N-halamine Polymers Research Articles

Preparation of N-Halamine Gelatin Sponge and Its Application in the Treatment of Skin Infection.

Nowadays, there has been an increasing research interest into N-halamine compounds due to their wide antimicrobial properties and no drug resistance. Most of the research mainly focuses on small molecular N-halamines, while few studies are on macromolecule N-halamines. In this work, antibacterial N-halamine polymer materials based on proteins (GS-Cl) were synthesized with an antibacterial component of oxidative chlorine, a support component of a gelatin sponge. After carrying out systematic characterization, the GS-Cls exhibited well-defined porous morphology and had a high efficiency in the killing of Gram-positive bacteria (E. coli) and Gram-negative bacteria (S. aureus). The loading of oxidative chlorine (Cl+%) could be controlled by changing the NaClO concentrations and chlorination times. The biocompatibility was confirmed as well. In vivo experiments suggested that the GS-Cl sample could effectively promote the healing of skin wounds in mice E. coli and S. aureus infection models. These studies show that proteins can be chlorinated and endowed with antimicrobial properties, which has great application potential in the treatment of bacteria-infected wounds.

In Situ Preparation of Chlorine-Regenerable Antimicrobial Polymer Molecular Sieve Membranes.

Microbial contamination has profoundly impacted human health, and the effective eradication of widespread microbial issues is essential for addressing serious hygiene concerns. Taking polystyrene (PS) membrane as an example, we herein developed report a robust strategy for the in situ preparation of chlorine-regenerable antimicrobial polymer molecular sieve membranes through combining post-crosslinking and nucleophilic substitution reaction. The cross-linking PS membranes underwent a reaction with 5,5-dimethylhydantoin (DMH), leading to the formation of polymeric N-halamine precursors (PS-DMH). These hydantoinyl groups within PS-DMH were then efficiently converted into biocidal N-halamine structures (PS-DMH-Cl) via a simple chlorination process. ATR-FTIR and XPS spectra were recorded to confirm the chemical composition of the as-prepared PS-DMH-Cl membranes. SEM analyses revealed that the chlorinated PS-DMH-Cl membranes displayed a rough surface with a multitude of humps. The effect of chlorination temperature and time on the oxidative chlorine content in the PS-DMH-Cl membranes was systematically studied. The antimicrobial assays demonstrated that the PS-DMH-Cl membranes could achieve a 6-log inactivation of E. coli and S. aureus within just 4 min of contact time. Additionally, the resulting PS-DMH-Cl membranes exhibited excellent stability and regenerability of the oxidative chlorine content.

Long-lasting renewable antibacterial N-halamine coating enable dental unit waterlines to prevention and control of contamination of dental treatment water

Developing bacterial biofilm on the dental unit waterlines increases the risk of cross-infection among oral patients. Although chemical disinfectants can achieve disinfection effects in a short period of time, corrosion damage of dental unit waterlines and water contamination can also occur after continuous use of it. Herein, this study explored a one-step deposition method to prepare a durable and renewable antibacterial N-halamine polymeric coating on polyurethane waterlines. The method utilized polyelectrolyte complexes formed with polyethylenimine (PEI) and phytic acid (PA), followed by chlorination to activate the antibacterial properties. The N-halamine polymeric coating reduces the polyurethane waterline’s water contact angle, thus reducing biofouling deposits and the obstruction of the active halide site on the waterlines, thereby facilitating the maintenance of the cleanliness of the coating. In addition, benefiting both from the active chlorine release and the high density of positive charges on the coating, the polyurethane waterline antimicrobial activity is significantly enhanced. Besides, the N-halamine polymeric coating is biocompatible. This study showed that long-lasting and renewable antimicrobial requirements can be achieved by simple surface modification of N-halamine polymer coatings, which provides a practicable strategy for the production of long-term and reproducible antibacterial dental unit waterlines to reduce the incidence of hospital infection in oral department.

