying smooth hydrophilic polyelectrolyte multilayers. We show that underwater superoleophobicity of a surface is not sufficient to enable water to clean up oil fouling on a dry surface, because the latter circumstance demands the surface to be able to strongly bond water not only in its pristine state but also in an oil-wetted state. The PMPC surface is unique with its described self-cleaning performance because the zwitterionic phosphorylcholine groups exhibit exceptional binding affinity to water even when they are already wetted by oil. Further, we show that applying this PMPC coating onto steel meshes produces oil-water separation membranes that are resilient to oil contamination with simply water rinsing. Consequently, we provide an effective solution to the oil contamination issue on the oil-water separation membranes, which is an imperative challenge in this field. Thanks to the self-cleaning effect of the PMPC surface, PMPC-coated steel meshes can not only separate oil from oil-water mixtures in a water-wetted state, but also can lift oil out from oil-water mixtures even in a dry state, which is a very promising technology for practical oil-spill remediation. In contrast, we show that oil contamination on conventional hydrophilic oil-water separation membranes would permanently induce the loss of oil-water separation function, and thus they have to be always used in a completely water-wetted state, which significantly restricts their application in practice.