Tetrasodium EDTA for the prevention of urinary catheter infections and blockages.

Long-term catheterised individuals are at significant risk of developing catheter-associated urinary tract infections (CAUTIs), with up to 50% of patients experiencing recurrent episodes of catheter encrustation and blockage. Catheter blockage is a result of accumulation of carbonate apatite and struvite formed upon precipitation of ions within urine due to an infection-induced rise in pH. The aim of this study was to investigate the antimicrobial and anti-encrustation activities of tetrasodium ethylenediaminetetraacetic acid (tEDTA) to evaluate its potential efficacy in preventing CAUTIs and catheter blockages. The antimicrobial activity of tEDTA against uropathogens was assessed using time kill assays performed in artificial urine (AU). Crystallisation studies and in vitro bladder model assays were conducted to investigate the effect of tEDTA on struvite crystallisation and catheter blockage. tEDTA displayed bacteriostatic activity against Proteus mirabilis and prevented precipitation of ions in the AU. Crystallisation studies confirmed tEDTA inhibits struvite nucleation and growth via Mg2+ chelation with 7.63 mM tEDTA, equimolar to the concentration of divalent cations in AU, preventing the formation of crystalline deposits and blockage of Foley catheters for ≥168 h. The promising chelating abilities of low tEDTA concentrations could be exploited to inhibit encrustation and blockage of indwelling catheters. The fundamental research presented will inform our future development of an effective tEDTA-eluting catheter coating aimed at preventing catheter encrustation.

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.

Hot-melt extrusion of photodynamic antimicrobial polymers for prevention of microbial contamination.

Infectious disease outbreaks within healthcare facilities can exacerbate patient illness and, in some cases, can be fatal. Contaminated surfaces and medical devices can act as a reservoir for transmission of pathogens and have been linked to the rising incidence of healthcare-acquired infections. Antimicrobial surfaces can reduce microbial contamination and transmission and have emerged as a crucial component in healthcare infection control in recent years. The aim of this study was to manufacture antimicrobial polymer surfaces containing the photosensitiser, toluidine blue O (TBO), using hot-melt extrusion (HME). Several concentrations of TBO were combined with a range of medically relevant polymers via HME. TBO-polymer extrudates displayed no significant differences in thermal properties and surface wettability relative to non-loaded polymers. Minimal leaching of TBO from the surface was confirmed through in vitro release studies. Antibacterial activity was observed to vary according to the polymer and concentration of incorporated TBO, with PEBAX® polymers modified with 0.1% w/w TBO demonstrating promising reductions of >99.9% in viable bacterial adherence of a range of common nosocomial pathogens, including Staphylococcus aureus, Staphylococcus epidermidis, Acinetobacter baumannii and Escherichia coli. This study demonstrates the use of HME as a facile alternative method to common encapsulation strategies for the production of light-activated antimicrobial polymer surfaces. This method can be easily translated to large-scale manufacture and, in addition, the polymers constitute promising antimicrobial base materials for the rapidly growing additive manufacturing industries.

Multifunctional, Low Friction, Antimicrobial Approach for Biomaterial Surface Enhancement.

Poly(vinyl chloride) (PVC) biomaterials perform a host of life-saving and life-enhancing roles when employed as medical devices within the body. High frictional forces between the device surface and interfacing tissue can, however, lead to a host of complications including tissue damage, inflammation, pain, and infection. We herein describe a versatile surface modification method using multifunctional hydrogel formulations to increase lubricity and prevent common device-related complications. In a clinically relevant model of the urinary tract, simulating the mechanical and biological environments encountered in vivo, coated candidate catheter surfaces demonstrated significantly lower frictional resistance than uncoated PVC, with reductions in coefficient of friction values of more than 300-fold due to hydration of the surface-localized polymer network. Furthermore, this significant lubrication capacity was retained following hydration periods of up to 28 days in artificial urine at pH 6 and pH 9, representing the pH of physiologically normal and infected urine, respectively, and during 200 repeated cycles of applied frictional force. Importantly, the modified surfaces also displayed excellent antibacterial activity, which could be facilely tuned to achieve reductions of 99.8% in adherence of common hospital-acquired pathogens, Staphylococcus aureus and Proteus mirabilis, relative to their uncoated counterparts through incorporation of chlorhexidine in the coating matrix as a model antiseptic. The remarkable, and pH-independent, tribological performance of these lubricious, antibacterial, and highly durable surfaces offers exciting promise for use of this PVC functionalization approach in facilitating smooth and atraumatic insertion and removal of a wide range of medical implants, ultimately maintaining user health and dignity.