Multifunctional polymeric guanidine and hydantoin halamines with broad biocidal activity

Prolonged and excessive use of biocides during the coronavirus disease era calls for incorporating new antiviral polymers that enhance the surface design and functionality for existing and potential future pandemics. Herein, we investigated previously unexplored polyamines with nucleophilic biguanide, guanidine, and hydantoin groups that all can be halogenated leading to high contents of oxidizing halogen that enables enhancement of the biocidal activity. Primary amino groups can be used to attach poly(N-vinylguanidine) (PVG) and poly(allylamine-co-4-aminopyridine-co-5-(4-hydroxybenzylidene)hydantoin) (PAH) as well as a broad-spectrum commercial biocide poly(hexamethylene biguanide) (PHMB) onto a solid support. Halogenation of polymer suspensions was conducted through in situ generation of excess hypobromous acid (HBrO) from bromine and sodium hydroxide or by sodium hypochlorite in aqueous solutions, resulting in N-halamines with high contents of active > N-Br or > N-Cl groups. The virucidal activity of the polymers against human respiratory coronavirus HCoV-229E increased dramatically with their halogenation. Brominated PHMB-Br showed activation activity value > 5 even at 1 mg/L, and complete virus inhibition was observed with either PHMB-Br or PAH-Br at 10 mg/mL. Brominated PVG-Br and PAH-Br possessed fungicidal activity against C. albicans, while PHMB was fungistatic. PHMB, PHMB-Br and PAH polymers demonstrated excellent bactericidal activity against the methicillin-resistant S. aureus and vancomycin-resistant E. faecium. Brominated polymers (PHMB-Br, PVG-Br, PAH-Br) were not toxic to the HeLa monolayers, indicating acceptable biocompatibility to cultured human cells. With these features, the N-halamine polymers of the present study are a worthwhile addition to the arsenal of biocides and are promising candidates for development of non-leaching coatings.

A gold nanoparticle-based photothermal hydrogel assisted by an N-halamine polymer for bacteria-infected skin wound healing.

Bacteria-infected wounds and antibiotic misuse have become a challenge in the treatment of clinical infections. Therefore, there is an urgent need to design non-antibiotic-dependent multifunctional wound dressings for the treatment of bacterially infected wounds. In this study, an injectable antibacterial hydrogel (pAMPS-Cl/AuNR@HA-DA) based on gold nanorods (AuNR) and N-halamine (pAMPS-Cl) with significant photothermal antibacterial properties was developed. The obtained pAMPS-Cl/AuNR@HA-DA hydrogel showed a sponge-like structure with excellent injectability, self-healing, tissue adhesion, and good hemocompatibility. In addition, the hydrogel exhibited excellent in vitro antibacterial capacity under near-infrared (NIR) laser irradiation through the synergistic action of photothermal therapy (PTT) and chemical release therapy. It also showed an excellent ability to eliminate bacterial infection and promote wound healing, indicating that the pAMPS-Cl/AuNR@HA-DA composite hydrogel could be a promising dressing for the treatment of skin wounds.

Durable and rechargeable antimicrobial cotton driven by enhanced UV stability and real-time detection of biocidal factors

In this study, graphene oxide/N-halamine nanocomposite was synthesized through Pickering miniemulsion polymerization, which was then coated on cotton surface. The modified cotton exhibited excellent superhydrophobicity, which could effectively prevent microbial infestation and reduce the probability of hydrolysis of active chlorine, with virtually no active chlorine released in water after 72 h. Deposition of reduced graphene oxide nanosheets endowed cotton with ultraviolet-blocking properties, attributing to enhanced UV adsorption and long UV paths. Moreover, encapsulation of polymeric N-halamine resulted in improved UV stability, thus extending the life of N-halamine-based agents. After 24 h of irradiation, 85 % of original biocidal component (active chlorine content) was retained, and approximately 97 % of initial chlorine could be regenerated. Modified cotton has been proven to be an effective oxidizing material against organic pollutants and a potential antimicrobial substance. Inoculated bacteria were completely killed after 1 and 10 min of contact time, respectively. An innovative and simple scheme for determination of active chlorine content was also devised, and real-time inspection of bactericidal activity could be achieved to assure antimicrobial sustainability. Moreover, this method could be utilized to evaluate hazard classification of microbial contamination in different locations, thus broadening the application scope of N-halamine-based cotton fabrics.

