Comparing an Integrated Amphiphilic Surfactant to Traditional Hydrophilic Coatings for the Reduction of Catheter-Associated Urethral Microtrauma.

Hydrophilic-coated intermittent catheters have improved the experience of intermittent urinary catheterization for patients compared to conventional gel-lubricated uncoated catheters. However, the incorporation of polyvinylpyrrolidone (PVP) within hydrophilic coatings can lead to significant issues with coating dry-out. Consequently, increased force on catheter withdrawal may cause complications, including urethral microtrauma and pain. Standard methods of evaluating catheter lubricity lack physiological relevance and an understanding of the surface interaction with the urethra. The tribological performance and urethral interaction of commercially available hydrophilic PVP-coated catheters and a coating-free integrated amphiphilic surfactant (IAS) catheter were evaluated by using a biomimetic urethral model designed from a modified coefficient of friction (CoF) assay. T24 human urothelial cells were cultured on customized silicone sheets as an alternate countersurface for CoF testing. Hydrophilic PVP-coated and coating-free IAS catheters were hydrated and the CoF obtained immediately following hydration, or after 2 min, mimicking in vivo indwell time for urine drainage. The model was observed for urethral epithelial cell damage postcatheterization. The majority of hydrophilic PVP-coated catheters caused significantly greater removal of cells from the monolayer after 2 min indwell time, compared to the IAS catheter. Hydrophilic PVP-coated catheters were shown to cause more cell damage than the coating-free IAS catheter. A biomimetic urethral model provides a more physiologically relevant model for understanding the factors that govern the frictional interface between a catheter surface and urethral tissue. From these findings, the use of coating-free IAS catheters instead of hydrophilic PVP-coated catheters may help reduce urethral microtrauma experienced during catheter withdrawal from the bladder, which may lead to a lower risk of infection.

Pharmacological Approaches for the Prevention of Breast Implant Capsular Contracture.

Capsular contracture is a common complication associated with breast implants following reconstructive or aesthetic surgery in which a tight or constricting scar tissue capsule forms around the implant, often distorting the breast shape and resulting in chronic pain. Capsulectomy (involving full removal of the capsule surrounding the implant) and capsulotomy (where the capsule is released and/or partly removed to create more space for the implant) are the most common surgical procedures used to treat capsular contracture. Various structural modifications of the implant device (including use of textured implants, submuscular placement of the implant, and the use of polyurethane-coated implants) and surgical strategies (including pre-operative skin washing and irrigation of the implant pocket with antibiotics) have been and/or are currently used to help reduce the incidence of capsular contracture. In this article, we review the pharmacological approaches-both commonly practiced in the clinic and experimental-reported in the scientific and clinical literature aimed at either preventing or treating capsular contracture, including (i) pre- and post-operative intravenous administration of drug substances, (ii) systemic (usually oral) administration of drugs before and after surgery, (iii) modification of the implant surface with grafted drug substances, (iv) irrigation of the implant or peri-implant tissue with drugs prior to implantation, and (v) incorporation of drugs into the implant shell or filler prior to surgery followed by drug release in situ after implantation.

Evaluation of the in vitro cytotoxicity and modulation of the inflammatory response by the bioresorbable polymers poly(D,L-lactide-co-glycolide) and poly(L-lactide-co-glycolide).

