Self-assembled nanogels of luminescent thiolated silver nanoclusters and chitosan as bactericidal agent and bacterial sensor.

Multifunctional theranostic agents with the features of good biocompatibility, long-term antibacterial efficacy, and rapid bacterial detection are the desired future medicine for infectious diseases, but which poses huge challenges on the design of such multifunctional nanocomposites in a single entity. Herein, self-assembled nanogels of thiolated silver nanoclusters (Ag NCs) and chitosan was designed and synthesized, which combines the desirable biocompatible, targeting specific, luminescent properties. This nanogel displays an amplified luminescence via strong matrix-ligand coordination between thiolate ligands and chitosan matrix to rigidify the molecular structure on the surface of Ag NCs. Concomitantly, this nanogel exhibits exceptional bactericidal activity, with approximately >10-fold stronger activity compared to its counterpart Ag NCs. Furthermore, a bacterial detection system was developed based on the bacterial binding on the fluorescent nanogels. This work provides a new strategy in designing multifunctional theranostic agents and this new composite Ag NC nanogel holds great promise for practical applications as the theranostic nanomedicines.

Ortho-Substituted α-Phenyl Mannoside Derivatives Promoted Early-Stage Adhesion and Biofilm Formation of E. coli 83972.

Prevention of catheter-associated urinary tract infection (CAUTI) over long-term usage of urinary catheters remains a great challenge. Bacterial interference using nonpathogenic bacteria, such as E. coli 83972, have been investigated in many pilot-scale clinical studies as a potentially nonantibiotic based strategy for CAUTI prevention. We have demonstrated that preforming a dense and stable biofilm of the nonpathogenic E. coli greatly enhances their capability to prevent pathogen colonization. Such nonpathogenic biofilms were formed by E. coli 83972 expressing type 1 fimbriae (fim+ E. coli 83972) on mannoside-presenting surfaces. In this work, we report the synthesis of a series of mannoside derivatives with a wide range of binding affinities, all being equipped with a handle for covalent attachment to silicone surfaces. We established a high-throughput competitive assay based on mannoside-modified particles and flow-cytometry to directly measure the binding affinity between the mannoside ligands and fim+ E. coli 83972. We demonstrated that the bacterial adhesion and biofilm formation were strongly correlated to the binding affinity of the immobilized mannoside ligands. Mass spectrometry based proteomic analysis indicated a substantial difference in the proteome of the extracellular polymeric substance (EPS) secreted by biofilms on different mannoside surfaces, which might be related to the biofilm stability.

Antimicrobial strategies for urinary catheters.

Over 75% of hospital-acquired or nosocomial urinary tract infections are initiated by urinary catheters, which are used during the treatment of 16% of hospitalized patients. Taking the United States as an example, the costs of catheter-associated urinary tract infections (CAUTI) are in excess of $451 million dollars/year. The biofilm formation by pathogenic microbes that protects pathogens from host immune defense and antimicrobial agents is the leading cause for CAUTI. Thus, tremendous efforts have been devoted to antimicrobial coating for urinary catheters in the past few decades, and it has been demonstrated to be one of the most direct and efficient strategies to reduce infections. In this article, we briefly summarize the current methods for preparation of antimicrobial coatings based on different stages in the biofilm formation, highlight recent progress in the urinary catheter coating material design and selection, discuss approaches to improving their long-term antimicrobial efficacy, biocompatibility, multidrug resistance and recurrent infections, and finally outline future requirements and prospects in antimicrobial coating material design. The scope of the works surveyed is confined to antimicrobial urinary catheters. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 445-467, 2019.

Artificial Asymmetric Cilia Array of Dielectric Elastomer for Cargo Transportation.

Inspired by natural ciliary movement, artificial cilia systems have recently been developed to transport microparticles and target biomolecules by the external stimuli-induced bend and twist. However, the directional transportation of cargo meets a major challenge. Here, we present an artificial asymmetric cilia array of dielectric elastomer and realize the cargo directional transportation under alternating-current (ac) electric field. Such a dielectric elastomer is composed of elastomer matrix and dielectric barium titanate (BaTiO3) nanoparticles, which can be polarized under an ac electric field and results in the swinging of artificial elastomer cilia. The asymmetry of the cilia endows themselves with the capability of asymmetric recovery stroke, which is essential for directional transportation of cargo. Transporting performance is also optimized by adjusting the applied frequencies and voltages. This study may provide a new clue to construct functional "smart" devices in electromechanical systems and biomedicine.

Poly(2-(diethylamino)ethyl methacrylate)-based, pH-responsive, copolymeric mixed micelles for targeting anticancer drug control release.

We have demonstrated a novel drug delivery system to improve the selectivity of the current chemotherapy by pH-responsive, polymeric micelle carriers. The micelle carriers were prepared by the self-assembly of copolymers containing the polybasic poly(2-(diethylamino) ethyl methacrylate) (PDEAEMA) block. The mixed copolymers exhibited a comparatively low critical micelle concentration (CMC; 1.95-5.25 mg/L). The resultant mixed micelles were found to be <100 nm and were used to encapsulate the anticancer drug doxorubicin (DOX) with pretty good drug-loading content (24%) and entrapment efficiency (55%). Most importantly, the micelle carrier exhibited a pH-dependent conformational conversion and promoted the DOX release at the tumorous pH. Our in vitro studies demonstrated the comparable level of DOX-loaded mixed micelle delivery into tumor cells with the free DOX (80% of the tumor cells were killed after 48 h incubation). The DOX-loaded mixed micelles were effective to inhibit the proliferation of tumor cells after prolonged incubation. Overall, the pH-responsive mixed micelle system provided desirable potential in the controlled release of anticancer therapeutics.