Preparation of quaternarized N-halamine-grafted graphene oxide nanocomposites and synergetic antibacterial properties

At present, frequent outbreaks of bacteria and viruses have seriously affected people's normal lives. Therefore, the study of broad-spectrum antibacterial nanocomposites is very promising. However, most antibacterial materials have some disadvantages, such as single bactericidal mechanisms and unrepeatable use. Based on the current situation, a kind of nanocomposite with three structures of graphene oxide (GO), quaternary ammonium salt (QAs) and N-halamine was prepared, which showed synergistic effect to improve antibacterial activity and combined with a variety of sterilization mechanisms. Meanwhile, GO can provide richer ways of sterilization and high specific surface area, which is conducive to the grafting of quaternarized N-halamine. The advantages of physical sterilization of GO, charge adsorption of QAs, reuse of N-halamine and efficient sterilization are fully utilized. The results showed that the quaternarized N-halamine-grafted GO was obtained successfully. GO grafted with quaternarized N-halamine polymer showed strong speedy bactericidal activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) (99%). It had good storage and regeneration properties.

Engineering a black phosphorus-based magnetic nanosystem armed with antibacterial N-halamine polymer for recyclable blood disinfection

Sepsis triggered by microorganism contamination in circulating blood poses a major threat to human health. In this work, we engineered a black phosphorus-based magnetic nanosystem armed with antibacterial N-halamine polymer for the recyclable treatment of blood infections. We designed hydrophilic, positively charged Fe3O4 nanoparticles capable of rapidly compounding with negatively charged BP and N-halamine polymers through electrostatic interaction. We then examined their antibacterial recyclability for the disinfection of blood, using both stationary and in-flow methods. In aqueous solution and stationary blood, 100% disinfection was achieved, and in low- and high-velocity circulating blood, it reduced the bacterial load from 106 to 101 and 102 CFU mL−1, respectively. The addition of Fe3O4 nanoparticles endowed the nanosystem with super-magnetic properties that allowed it to be completely separated from blood. The N-halamine polymer render the nanosystem excellent antibacterial rechargeability via transformation between N–H and N-Cl. Importantly, the as-prepared nanosystem also exhibited excellent hemocompatibility. These results indicate that the synergistic combination of recyclable Fe3O4 nanoparticles, renewable N-halamine, and biocompatible BP could be effective for disinfecting blood and treating sepsis.

Cow dung-derived biochars engineered as antibacterial agents for bacterial decontamination

Disposal of the pollutants arising from farming cattle and other livestock threatens the environment and public safety in diverse ways. Herein, we report on the synthesis of engineered biochars using cow dung as raw material, and investigating these biochars as antibacterial agents for water decontamination. By coating the biochars with N-halamine polymer and loading them with active chlorine (i.e., Cl+), we were able to regulate them on demand by tuning the polymer coating and bleaching conditions. The obtained N-halamine-modified biochars were found to be extremely potent against Escherichia coli and Staphylococcus aureus. We also investigated the possibility of using these N-halamine-modified biochars for bacterial decontamination in real-world applications. Our findings indicated that a homemade filter column packed with N-halamine-modified biochars removed pathogenic bacteria from mining sewage, dairy sewage, domestic sewage, and artificial seawater. This proposed strategy could indicate a new way for utilizing livestock pollutants to create on-demand decontaminants.

N-halamine polyelectrolytes used for preparation of antibacterial polypropylene nonwoven fabrics and study on their basal cytotoxicity and mutagenicity