Bioresorbable polymers composed of poly(D,L-lactide-co-glycolide) (PDLLGA) and poly(L-lactide-co-glycolide) (PLLGA) have become increasingly popular for the preparation of bone substitute constructs. However, there are reports of a delayed inflammatory reaction occurring months or years after implantation. Due to the long polymer degradation times, in vitro tests carried out at physiological temperature, 37°C, tend to assess only the short-term biocompatibility of these materials. The aim of this work is to develop an in vitro protocol that can be used to assess the long-term cytotoxicity of bioresorbable polymers in a time efficient manner. This study used a previously developed and validated accelerated degradation protocol to obtain samples of PDLLGA and PLLGA at increasing levels of degradation. Samples were then applied to standard ISO 10993-5 direct contact cytotoxicity testing and it was found that PDLLGA samples showed increasing levels of cytotoxicity at the later stages of degradation, with PLLGA samples demonstrating significantly less cytotoxic behaviour. Following concern that accumulation of acidic degradation products in a closed multi-well culture environment could overestimate cytotoxicity, we developed and validated a new dynamic flow culture methodology, for testing the cytotoxicity of these degradable materials, by adapting a commercial "organ on a chip" flow culture system, Quasi Vivo®. In addition to cytotoxicity testing, we have carried out profiling of inflammatory cytokines released by cells in response to degraded PDLLGA and PLLGA, and have suggested mechanism by which lactide-based bioresorbable materials could modulate the inflammatory response through the G-protein coupled receptor (GPCR), hydroxycarboxylic acid receptor 1 (HCA1). STATEMENT OF SIGNIFICANCE: Bioresorbable materials naturally disintegrate over time when implanted into the body. They are often used to make screws and clips for repair of broken bones. Unfortunately, some patients can react badly to the material, resulting in painful inflammation. Biomaterials scientists are interested in developing materials that are more compatible with the body. However, it is very difficult to predict the long-term compatibility of bioresorbable materials in the lab. In our study, we have developed a method that will allow us to study the effects of the materials as they continue to break down. This will help us understand why the materials may cause inflammation, and will support research into the development of new and improved materials for bone repair.

The Vaginal Microbiota, Bacterial Biofilms and Polymeric Drug-Releasing Vaginal Rings.

The diversity and dynamics of the microbial species populating the human vagina are increasingly understood to play a pivotal role in vaginal health. However, our knowledge about the potential interactions between the vaginal microbiota and vaginally administered drug delivery systems is still rather limited. Several drug-releasing vaginal ring products are currently marketed for hormonal contraception and estrogen replacement therapy, and many others are in preclinical and clinical development for these and other clinical indications. As with all implantable polymeric devices, drug-releasing vaginal rings are subject to surface bacterial adherence and biofilm formation, mostly associated with endogenous microorganisms present in the vagina. Despite more than 50 years since the vaginal ring concept was first described, there has been only limited study and reporting around bacterial adherence and biofilm formation on rings. With increasing interest in the vaginal microbiome and vaginal ring technology, this timely review article provides an overview of: (i) the vaginal microbiota, (ii) biofilm formation in the human vagina and its potential role in vaginal dysbiosis, (iii) mechanistic aspects of biofilm formation on polymeric surfaces, (iv) polymeric materials used in the manufacture of vaginal rings, (v) surface morphology characteristics of rings, (vi) biomass accumulation and biofilm formation on vaginal rings, and (vii) regulatory considerations.

Infection-Triggered, Self-Cleaning Surfaces with On-Demand Cleavage of Surface-Localized Surfactant Moieties.

Biofouling of surfaces is a major cause of infection and leads to significant patient morbidity and mortality within healthcare settings. With ever-increasing concerns over antibiotic resistance and associated challenges in eradicating surface-attached biofilm communities, efficacious antifouling materials are urgently required. We herein describe the development of an inherently antiadherent polymer system with the capacity for on-demand cleavage of surface-localized surfactant moieties. The nonionic surfactant, Triton X-100, was linked to hydrogel monomers via hydrolytically labile ester bonds. Synthesized copolymers exhibited pH-dependent switching of surfactant release, with elution triggered under the alkaline conditions characteristic of catheter-associated urinary tract infections and subsequently slowed down as the pH decreased, representing eradication of infection. In addition, the materials demonstrated complete resistance to adherence of Staphylococcus aureus following 24 h incubation in infected artificial urine, with reductions in adherence of Proteus mirabilis of up to 89% also observed. This dual-pronged approach with active, infection-responsive cleavage of surfactant to enhance the antiadherent properties of the surfactant-modified surfaces represents a promising self-cleaning strategy without associated concerns over bacterial resistance.

Titanium for Orthopedic Applications: An Overview of Surface Modification to Improve Biocompatibility and Prevent Bacterial Biofilm Formation.