Time-Resolved Dynamics of Struvite Crystallization: Insights from the Macroscopic to Molecular Scale.

The crystallization of magnesium ammonium phosphate hexahydrate (struvite) often occurs under conditions of fluid flow, yet the dynamics of struvite growth under these relevant environments has not been previously reported. In this study, we use a microfluidic device to evaluate the anisotropic growth of struvite crystals at variable flow rates and solution supersaturation. We show that bulk crystallization under quiescent conditions yields irreproducible data owing to the propensity of struvite to adopt defects in its crystal lattice, as well as fluctuations in pH that markedly impact crystal growth rates. Studies in microfluidic channels allow for time-resolved analysis of seeded growth along all three principle crystallographic directions and under highly controlled environments. After having first identified flow rates that differentiate diffusion and reaction limited growth regimes, we operated solely in the latter regime to extract the kinetic rates of struvite growth along the [100], [010], and [001] directions. In situ atomic force microscopy was used to obtain molecular level details of surface growth mechanisms. Our findings reveal a classical pathway of crystallization by monomer addition with the expected transition from growth by screw dislocations at low supersaturation to that of two-dimensional layer generation and spreading at high supersaturation. Collectively, these studies present a platform for assessing struvite crystallization under flow conditions and demonstrate how this approach is superior to measurements under quiescent conditions.

Lignin/poly(butylene succinate) composites with antioxidant and antibacterial properties for potential biomedical applications.

Lignin (LIG) is a renewable biopolymer with well-known antimicrobial and antioxidant properties. In the present work LIG was combined with poly(butylene succinate) (PBS), a biocompatible/biodegradable polymer, to obtain composites with antimicrobial and antioxidant properties. Hot melt extrusion was used to prepare composites containing up to 15% (w/w) of LIG. Water contact angle measurements suggested that the incorporation of LIG did not alter the wettability of the material. The material density increased slightly when LIG was incorporated (<1%). Moreover, the melt flow index test showed an increase in the fluidity of the material (from 6.9 to 27.7 g/10 min) by increasing the LIG content. The Young's modulus and the tensile deformation of the material were practically unaffected when LIG was added. Infrared spectroscopy and differential scanning calorimeter confirmed that there were interactions between LIG and PBS. The DPPH assay was used to evaluate the antioxidant properties of the materials. The results suggested that all the materials were capable of reducing the DPPH concentrations up to 80% in <5 h. Finally, LIG-containing composites showed resistance to adherence of the common nosocomial pathogen, Staphylococcus aureus. All tested materials showed ca. 90% less bacterial adherence than PBS.

Antioxidant PLA Composites Containing Lignin for 3D Printing Applications: A Potential Material for Healthcare Applications.

Lignin (LIG) is a natural biopolymer with well-known antioxidant capabilities. Accordingly, in the present work, a method to combine LIG with poly(lactic acid) (PLA) for fused filament fabrication applications (FFF) is proposed. For this purpose, PLA pellets were successfully coated with LIG powder and a biocompatible oil (castor oil). The resulting pellets were placed into an extruder at 200 °C. The resulting PLA filaments contained LIG loadings ranging from 0% to 3% (w/w). The obtained filaments were successfully used for FFF applications. The LIG content affected the mechanical and surface properties of the overall material. The inclusion of LIG yielded materials with lower resistance to fracture and higher wettabilities. Moreover, the resulting 3D printed materials showed antioxidant capabilities. By using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, the materials were capable of reducing the concentration of this compound up to ca. 80% in 5 h. This radical scavenging activity could be potentially beneficial for healthcare applications, especially for wound care. Accordingly, PLA/LIG were used to design meshes with different designs for wound dressing purposes. A wound healing model compound, curcumin (CUR), was applied in the surface of the mesh and its diffusion was studied. It was observed that the dimensions of the meshes affected the permeation rate of CUR. Accordingly, the design of the mesh could be modified according to the patient's needs.

