In vivo catheterization study of chlorhexidine‐loaded nanoparticle coated Foley urinary catheters in male New Zealand white rabbits
Abstract: Foley urinary catheters were coated with chlorhexidine‐loaded nanoparticles (CHX‐NPs), encapsulated in the form of micelles and nanospheres. Both of nanoparticles were deposited by multilayer nanocoating through dip and spray coating on the catheter surface both inner and outer surface. In our previous studies, the nanocoating of Foley urinary catheters was studied for chlorhexidine release, degradation, antibacterial evaluation, cytotoxicity assessment, hemocompatibility, skin irritation, skin sensitization, … Show more
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Cited by 10 publications
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lnfectious diseases are the leading cause of death worldwide while the constantly raising antimicrobial resistance (AMR) is a major concern for the public health. During the infection establishment bacteria! pathogens communicate via expression of signaling molecules, controlled through a phenomenon called quorum sensing (QS). As a result of this, bacteria produce virulence factors and form resistant biofilms on living and non-living surfaces causing persistent infections. The infection complexity, especially in chronic diseases, requires the use of broad-spectrum antibiotics responsive for the appearance and the spread of drug resistant species. lnfections caused by antibiotic-resistant pathogens are associated with high morbidity, mortality, and huge economic burden. Unlike the decrease over the past three decades of the number of novel marketed antimicrobial drugs, the number of antibiotic resistant bacteria! strains steadily increases. Thus, there is an urgent need for development of alternative strategies to manage difficult-to-treat infections. This thesis aims at the engineering of advanced nano-enabled materials and nanostructured coatings for controlling bacteria! pathogenesis and resistance occurrence. To achieve this, biopolymers, antibiofilm and anti-infective enzymes. and inorganic compounds were nano-hybridized as altemative modalities to the conventional antibiotics. The nanoform was able to provide enhanced interaction with bacteria! cell membranes and easier penetration into biofilms, increasing the antimicrobial efficacy at lower dosages, while preventing from development of antimicrobial resistance. Additionally, specific targeting moieties increased the nanomaterial's interaction with the pathogens, avoiding the drug resistance appearance and cytotoxicity. The first part ofthe thesis describes the functionalization of biologically inert nanoparticles (NPs) with membrane disturbing antimicrobial aminocellulose (AM) and biocompatible hyaluronic acid (HA) in an Lbl fashion for elimination of medically relevant pathogens. The generated nanoentities demonstrated high potential to inhibit the biofilm formation, without affecting the human cell viability. Further, the Lbl technique was applied to decorate antimicrobial, but potentially toxic silver (Ag) nano-templates with biocompatible AM and quorum quenching (QQ) acylase in order to obtain safe antibacterial and antibiofilm nanomaterials. The deposition of acylase and AM on the Ag core interfered with the QS signaling and bacteria! pathogenesis, and enhanced the NPs interaction with the bacteria! membrane. The integration of a triple mechanisms of action in the hybrid nanoentities resulted in complete bacteria and biofilm eradication and improved biocompatibility ofthe AgNPs. The thesís also describes the development of targeted nanocapsules (NCs) for selective elimination of Staphylococcus aureus. Herein, self-assembling nanoencapsulation technology using the biocompatible and biodegradable proteín zein was applied for the generation of zein NCs loaded with bactericida! oregano essential oil (EO). An antibody specifically targeting S. aureus was covalently grafted on the NCs surface. The obtained targeted NCs demonstrated antibacterial selectivity in a mixed bacteria! inoculum, and the treatment efficacy was validated in an in vitro coculture model of bacteria and mammalian cells. Finally, high intensity ultrasonochemistry (US) process was employed for engineering of durable antibacterial/antibiofilm coating on urinary catheters. The simultaneous deposition of zinc oxide (ZnO) NPs anda matrix-degrading amylase enzyme improved the NPs adhesion on the silicone material, and prevented its bacteria! colonization and biofilm formation in vitro. The hybrid nanostructured coating delayed the occurrence of early onset urinary tract infections (UTls) and showed excellent biosafety in an in vivo animal model. Las enfermedades infecciosas son la principal causa de muerte en todo el mundo. Mientras que la resistencia a los