Polymeric N-halamine precursors, cationic poly((3-acrylamidopropyl) trimethylammonium chloride) (CHP) and anionic poly(2-acrylamido-2-methylpropane sulfonic acid sodium salt) (AHP), were synthesized and coated onto polypropylene nonwoven fabrics via eco-friendly dipping and spraying methods. The successful coatings were characterized by EDS analysis. After exposure to diluted sodium hypochlorite solution, the coatings became biocidal. Antibacterial tests showed that PP-Dip-Cl samples could inactivate more than 5 logs of Staphylococcus aureus and Escherichia coli O157:H7 within 60 and 30 min, respectively. Although PP-Spray-Cl samples had a relatively low active chlorine content, all inoculated bacteria were inactivated within 60 min for both S. aureus and E. coli O157:H7. All the coatings showed proper storage stability under dark and lab-light conditions. The coated samples showed good air permeability. Basal cytotoxicity test showed that the estimated acute oral LD50 value was 209 ± 14 mg/kg b. w. and 353 ± 14 mg/kg b. w. for CHP-Cl and AHP-Cl, respectively and no indication of mutagenicity was observed with and without external metabolizing enzyme system (rat liver S9 mix) for both the two N-halamine compounds. The eco-friendly coatings have great potential for applications in hospitals.

Graphene oxide as a polymeric N-halamine carrier and release platform: Highly-efficient, sustained-release antibacterial property and great storage stability.

N-halamine compounds have been applied as antibacterial agents owing to the oxidative chlorine. In this work, graphene oxide (GO) as carrier was used to load N-halamine compounds for the sustained-release of chlorine in order to maintain long-term biocidal efficacies. 3‑(3'‑Acrylic acid propylester)‑5,5‑dimethylhydantoin (APDMH) was synthesized using 5,5‑dimethylhydantoin as a heterocyclic precursor and attached on the surface of GO nanosheets via in-situ polymerization. The modified GO composites were characterized by Fourier transform infrared (FT-IR) spectra, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA). The chlorinated GO nanosheets modified with polymerized APDMH (PAPDMH) were very stable and possessed long-term antibacterial properties. The GO-PAPDMH-Cl composites exhibited good antimicrobial efficacies against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli O157:H7) with log reductions of 7.20 and 7.06 within 30 min of contact time, respectively.

Construction of Antibacterial N‐Halamine Polymer Nanomaterials Capable of Bacterial Membrane Disruption for Efficient Anti‐Infective Wound Therapy

Front Cover: N-Halamine polymer-based wound dressing is designed and synthesized, and shows a good wound therapy efficiency in skin tissue–related bacterial infections owing to the antibacterial function of N-Cl bonds. A four-step mechanism unlocks the antibacterial action and therapy process of N-halamine polymer nanomaterials when used as wound dressings in biological and chemical surroundings. This is reported by Yangyang Gao, Nan Song, Wenxin Liu, Alideertu Dong, Yan-Jie Wang, and Ying-Wei Yang in article number 1800453.

Construction of Antibacterial N-Halamine Polymer Nanomaterials Capable of Bacterial Membrane Disruption for Efficient Anti-Infective Wound Therapy.

The increasing occurrence of bacterial infection at the wound sites is a serious global problem, demanding the rapid development of new antibacterial materials for wound dressing to avoid the abuse of antibiotics and thereby antibiotic resistance. In this work, the authors first report on antibacterial N-halamine polymer nanomaterials based on a strategic copolymerization of 3-allyl-5,5-dimethylhydantoin (ADMH) and methyl methacrylate (MMA), which exhibits in vitro and in vivo antimicrobial efficacy against pathogenic bacteria including Staphylococcus aureus and Escherichia coli. Particularly, when a biological evaluation is run for wound therapy, the N-halamine polymer nanomaterials exhibit a powerful antibacterial efficiency and wound healing ability after a series of histological examination of mouse wound. After the evaluation of biological and chemical surroundings, the proposed four-stage mechanism suggests that, with unique antibacterial NCl bonds, the N-halamine polymer nanomaterials can disrupt the bacterial membrane, as a result causing intracellular content leaked out and thereby cell death. Based on the synergistic action of antibacterial and wound therapy, the N-halamine polymer nanomaterials are expected to be promising as wound dressing materials in medical healing and biomaterials.

Preparation of antibacterial polyvinylidene fluoride (PVDF) ultrafiltration membranes with direct addition of N-halamine polymers

ABSTRACTIn this study, novel antibacterial ultrafiltration polyvinylidene fluoride (PVDF) flat sheet membranes were produced with addition of synthesized N-halamine polymers. The ternary phase diagrams of PVDF and the synthesized polymers with N-methyl-2-pyrrolidone and water systems were prepared. The water flux and BSA rejection performances of the produced membranes were assessed both with and without PVP addition, and compared with a commercial membrane. The produced membranes were characterized with FTIR, XPS, DSC, and SEM analysis. Addition of N-halamine polymers to the membrane structure significantly improved the biocidal performance of the produced membranes against Staphylococcus aureus and Escherichia coli (105 CFU).