Titanium and its alloys have emerged as excellent candidates for use as orthopedic biomaterials. Nevertheless, there are often complications arising after implantation of orthopedic devices, most notably prosthetic joint infection and aseptic loosening. To ensure that implanted devices remain functional in situ, innovation in surface modification has attracted much attention in the effort to develop orthopedic materials with optimal characteristics at the biomaterial-tissue interface. This review will draw together metallurgy, surface engineering, biofilm microbiology, and biomaterial science. It will serve to appreciate why titanium and its alloys are frequently used orthopedic biomaterials and address some of the challenges facing these biomaterials currently, including the significant problem of device-associated infection. Finally, the authors shall consolidate and evaluate surface modification techniques employed to overcome some of these issues by offering a unique perspective as to the direction in which research is headed from a broad, interdisciplinary point of view.

Optimization of anti-wear and anti-bacterial properties of beta TiNb alloy via controlling duty cycle in open-air laser nitriding.

A multifunctional beta TiNb surface, featuring wear-resistant and antibacterial properties, was successfully created by means of open-air fibre laser nitriding. Beta TiNb alloy was selected in this study as it has low Young's modulus, is highly biocompatible, and thus can be a promising prosthetic joint material. It is, however, necessary to overcome intrinsically weak mechanical properties and poor wear resistance of beta TiNb in order to cover the range of applications to load-bearing and/or shearing parts. To this end, open-air laser nitriding technique was employed. A control of single processing parameter, namely duty cycle (between 5% and 100%), led to substantially different structural and functional properties of the processed beta TiNb surfaces as analyzed by an array of analytical tools. The TiNb samples nitrided at the DC condition of 60% showed a most enhanced performance in terms of improving surface hardness, anti-friction, anti-wear and anti-bacterial properties in comparison with other conditions. These findings are expected to be highly important and useful when TiNb alloys are considered as materials for hip/knee articular joint implants.

Atmospheric pressure non-thermal plasma exposure reduces Pseudomonas aeruginosa lipopolysaccharide toxicity in vitro and in vivo.

Lipopolysaccharide (LPS) is an endotoxin composed of a polysaccharide and lipid component. It is intrinsically responsible for the pathogenicity of Gram-negative bacteria and is involved in the development of bacterial sepsis. Atmospheric pressure non-thermal plasma is proposed as a potential new approach for the treatment of infected tissue such as chronic wounds, with both antibacterial and wound-healing activities extensively described. Using both the RAW264.7 murine macrophage cell line in vitro assays and the Galleria mellonella insect in vivo toxicity model, the effect non-thermal plasma exposure on LPS-mediated toxicity has been characterised. Short (60 s) non-thermal plasma exposures of Pseudomonas aeruginosa conditioned growth media, membrane lysates and purified P. aeruginosa LPS, resulted in a substantial detoxification and reduction of LPS-induced cytotoxicity in RAW264.7 murine macrophages. Non-thermal plasma exposure (60 s) of purified P. aeruginosa LPS led to a significant (p < 0.05) improvement in the G. mellonella health index (GHI) score, a measure of in vivo toxicity. These findings demonstrate the ability of short plasma exposures to significantly reduce LPS-induced cytotoxicity both in vitro and in vivo; attenuating the toxicity of this important virulence factor intrinsic to the pathogenicity of Gram-negative bacteria.

Anti-Adherent Biomaterials for Prevention of Catheter Biofouling.

Medical device-associated infections present a leading global healthcare challenge, and effective strategies to prevent infections are urgently required. Herein, we present an innovative anti-adherent hydrogel copolymer as a candidate catheter coating with complementary hydrophobic drug-carrying and eluting capacities. The amphiphilic block copolymer, Poloxamer 188, was chemically-derivatized with methacryloyl moieties and copolymerized with the hydrogel monomer, 2-hydroxyethyl methacrylate. Performance of the synthesized copolymers was evaluated in terms of equilibrium swelling, surface water wettability, mechanical integrity, resistance to encrustation and bacterial adherence, and ability to control release of the loaded fluoroquinolone antibiotic, ofloxacin. The developed matrices were able to provide significant protection from fouling, with observed reductions of over 90% in both adherence of the common urinary pathogen Escherichia coli and encrusting crystalline deposits of calcium and magnesium salts relative to the commonly employed hydrogel, poly (hydroxyethyl methacrylate). Additionally, the release kinetics of a loaded hydrophobic drug could be readily tuned through facile manipulation of polymer composition. This combinatorial approach shows significant promise in the development of suitable systems for prevention of catheter-associated infections.