Use of in vitro and haptic assessments in the characterisation of surface lubricity.

Lubricity is a key property of hydrophilic-coated urinary catheter surfaces. In vitro tests are commonly employed for evaluation of surface properties in the development of novel catheter coating technologies; however, their value in predicting the more subjective feeling of lubricity requires validation. We herein perform a range of in vitro assessments and human organoleptic studies to characterise surface properties of developmental hydrophilic coating formulations, including water wettability, coefficient of friction, dry-out kinetics and lubricity. Significant reductions of up to 40% in the contact angles and coefficient of friction values of the novel coating formulations in comparison with the control poly(vinylpyrrolidone)-coated surfaces were demonstrated during quantitative laboratory assessments. In contrast, no significant differences in the more subjective feeling of lubricity between the novel formulations and the control-coated surfaces were observed when formulations were haptically assessed by the techniques described herein. This study, importantly, highlights the need for optimisation of in vitro and human haptic assessments to more reliably predict patient preferences.

Synthesis and Characterization of Lignin Hydrogels for Potential Applications as Drug Eluting Antimicrobial Coatings for Medical Materials.

Lignin is the second most abundant biopolymer on the planet. It is a biocompatible, cheap, environmentally friendly and readily accessible material. It has been reported that these biomacromolecules have antimicrobial activities. Consequently, lignin (LIG) has the potential to be used for biomedical applications. In the present work, a simple method to prepare lignin-based hydrogels is described. The hydrogels were prepared by combining LIG with poly(ethylene glycol) and poly(methyl vinyl ether-co-maleic acid) through an esterification reaction. The synthesis took place in the solid state and can be accelerated significantly (24 vs 1 h) by the use of microwave (MW) radiation. The prepared hydrogels were characterized by evaluation of their swelling capacities and with the use of infrared spectroscopy/solid-state nuclear magnetic resonance. The prepared hydrogels showed LIG contents ranging between 40% and 24% and water uptake capabilities up to 500%. Furthermore, the hydrophobic nature of LIG facilitated loading of a model hydrophobic drug (curcumin). The hydrogels were capable of sustaining the delivery of this compound for up to 4 days. Finally, the materials demonstrated logarithmic reductions in adherence of Staphylococcus aureus and Proteus mirabilis of up to 5.0 relative to the commonly employed medical material poly(vinyl chloride) (PVC).

Synthesis and characterization of hyaluronic acid hydrogels crosslinked using a solvent-free process for potential biomedical applications.

Hyaluronic acid (HA) is a natural linear polysaccharide that has been used extensively in the biomedical field as it is a biocompatible, biodegradable, nontoxic and non-immunogenic polymer with high water affinity. Besides, the presence of multiple acid and hydroxyl groups in the HA molecule makes it an ideal candidate for chemical modification. The present paper describes the synthesis and characterization of HA-based hydrogels. For this purpose, aqueous mixtures containing 5% (w/w) of HA and different concentrations of Gantrez S97 (GAN) (1, 3 and 5% w/w) were used to prepare HA-based hydrogels. The mixtures were dried and the hydrogels were obtained after heating the solid material at 80°C for 24h. GAN is the acid form of an methylvinylether and maleic anhydride copolymer and contains multiple acid groups that can form ester bonds when reacting with the multiple hydroxyl groups present in HA chains. The method described here present potential to be applied for the preparation of HA-based biomaterials with a defined form as the crosslinking reaction between HA and the crosslinker takes place in solid phase. Besides, the method can be considered an environmental-friendly process as no organic solvents or potentially toxic substances were used. The esterification reaction was confirmed by infrared spectroscopy and dynamic scanning calorimetry measurements. The loading and release capabilities of the hydrogels were evaluating by using methylene blue (MB) as a model molecule. The hydrogels showed a high affinity for MB showing loadings up to 0.35mg MB per mg of hydrogel. Moreover, the hydrogels were capable of sustaining the MB release over two days. The use of microwave radiation was evaluated to reduce the crosslinking time from 24h to 1h, but this procedure needs to be optimized in future studies. As the crosslinking procedure takes place in solid state, the HA/GAN hydrogels were used to prepare micro-engineered device, microneedle arrays. Finally, the antimicrobial properties of the hydrogels were evaluated. The results showed that the hydrogels presented anti-infective properties.