Fabrication of cotton fabrics through in-situ reduction of polymeric N-halamine modified graphene oxide with enhanced ultraviolet-blocking, self-cleaning, and highly efficient, and monitorable antibacterial properties

In this study, graphene oxide modified polymeric N-halamine precursor was coated onto cotton fabrics through a conventional “dipping-drying” method. The functionalized cotton fabrics were in-situ reduced by treating with L-ascorbic acid. The coated cotton fabrics were then treated with household bleach for enhanced antibacterial activity. After chlorination, the coated cotton fabrics showed an UPF value of 132, and the value increased after oxidative chlorine being consumed. The coated fabrics were also endowed with great hydrophobicity, with values higher than 140°, indicating great self-cleaning ability. The chlorinated fabrics could completely inactivate inoculated S. aureus and E. coli O157:H7 within 1 min and 5 min with 5.07 and 5.18 log reductions, respectively. Due to the proportional relationship of the electrical conductivity and chlorine content of the cotton/rGO-PSPH-Cl fabric, the electrical conductivity of cotton/rGO-PSPH-Cl fabric can be used for monitoring the antimicrobial activity.

Immobilization of N-Halamine Based Polycation on Nanodiamonds for High Dispersity and Enhanced Biocidal Activity.

Novel bactericidal materials, polycation-based N-halamine functionalized nanodiamonds (PCN-NDs), were fabricated by coating of nanodiamonds (NDs) with quaternarized N-halamine polymers via a facile approach. Chemical modification of the particles was confirmed by FTIR, XPS and TGA. The particle diameters and dispersity of the functionalized NDs were investigated by TEM and DLS measurements. It was found that ND tight core aggregates could be broken into tiny nanoparticles with 40-50 nm through functionalization procedure, which resulted in stable colloidal dispersion solution over one month. The antibacterial tests showed that the PCN-NDs exhibited enhanced antibacterial activity against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) compared with their bulk counterparts. The minimum inhibitory concentration values of the as-prepared PCN-NDs are 62.5 μg/mL for both E. coli and S. aureus, even PCN-NDs eliminated nearly 100% of E. coil and S. aureus (107-108 CFU/mg nanoparticles) within 15 min. Furthermore, the as-prepared antimicrobial PCN-NDs exhibited good storage stability and regenerability.

Cationic polymeric N-halamines bind onto biofilms and inactivate adherent bacteria.

A series of amine-based cationic polymeric N-halamine precursors, poly(2,2,6,6-tetramethyl-4-piperidyl methacrylate-co-trimethyl-2-methacryloxyethylammonium chloride)(PMPQ), were synthesized by copolymerizing 2,2,6,6-tetramethyl-4-piperidyl methacrylate (TMPM) with trimethyl-2-methacryloxyethylammonium chloride (TMAC) at different molar ratios (TMPM:TMAC = 10:90,30:70,50:50,70:30, and 90:10). After chlorine bleach treatment, the TMPM moieties in the new copolymers were transformed into amine-based N-halamines (Cl-PMPQ). The chemical structures of the samples were characterized with 1H NMR, FT-IR, and UV spectra, and the molecular weights were determined by dynamic light scattering (DLS). With lower than 70 mol% of the original TMPM content, the resulting Cl-PMPQ copolymers were soluble in water, and demonstrated potent antibacterial functions against Escherichia coli (E. coli, a representative Gram-negative bacteria) and Staphylococcus epidermidis (S. epidermidis, a representative Gram-positive bacteria). E. coli and S. epidermidis were allowed to form biofilms on glass slides. Zeta potential analyses demonstrated that the Cl-PMPQ copolymers rapidly adsorbed onto the preexisting biofilms, and bacterial culturing studies confirmed that the bound Cl-PMPQ provided a total kill of the adherent bacteria in the biofilms. The kinetics of the Cl-PMPQ binding onto the preexisting biofilms were studied with UV analyses. The data fitted well to the bimodal model. The binding kinetic parameters of Cl-PMPQ onto the bacterial biofilms were thus determined.