antimicrobianos es una preocupación importante para la salud pública. Durante el establecimiento de la infección los patógenos bacterianos se comunican mediante la expresión de moléculas de señalización controladas mediante un fenómeno llamado detección de quórum (QS). Como resultado, las bacterias producen factores de virulencia y forman biopelículas resistentes que causan infecciones persistentes. Las infecciones causadas por patógenos resistentes a los antibióticos se asocian con una alta morbilidad mortalidad y una enorme carga económica. A diferencia de la disminución en las últimas tres décadas del número de nuevos medicamentos antimicrobianos comercializados el número de cepas bacterianas resistentes a los antibióticos aumenta constantemente. Por lo tanto existe la necesidad urgente de desarrollar estrategias alternativas para manejar infecciones diflciles de tratar. Esta tesis tiene como objeto de trabajo la ingenieria de materiales y recubrimientos avanzados nano estructurados para controlar la patogénesis bacteriana y la aparición de resistencias. Para lograrlo se combina polímeros anti biopelícula, enzimas anti infecciosas y compuestos inorgánicos como estrategias alternativas a los antibióticos convencionales. La nanoforma puede proporcionar una interacción mejorada con las membranas celulares bacterianas y una penetración más fácil en las biopelículas, aumentando la eficacia antimicrobiana en dosis más bajas al mismo tiempo que previene el desarrollo de resistencia antimicrobiana. Además las fracciones de orientación especificas aumentan la interacción del nano material con los patógenos evitando la aparición de resistencia al fármaco y la citotoxicidad.La primera parte de la tesis describe la funcionalización de nano partículas (NP) biológicamente inertes con aminocelulosa antimicrobiana (AM) perturbadora de la membrana y ácido hialurónico (HA) biocompatible en forma de LbL para la eliminación de patógenos médicamente relevantes. Las nanoentidades generadas demuestran un alto potencial para inhibir la formación de biopelículas sin afectar la viabilidad en las células humanas. Además, la técnica L.bL se aplica para decorar nanoplantillas de plata (Ag) antimicrobianas,pero potencialmente tóxicas con PNt biocompatible y acilasa de extinción de quórum (QQ) para obtener nanomateriales antibacterianos y anti biopelícula seguros. La deposición de acilasa y PNt en el núcleo de Ag interfiere con la señalización de QS y la patogénesis bacteriana y mejora la interacción de las NP con la membrana bacteriana. La integración de un triple mecanismo de acción en las nanoentidades híbridas da como resultado la erradicación completa de bacterias y biopelículas y una mejor biocompatibilidad de los AgNP. La tesis también describe el desarrollo de nanocápsulas dirigidas (NC) para la eliminación selectiva de Staphylococcus aureus. En este trabajo se aplica la tecnología de nanoencapsulación de autoensamblaje que utiliza la proteína Zeína biocompatible y biodegradable para la generación de NC de Zelna cargadas con aceite esencial de orégano bactericida.Un anticuerpo dirigido específicamente a S.aureus se injerta covalentemente en la superficie de las NC. Las NC dirigidos obtenidos demuestran selectividad antibacteriana en un inóculo bacteriano mixto.y la eficacia del tratamiento se valida en un modelo de cocultivo in vitro de bacterias y células de mamíferos.Finalmente, se emplea un proceso de ultrasonoqufmica de alta intensidad. Para la ingeniería de un recubrimiento antibacterlano/anti biopelícula duradero en catéteres urinarios. La deposición de NP de Óxido de Zinc y enzima amilasa que degrada la matriz.mejora la adhesión de las NP en el material de silicona evitando su colonización bacteriana y la formación de biopeliculas in vitro
lnfectious diseases are the leading cause of death worldwide while the constantly raising antimicrobial resistance (AMR) is a major concern for the public health. During the infection establishment bacteria! pathogens communicate via expression of signaling molecules, controlled through a phenomenon called quorum sensing (QS). As a result of this, bacteria produce virulence factors and form resistant biofilms on living and non-living surfaces causing persistent infections. The infection complexity, especially in chronic diseases, requires the use of broad-spectrum antibiotics responsive for the appearance and the spread of drug resistant species. lnfections caused by antibiotic-resistant pathogens are associated with high morbidity, mortality, and huge economic burden. Unlike the decrease over the past three decades of the number of novel marketed antimicrobial drugs, the number of antibiotic resistant bacteria! strains steadily increases. Thus, there is an urgent need for development of alternative strategies to manage difficult-to-treat