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.

Photochemically Controlled Drug Dosing from a Polymeric Scaffold.

PURPOSE: To develop the first photoactive biomaterial coating capable of controlled drug dosing via inclusion of synthesised drug-3,5-dimethoxybenzoin (DMB) conjugates in a poly(2-methyoxyethyl acrylate) (pMEA) scaffold. METHODS: Flurbiprofen- and naproxen-DMB conjugates were prepared via esterification and characterised via NMR spectroscopy and mass spectrometry following chromatographic purification. Conjugate photolysis was investigated in acetonitrile solution and within the pMEA matrix following exposure to low-power 365 nm irradiation. Photo-liberation of drug from pMEA into phosphate buffered saline was monitored using UV-vis spectroscopy. RESULTS: The synthetic procedures yielded the desired drug conjugates with full supporting characterisation. Drug regeneration through photolysis of the synthesised conjugates was successful in both acetonitrile solution and within the pMEA scaffold upon UV irradiation. Conjugates were retained within the pMEA scaffold with exclusive drug liberation following irradiation and increased drug dose with increasing exposure. Multi-dosing capacity was demonstrated though the ability of successive irradiation periods to generate further bursts of drug. CONCLUSION: This study demonstrates the first application of photochemically controlled drug release from a biomaterial coating and the feasibility of using pMEA as a scaffold for housing the photoactive drug-DMB conjugates.

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.

Hydrogel-Forming Microneedle Arrays Made from Light-Responsive Materials for On-Demand Transdermal Drug Delivery.

We describe, for the first time, stimulus-responsive hydrogel-forming microneedle (MN) arrays that enable delivery of a clinically relevant model drug (ibuprofen) upon application of light. MN arrays were prepared using a polymer prepared from 2-hydroxyethyl methacrylate (HEMA) and ethylene glycol dimethacrylate (EGDMA) by micromolding. The obtained MN arrays showed good mechanical properties. The system was loaded with up to 5% (w/w) ibuprofen included in a light-responsive 3,5-dimethoxybenzoin conjugate. Raman spectroscopy confirmed the presence of the conjugate inside the polymeric MN matrix. In vitro, this system was able to deliver up to three doses of 50 mg of ibuprofen upon application of an optical trigger over a prolonged period of time (up to 160 h). This makes the system appealing as a controlled release device for prolonged periods of time. We believe that this technology has potential for use in "on-demand" delivery of a wide range of drugs in a variety of applications relevant to enhanced patient care.

Infection-responsive drug delivery from urinary biomaterials controlled by a novel kinetic and thermodynamic approach.

PURPOSE: The pH-dependent physicochemical properties of the antimicrobial quinolone, nalidixic acid, were exploited to achieve 'intelligent' drug release from a potential urinary catheter coating, poly(2-hydroxyethylmethacrylate) (p(HEMA)), in direct response to the elevated pH which occurs at the onset of catheter infection. METHODS: p(HEMA) hydrogels, and reduced-hydrophilicity copolymers incorporating methyl methacrylate, were loaded with nalidixic acid by a novel, surface particulate localization method, and characterized in terms of pH-dependent drug release and microbiological activity against the common urease-producing urinary pathogen Proteus mirabilis. RESULTS: The pH-dependent release kinetics of surface-localized nalidixic acid were 50- and 10-fold faster at pH 9, representing the alkaline conditions induced by urease-producing urinary pathogens, compared to release at pH 5 and pH 7 respectively. Furthermore, microbiological activity against P. mirabilis was significantly enhanced after loading surface particulate nalidixic acid in comparison to p(HEMA) hydrogels conventionally loaded with dispersed drug. The more hydrophobic methyl methacrylate-containing copolymers also demonstrated this pH-responsive behavior, but additionally exhibited a sustained period of zero-order release. CONCLUSIONS: The paradigm presented here provides a system with latent, immediate infection-responsive drug release followed by prolonged zero-order antimicrobial delivery, and represents an 'intelligent', infection-responsive, self-sterilizing biomaterial.