Probiotic E. coli Nissle 1917 biofilms on silicone substrates for bacterial interference against pathogen colonization.

Bacterial interference is an alternative strategy to fight against device-associated bacterial infections. Pursuing this strategy, a non-pathogenic bacterial biofilm is used as a live, protective barrier to fence off pathogen colonization. In this work, biofilms formed by probiotic Escherichia coli strain Nissle 1917 (EcN) are investigated for their potential for long-term bacterial interference against infections associated with silicone-based urinary catheters and indwelling catheters used in the digestive system, such as feeding tubes and voice prostheses. We have shown that EcN can form stable biofilms on silicone substrates, particularly those modified with a biphenyl mannoside derivative. These biofilms greatly reduced the colonization by pathogenic Enterococcus faecalis in Lysogeny broth (LB) for 11days. STATEMENT OF SIGNIFICANCE: Bacterial interference is an alternative strategy to fight against device-associated bacterial infections. Pursuing this strategy, we use non-pathogenic bacteria to form a biofilm that serves as a live, protective barrier against pathogen colonization. Herein, we report the first use of preformed probiotic E. coli Nissle 1917 biofilms on the mannoside-presenting silicone substrates to prevent pathogen colonization. The biofilms serve as a live, protective barrier to fence off the pathogens, whereas current antimicrobial/antifouling coatings are subjected to gradual coverage by the biomass from the rapidly growing pathogens in a high-nutrient environment. It should be noted that E. coli Nissle 1917 is commercially available and has been used in many clinical trials. We also demonstrated that this probiotic strain performed significantly better than the non-commercial, genetically modified E. coli strain that we previously reported.

Coating of silicone with mannoside-PAMAM dendrimers to enhance formation of non-pathogenic Escherichia coli biofilms against colonization of uropathogens.

Bacterial interference using non-pathogenic Escherichia coli 83972 is a novel strategy for preventing catheter-associated urinary tract infection (CAUTI). Crucial to the success of this strategy is to establish a high coverage and stable biofilm of the non-pathogenic bacteria on the catheter surface. However, this non-pathogenic strain is sluggish to form biofilms on silicone as the most widely used material for urinary catheters. We have addressed this issue by modifying the silicone catheter surfaces with mannosides that promote the biofilm formation, but the stability of the non-pathogenic biofilms challenged by uropathogens over long-term remains a concern. Herein, we report our study on the stability of the non-pathogenic biofilms grown on propynylphenyl mannoside-modified silicone. The result shows that 94% non-pathogenic bacteria were retained on the modified silicone under >0.5 Pa shear stress. After being challenged by three multidrug-resistant uropathogenic isolates in artificial urine for 11 days, large amounts (>4 × 106 CFU cm-2) of the non-pathogenic bacteria remained on the surfaces. These non-pathogenic biofilms reduced the colonization of the uropathogens by >3.2-log. STATEMENT OF SIGNIFICANCE: In bacterial interference, the non-pathogenic Escherichia coli strains are sluggish to form biofilms on the catheter surfaces, due to rapid removal by urine flow. We have demonstrated a solution to this bottleneck by pre-functionalization of mannosides on the silicone surfaces to promote E. coli biofilm formation. A pre-conjugated high affinity propynylphenyl mannoside ligand tethered to the nanometric amino-terminated poly(amido amine) (PAMAM) dendrimer is used for binding to a major E. coli adhesin FimH. It greatly improves the efficiency for the catheter modification, the non-pathogenic biofilm coverage, as well as the (long-term) stability for prevention of uropathogen infections.

Surfaces presenting α-phenyl mannoside derivatives enable formation of stable, high coverage, non-pathogenic Escherichia coli biofilms against pathogen colonization.

Prevention of pathogenic colonization on medical devices over a long period of time remains a great challenge, especially in a high-nutrient environment that accelerates the production of biomass leading to biofouling of the device. Since biofouling and the subsequent pathogen colonization is eventually inevitable, a new strategy using non-pathogenic bacteria as living guards against pathogenic colonization on medical devices has attracted increasing interest. Crucial to the success of this strategy is to pre-establish a high coverage and stable biofilm of benign bacteria on the surface. Silicone elastomers are one of the most widely used materials in biomedical devices. In this work, we modified silicone surfaces to promote formation of high coverage and stable biofilms by a non-pathogenic Escherichia coli strain 83972 with type 1 fimbriae (fim+) to interfere with the colonization of an aggressive biofilm-forming, uropathogenic Enterococcus faecalis. Although it is well known that mannoside surfaces promote the initial adherence of fim+ E. coli through binding to the FimH receptor at the tip of the type 1 fimbriae, it is not clear whether the fast initial adherence could lead to a high coverage and stable protective biofilm. To explore the role of mannoside ligands, we synthesized a series of alkyl and aryl mannosides varied in the structure and immobilized them on silicone surfaces pre-coated with a poly(amidoamine) (PAMAM) dendrimer. We found that stable and densely packed benign E. coli biofilms were formed on the surfaces presenting biphenyl mannoside with the highest initial adherence of fim+ E. coli. These non-pathogenic biofilms prevented the colonization of E. faecalis for 11 days at a high concentration (10(8) CFU mL(-1), 100,000 times above the diagnostic threshold for urinary tract infection) in the nutrient-rich Lysogeny Broth (LB) media. The result shows a correlation among the initial adherence of fim+ E. coli 83972, the coverage and long-term stability of the resulting biofilms, as well as their efficiency for preventing the pathogen colonization.