infections. This thesis aims at the engineering of advanced nano-enabled materials and nanostructured coatings for controlling bacteria! pathogenesis and resistance occurrence. To achieve this, biopolymers, antibiofilm and anti-infective enzymes. and inorganic compounds were nano-hybridized as altemative modalities to the conventional antibiotics. The nanoform was able to provide enhanced interaction with bacteria! cell membranes and easier penetration into biofilms, increasing the antimicrobial efficacy at lower dosages, while preventing from development of antimicrobial resistance. Additionally, specific targeting moieties increased the nanomaterial's interaction with the pathogens, avoiding the drug resistance appearance and cytotoxicity. The first part ofthe thesis describes the functionalization of biologically inert nanoparticles (NPs) with membrane disturbing antimicrobial aminocellulose (AM) and biocompatible hyaluronic acid (HA) in an Lbl fashion for elimination of medically relevant pathogens. The generated nanoentities demonstrated high potential to inhibit the biofilm formation, without affecting the human cell viability. Further, the Lbl technique was applied to decorate antimicrobial, but potentially toxic silver (Ag) nano-templates with biocompatible AM and quorum quenching (QQ) acylase in order to obtain safe antibacterial and antibiofilm nanomaterials. The deposition of acylase and AM on the Ag core interfered with the QS signaling and bacteria! pathogenesis, and enhanced the NPs interaction with the bacteria! membrane. The integration of a triple mechanisms of action in the hybrid nanoentities resulted in complete bacteria and biofilm eradication and improved biocompatibility ofthe AgNPs. The thesís also describes the development of targeted nanocapsules (NCs) for selective elimination of Staphylococcus aureus. Herein, self-assembling nanoencapsulation technology using the biocompatible and biodegradable proteín zein was applied for the generation of zein NCs loaded with bactericida! oregano essential oil (EO). An antibody specifically targeting S. aureus was covalently grafted on the NCs surface. The obtained targeted NCs demonstrated antibacterial selectivity in a mixed bacteria! inoculum, and the treatment efficacy was validated in an in vitro coculture model of bacteria and mammalian cells. Finally, high intensity ultrasonochemistry (US) process was employed for engineering of durable antibacterial/antibiofilm coating on urinary catheters. The simultaneous deposition of zinc oxide (ZnO) NPs anda matrix-degrading amylase enzyme improved the NPs adhesion on the silicone material, and prevented its bacteria! colonization and biofilm formation in vitro. The hybrid nanostructured coating delayed the occurrence of early onset urinary tract infections (UTls) and showed excellent biosafety in an in vivo animal model. Las enfermedades infecciosas son la principal causa de muerte en todo el mundo. Mientras que la resistencia a los antimicrobianos es una preocupación importante para la salud pública. Durante el establecimiento de la infección los patógenos bacterianos se comunican mediante la expresión de moléculas de señalización controladas mediante un fenómeno llamado detección de quórum (QS). Como resultado, las bacterias producen factores de virulencia y forman biopelículas resistentes que causan infecciones persistentes. Las infecciones causadas por patógenos resistentes a los antibióticos se asocian con una alta morbilidad mortalidad y una enorme carga económica. A diferencia de la disminución en las últimas tres décadas del número de nuevos medicamentos antimicrobianos comercializados el número de cepas bacterianas resistentes a los antibióticos aumenta constantemente. Por lo tanto existe la necesidad urgente de desarrollar estrategias alternativas para manejar infecciones diflciles de tratar. Esta tesis tiene como objeto de trabajo la ingenieria de materiales y recubrimientos avanzados nano estructurados para controlar la patogénesis bacteriana y la aparición de resistencias. Para lograrlo se combina polímeros anti biopelícula, enzimas anti infecciosas y compuestos inorgánicos como estrategias alternativas a los antibióticos convencionales. La nanoforma puede proporcionar una interacción mejorada con las membranas celulares bacterianas y una penetración más fácil en las biopelículas, aumentando la eficacia antimicrobiana en dosis más bajas al mismo tiempo que previene el desarrollo de resistencia antimicrobiana. Además las fracciones de orientación especificas aumentan la interacción del nano material con los patógenos evitando la aparición de resistencia al fármaco y la citotoxicidad.La primera parte de la tesis describe la funcionalización de nano partículas (NP) biológicamente inertes con aminocelulosa antimicrobiana (AM) perturbadora de la membrana