Optimization of singlet oxygen production from photosensitizer-incorporated, medically relevant hydrogels.

Photodynamic therapy and photodynamic antimicrobial chemotherapy are widely used, but despite this, the relationships between fluence, wavelength of irradiation and singlet oxygen (1 O2 ) production are poorly understood. To establish the relationships between these factors in medically relevant materials, the effect of fluence on 1 O2 production from a tetrakis(4-N-methylpyridyl)porphyrin (TMPyP)-incorporated 2-hydroxyethyl methacrylate: methyl methacrylate: methacrylic acid (HEMA: MMA:MAA) copolymer, a total energy of 50.48 J/cm2 , was applied at varying illumination power, and times. 1 O2 production was characterized using anthracene-9,10-dipropionic acid, disodium salt (ADPA) using a recently described method. Using two light sources, a white LED array and a white halogen source, the LED array was found to produce less 1 O2 than the halogen source when the same power (over 500 - 600 nm) and time conditions were applied. Importantly, it showed that the longest wavelength Q band (590 nm) is primarily responsible for 1 O2 generation, and that a linear relationship exists between increasing power and time and the production of singlet oxygen. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 320-326, 2017.

An Infection-Responsive Approach To Reduce Bacterial Adhesion in Urinary Biomaterials.

Infection is an inevitable consequence of chronic urinary catheterization with associated problems of recurrent catheter encrustation and blockage experienced by approximately 50% of all long-term catheterized patients. In this work, we have exploited, for the first time, the reported pathogen-induced elevation of urine pH as a trigger for "intelligent" antimicrobial release from novel hydrogel drug delivery systems of 2-hydroxyethyl methacrylate and vinyl-functionalized nalidixic acid derivatives, developed as candidate infection-resistant urinary catheter coatings. Demonstrating up to 20-fold faster rates of drug release at pH 10, representing infected urine pH, than at pH 7 and achieving reductions of up to 96.5% in in vitro bacterial adherence, our paradigm of pH-responsive drug delivery, which requires no external manipulation, therefore represents a promising development toward the prevention of catheter-associated urinary tract infections in vivo.

Medication use review in Qatar: are community pharmacists prepared for the extended professional role?

BACKGROUND: The incidence of chronic illnesses is increasing globally. Non-adherence to medications and other medication-related problems are common among patients receiving long-term medications. Medication use review (MUR) is a service provision with an accredited pharmacist undertaking structured, adherence-centered reviews with patients receiving multiple medications. MUR services are not yet available in community pharmacies in Qatar. OBJECTIVE: The current study aims to evaluate community pharmacists' knowledge, attitudes, and perception towards establishing MUR as an extended role in patient care. SETTING: Private community pharmacies in Qatar including chains and independent pharmacies. Methodology A cross-sectional survey using a self-administered questionnaire was conducted among licensed community pharmacists from December 2012 to January 2013. Data analysis was conducted using descriptive and inferential statistics. MAIN OUTCOME MEASURES: Knowledge, attitudes, and practices related to MUR concept and services. RESULTS: A total of 123 participants responded to the survey (response rate 56%). The mean total knowledge score was 71.4 ± 14.7%. An overwhelming proportion of the participants (97%) were able to identify the scope of MUR in relation to chronic illnesses and at enhancing the quality of pharmaceutical care. Furthermore, 80% of the respondents were able to identify patients of priority for inclusion in an MUR program. However, only 43% of the participants knew that acute medical conditions were not the principal focus of an MUR service, while at least 97% acknowledged that the provision of MUR services is a great opportunity for an extended role of community pharmacists and that MUR makes excellent use of the pharmacist's professional skills in the community. The participants generally reported concerns about time, dedicated consultation area, and support staff as significant barriers towards MUR implementation. CONCLUSION: This study suggests that community pharmacists in Qatar had sufficient knowledge about the concept of MUR and its scope, but there were still important deficiencies that warrant further education. The findings have important implications on policy and practice pertaining to the implementation of MUR as an extended role of pharmacists and as part of Qatar's National Health Strategy to move primary health care forward.