Preparation of antimicrobial and hemostatic cotton with modified mesoporous particles for biomedical applications.

N-halamine polymers have been successfully attached surfaces of mesoporous materials. The modified mesoporous materials have been applied on the modification of cotton. Soaking in household bleach, the coated cotton shows good antimicrobial efficacy against S. aureus and E. coli O157:H7. The chlorinated samples could completely inactivate 100% S. aureus within 10 min, and 99.99% E. coli O157:H7 within 30 min. The chlorinated sample had better platelet adhesion and red blood cell cohesion than the control sample. The blood clotting index and fluid absorptive property of the samples enhanced after coating with modified mesoporous materials, indicating that the coated sample can prevent wound infection from bacteria and control hemorrhaging simultaneously. The coating of the modified mesoporous materials and N-halamines on cotton has not affect the bioactivity of cotton in the simulated body fluid. The active chlorine of the coated sample decreased 30% after soaking in the whole blood for 1 h. Considering the good antimicrobial efficacy against microorganisms and hemostasis property in blood control of the prepared materials, they have potentials for biomedical applications in wound dressing.

N-Halamine polymer from bipolymer to amphiphilic terpolymer with enhancement in antibacterial activity.

A novel N-halamine terpolymer, i.e., P(ADMH-MMA-HEMA)-Cl, with high antibacterial efficacies were fabricated via a free-radical copolymerization of 3-allyl-5,5-dimethylhydantoin(ADMH), methyl methacrylate(MMA), and hydroxyethyl methacrylate (HEMA), followed by a chlorination treatment using sodium hypochlorite as chlorinating agent. A controllable synthesis of P(ADMH-MMA-HEMA)-Cl was achieved by tuning chlorination conditions, such as chlorination temperature, reactant concentration, chlorination time, etc. A series of antibacterial assays were conducted, and the as-prepared products P(ADMH-MMA-HEMA)-Cl showed good killing capabilities against both Gram-positive and Gram negative bacteria. Remarkably, compared to N-halamine biopolymer counterparts, e.g., P(ADMH-HEMA)-Cl and P(ADMH-MMA)-Cl, and the as-prepared N-halamine terpolymer P(ADMH-MMA-HEMA)-Cl presented the enhancement in antibacterial efficiency toward pathogens. It is believed that this approach offers great potential to be utilized in various fields where antibacterial properties are highly required.

Tyrosine-derived novel antimicrobial hydantoin polymers: synthesis and evaluation of anti-bacterial activities

A new approach for the design and synthesis of cyclic N-halamine polymers having anti-bacterial activity based on a vinyl derivative of tyrosine-derived hydantoin is reported. The synthesis of N-halamine polymers generally involves the chemical modification of 5,5′-disubstituted hydantoin to introduce polymerizable vinyl moieties thereby restricting the halogen capture only on the amide nitrogen. Here we show the possibility of synthesizing vinyl monomers of N-halamine from α-amino acids wherein both the amide and imide nitrogens are available for halogen capture. Thus, a hydantoin monomer was synthesized from L-tyrosine and copolymerized with methyl methacrylate and 2-(hydroxyethyl)methacrylate, to obtain random co-polymers. The monomer and its co-polymers were characterized using NMR, IR, HRMS, GPC, DSC, EDAX and TGA analysis. Films of the co-polymers cast from 10% acetone solutions were exposed to sodium hypochlorite solution to activate the hydantoin moieties. The oxidative chlorine content of the films ranged from 0.6 to 0.9%. The activated films were exposed to both Gram positive (S. aureus) and Gram negative (E. coli) bacteria using standard protocols. Polymers having chlorine content as little as 0.6% exhibited 6 log reduction in the bacterial growth within 30 min of exposure. The method allows the halogenation of both amide and imide nitrogens and could be applied to the preparation of a number of vinyl hydantoins from many amino acids.