y ácido hialurónico (HA) biocompatible en forma de LbL para la eliminación de patógenos médicamente relevantes. Las nanoentidades generadas demuestran un alto potencial para inhibir la formación de biopelículas sin afectar la viabilidad en las células humanas. Además, la técnica L.bL se aplica para decorar nanoplantillas de plata (Ag) antimicrobianas,pero potencialmente tóxicas con PNt biocompatible y acilasa de extinción de quórum (QQ) para obtener nanomateriales antibacterianos y anti biopelícula seguros. La deposición de acilasa y PNt en el núcleo de Ag interfiere con la señalización de QS y la patogénesis bacteriana y mejora la interacción de las NP con la membrana bacteriana. La integración de un triple mecanismo de acción en las nanoentidades híbridas da como resultado la erradicación completa de bacterias y biopelículas y una mejor biocompatibilidad de los AgNP. La tesis también describe el desarrollo de nanocápsulas dirigidas (NC) para la eliminación selectiva de Staphylococcus aureus. En este trabajo se aplica la tecnología de nanoencapsulación de autoensamblaje que utiliza la proteína Zeína biocompatible y biodegradable para la generación de NC de Zelna cargadas con aceite esencial de orégano bactericida.Un anticuerpo dirigido específicamente a S.aureus se injerta covalentemente en la superficie de las NC. Las NC dirigidos obtenidos demuestran selectividad antibacteriana en un inóculo bacteriano mixto.y la eficacia del tratamiento se valida en un modelo de cocultivo in vitro de bacterias y células de mamíferos.Finalmente, se emplea un proceso de ultrasonoqufmica de alta intensidad. Para la ingeniería de un recubrimiento antibacterlano/anti biopelícula duradero en catéteres urinarios. La deposición de NP de Óxido de Zinc y enzima amilasa que degrada la matriz.mejora la adhesión de las NP en el material de silicona evitando su colonización bacteriana y la formación de biopeliculas in vitro
Dual‐Layer Nanoengineered Urinary Catheters for Enhanced Antimicrobial Efficacy and Reduced Cytotoxicity
Catheter‐associated urinary tract infection (CAUTI) is the most common healthcare‐associated infection; however, current therapeutic strategies remain insufficient for standard clinical application. A novel urinary catheter featuring a dual‐layer nanoengineering approach using zinc (Zn) and silver nanoparticles (AgNPs) is successfully fabricated. This design targets microbial resistance, minimizes cytotoxicity, and maintains long‐term efficacy. The inner AgNPs layer provides immediate antibacterial effects against the UTI pathogens, while the outer porous Zn layer controls zero‐order Ag release and generates reactive oxygen species, thus enhancing long‐term bactericidal performance. Enhanced antibacterial properties of Zn/AgNPs‐coated catheters are observed, resulting in 99.9% of E. coli and 99.7% of S. aureus reduction, respectively. The Zn/AgNPs‐coated catheter significantly suppresses biofilm with sludge formation compared to AgNP‐coated and uncoated catheters (all, p < 0.05). The Zn/AgNP‐coated catheter in a rabbit model demonstrated a durable, effective barrier against bacterial colonization, maintaining antimicrobial properties during the catheter indwelling period with significantly reduced inflammation and epithelial disruption compared with AgNP and uncoated groups. This innovation has the potential to revolutionize the design of antimicrobial medical devices, particularly for applications requiring long‐term implantation. Although further preclinical studies are required to verify its efficacy and safety, this strategy seems to be a promising approach to preventing CAUTI‐related complications.
Tackling catheter‐associated urinary tract infections with next‐generation antimicrobial technologies
Urinary catheters and other medical devices associated with the urinary tract such as stents are major contributors to nosocomial urinary tract infections (UTIs) as they provide an access path for pathogens to enter the bladder. Considering that catheter‐associated urinary tract infections (CAUTIs) account for approximately 75% of UTIs and that UTIs represent the most common type of healthcare‐associated infections, novel anti‐infective device technologies are urgently required. The rapid rise of antimicrobial resistance in the context of CAUTIs further highlights the importance of such preventative strategies. In this review, the risk factors for pathogen colonization in the urinary tract are dissected, taking into account the nature and mechanistics of this unique environment. Moreover, the most promising next‐generation preventative strategies are critically assessed, focusing in particular on anti‐infective surface coatings. Finally, emerging approaches in this field and their likely clinical impact are examined.
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