Photodynamic antimicrobial polymers for infection control.

Hospital-acquired infections pose both a major risk to patient wellbeing and an economic burden on global healthcare systems, with the problem compounded by the emergence of multidrug resistant and biocide tolerant bacterial pathogens. Many inanimate surfaces can act as a reservoir for infection, and adequate disinfection is difficult to achieve and requires direct intervention. In this study we demonstrate the preparation and performance of materials with inherent photodynamic, surface-active, persistent antimicrobial properties through the incorporation of photosensitizers into high density poly(ethylene) (HDPE) using hot-melt extrusion, which require no external intervention except a source of visible light. Our aim is to prevent bacterial adherence to these surfaces and eliminate them as reservoirs of nosocomial pathogens, thus presenting a valuable advance in infection control. A two-layer system with one layer comprising photosensitizer-incorporated HDPE, and one layer comprising HDPE alone is also described to demonstrate the versatility of our approach. The photosensitizer-incorporated materials are capable of reducing the adherence of viable bacteria by up to 3.62 Log colony forming units (CFU) per square centimeter of material surface for methicillin resistant Staphylococcus aureus (MRSA), and by up to 1.51 Log CFU/cm(2) for Escherichia coli. Potential applications for the technology are in antimicrobial coatings for, or materials comprising objects, such as tubing, collection bags, handrails, finger-plates on hospital doors, or medical equipment found in the healthcare setting.

Surface localisation of photosensitisers on intraocular lens biomaterials for prevention of infectious endophthalmitis and retinal protection.

Cataract surgery is one of the most commonly-practiced surgical procedures in Western medicine, and, while complications are rare, the most serious is infectious postoperative endophthalmitis. Bacteria may adhere to the implanted intraocular lens (IOL) and subsequent biofilm formation can lead to a chronic, difficult to treat infection. To date, no method to reduce the incidence of infectious endophthalmitis through bacterial elimination, while retaining optical transparency, has been reported. In this study we report a method to optimise the localisation of a cationic porphyrin at the surface of suitable acrylate copolymers, which is the first point of contact with potential pathogens. The porphyrin catalytically generates short-lived singlet oxygen, in the presence of visible light, which kills adherent bacteria indiscriminately. By restricting the photosensitiser to the surface of the biomaterial, reduction in optical transparency is minimised without affecting efficacy of singlet oxygen production. Hydrogel IOL biomaterials incorporating either methacrylic acid (MAA) or methyl methacrylate (MMA) co-monomers allow tuning of the hydrophobic and anionic properties to optimise the localisation of porphyrin. Physiochemical and antimicrobial properties of the materials have been characterised, giving candidate materials with self-generating, persistent anti-infective character against Gram-positive and Gram-negative organisms. Importantly, incorporation of porphyrin can also serve to protect the retina by filtering damaging shortwave visible light, due to the Soret absorption (λmax 430 nm).

Comparison of the binding specificity of two bacterial metalloproteases, LasB of Pseudomonas aeruginosa and ZapA of Proteus mirabilis, using N-alpha mercaptoamide template-based inhibitor analogues.

The metalloproteases ZapA of Proteus mirabilis and LasB of Pseudomonas aeruginosa are known to be virulence factors their respective opportunistic bacterial pathogens, and are members of the structurally related serralysin and thermolysin families of bacterial metalloproteases respectively. Secreted at the site of infection, these proteases play a key role in the infection process, contributing to tissue destruction and processing of components of the host immune system. Inhibition of these virulence factors may therefore represent an antimicrobial strategy, attenuating the virulence of the infecting pathogen. Previously we have screened a library of N-alpha mercaptoamide dipeptide inhibitors against both ZapA and LasB, with the aim of mapping the S1' binding site of the enzymes, revealing both striking similarities and important differences in their binding preferences. Here we report the design, synthesis, and screening of several inhibitor analogues, based on two parent inhibitors from the original library. The results have allowed for further characterization of the ZapA and LasB active site binding pockets, and have highlighted the possibility for development of broad-spectrum bacterial protease inhibitors, effective against enzymes of the thermolysin and serralysin metalloprotease families.

Comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin).

In this study we report for the first time the comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin) using a 160 compound focused library of N-alpha mercaptoamide dipeptides, in order to map the S(1)(') and S(2)(') binding site preferences of this important enzyme. This study has revealed a preference for the aromatic residues tyrosine and tryptophan in P(1)(') and aliphatic residues in P(2)('). From this library, six compounds were identified which exhibited sub- to low-micromolar K(i) values. The most potent inactivator, SH-CO(2)-Y-V-NH(2) was capable of preventing ZapA-mediated hydrolysis of heat-denatured IgA, indicating that these inhibitors may be capable of protecting host proteins against ZapA during colonisation and infection.

The use of lytic bacteriophages in the prevention and eradication of biofilms of Proteus mirabilis and Escherichia coli.

Antibiotics have been the cornerstone of the clinical management of bacterial infections since their discovery in the early part of the last century. Eight decades later, their widespread, often indiscriminate use, has resulted in an overall reduction in their effectiveness, with reports of multidrug-resistant bacteria now commonplace. Increasing reliance on indwelling medical devices, which are inherently susceptible to biofilm-mediated infections, has contributed to unacceptably high rates of nosocomial infections, placing a strain on healthcare budgets. This study investigates the use of lytic bacteriophages in the treatment and prevention of biofilms of bacterial species commonly associated with infections of indwelling urological devices and catheter-associated urinary tract infections. The use of lytic bacteriophages against established biofilms of Proteus mirabilis and Escherichia coli is described, whereby biofilm populations have been reduced successfully by three to four log cycles (99.9-99.99% removal). The prevention of biofilm formation on Foley catheter biomaterials following impregnation of hydrogel-coated catheter sections with a lytic bacteriophage has also been investigated. This has revealed an approximate 90% reduction in both P. mirabilis and E. coli biofilm formation on bacteriophage-treated catheters when compared with untreated controls.

Synthesis, kinetic evaluation, and utilization of a biotinylated dipeptide proline diphenyl phosphonate for the disclosure of dipeptidyl peptidase IV-like serine proteases.

In this study, we report on the synthesis, kinetic characterisation, and application of a novel biotinylated and active site-directed inactivator of dipeptidyl peptidase IV (DPP-IV). Thus, the dipeptide-derived proline diphenyl phosphonate NH(2)-Glu(biotinyl-PEG)-Pro(P)(OPh)(2) has been prepared by a combination of classical solution- and solid-phase methodologies and has been shown to be an irreversible inhibitor of porcine DPP-IV, exhibiting an over all second-order rate constant (k(i)/K(i)) for inhibition of 1.57 x 10(3) M(-1) min(-1). This value compares favourably with previously reported rates of inactivation of DPP-IV by dipeptides containing a P(1) proline diphenyl phosphonate grouping [B. Boduszek, J. Oleksyszyn, C.M. Kam, J. Selzler, R.E. Smith, J.C. Powers, Dipeptide phophonates as inhibitors of dipeptidyl peptidase IV, J. Med. Chem. 37 (1994) 3969-3976; B.F. Gilmore, J.F. Lynas, C.J. Scott, C. McGoohan, L. Martin, B. Walker, Dipeptide proline diphenyl phosphonates are potent, irreversible inhibitors of seprase (FAPalpha), Biochem, Biophys. Res. Commun. 346 (2006) 436-446.], thus demonstrating that the incorporation of the side-chain modified (N-biotinyl-3-(2-(2-(3-aminopropyloxy)-ethoxy)-ethoxy)-propyl) glutamic acid residue at the P(2) position is compatible with inhibitor efficacy. The utilisation of this probe for the detection of both purified dipeptidyl peptidase IV and the disclosure of a dipeptidyl peptidase IV-like activity from a clinical isolate of Porphyromonas gingivalis, using established electrophoretic and Western blotting techniques previously developed by our group, is also demonstrated.