Superparamagnetic Iron Oxide Nanoparticles (SPION) for the Treatment of Antibiotic‐Resistant Biofilms

Bacterial infections caused by antibiotic‐resistant strains are of deep concern due to an increasing prevalence, and are a major cause of morbidity in the United States of America. In particular, medical device failures, and thus human lives, are greatly impacted by infections, where the treatments required are further complicated by the tendency of pathogenic bacteria, such as Staphylococcus aureus, to produce antibiotic resistant biofilms. In this study, a panel of relevant antibiotics used clinically including penicillin, oxacillin, gentamicin, streptomycin, and vancomycin are tested, and although antibiotics are effective against free‐floating planktonic S. aureus, either no change in biofilm function is observed, or, more frequently, biofilm function is enhanced. As an alternative, superparamagnetic iron oxide nanoparticles (SPION) are synthesized through a two‐step process with dimercaptosuccinic acid as a chelator, followed by the conjugation of metals including iron, zinc, and silver; thus, the antibacterial properties of the metals are coupled to the superparamagnetic properties of SPION. SPION might be the ideal antibacterial treatment, with a superior ability to decrease multiple bacterial functions, target infections in a magnetic field, and had activity better than antibiotics or metal salts alone, as is required for the treatment of medical device infections for which no treatment exists today.     

In Vivo Dynamic Monitoring of Bacterial Infection by NIR‐II Fluorescence Imaging

Time window of antibiotic administration is a critical but long‐neglected point in the treatment of bacterial infection, as unnecessary prolonged antibiotics are increasingly causing catastrophic drug‐resistance. Here, a second near‐infrared (NIR‐II) fluorescence imaging strategy based on lead sulfide quantum dots (PbS QDs) is presented to dynamically monitor bacterial infection in vivo in a real‐time manner. The prepared PbS QDs not only provide a low detection limit (10⁴ CFU mL^?1) of four typical bacteria strains in vitro but also show a particularly high labeling efficiency with Escherichia coli (E. coli). The NIR‐II in vivo imaging results reveal that the number of invading bacteria first decreases after post‐injection, then increases from 1 d to 1 week and drop again over time in infected mouse models. Meanwhile, there is a simultaneous variation of dendritic cells, neutrophils, macrophages, and CD8+ T lymphocytes against bacterial infection at the same time points. Notably, the infected mouse self‐heals eventually without antibiotic treatment, as a robust immune system can successfully prevent further health deterioration. The NIR‐II imaging approach enables real‐time monitoring of bacterial infection in vivo, thus facilitating spatiotemporal deciphering of time window for antibiotic treatment.     

Resorbable Antibiotic Coatings for Bone Substitutes and Implantable Devices

Antibiotic delivery systems based on biodegradable coatings have found considerable interest for the prophylaxis and local therapy of biomaterial‐related infections. In this study sparingly water‐soluble gentamicin salts have been prepared and tested as biodegradable antibiotic‐releasing coating systems. Using the coating systems, homogeneous, well adhering films can be produced on various implant materials, like ceramics, glasses or metals surfaces, with different surface morphologies. The in vitro release profiles of the antibiotic coating systems were characterized by an initial burst release followed by a sustained release of small antibiotic amounts up to several weeks. It was found that the in vitro release, especially in the initial phase, can be modulated by the ratio between highly water‐soluble gentamicin salts and sparingly soluble ones in the coating. Coating systems of the same type as described for gentamicin are available from a wide range of antibiotics differing in structure and mechanism of antibacterial action. Based on these results, the developed antibiotic coatings offer new perspectives to prevent and treat biomaterial‐related infections.     

Staphylococcus aureus nasal carriage in a Moroccan dialysis center and isolates characterization

Staphylococcus aureus, which has its ecological niche in the anterior nares, has been shown to cause a variety of infectious diseases mainly for patients in hemodialysis units. We performed this study to evaluate the prevalence of nasal S. aureus carriage among hemodialysis outpatients, to determine the antimicrobial susceptibility of isolates, to characterize the virulence genes, and to identify associated risk factors. Nares swab specimens were obtained from 70 outpatients on hemodialysis between March and June 2010. Samples were plated immediately onto S. aureus specific media and pattern of antibacterial sensitivity was determined using disk diffusion method. Polymerase chain reaction was used to detect nuc, mecA, and genes encoding staphylococcal toxins. Medical record of patients was explored to determine S.aureus carriage risk factors. Nasal screening identified 42.9% S. aureus carriers with only one (3.3%) methicillin‐resistant S. aureus isolate. Among the methicillin‐susceptible S. aureus isolates, high rate of penicillin resistance (81.8%) has been detected. The identified risk factors were male gender and age ≤ 30 years. Research of virulence factors showed a high genetic diversity among the 30 S. aureus isolates. Twenty‐one (70%) of them had at least one virulence gene, of which 3.3% were Panton‐Valentine leukocidin (lukS/F‐PV) genes. S. aureus carriage must be screened for at regular intervals in hemodialysis patients. Setting up a bacterial surveillance system is one of the strategies to understand the epidemiology of methicillin‐resistant S. aureus, to guide local antibiotic policy and prevent spread of antibiotic‐resistant S. aureus.     

Mode I–III Decomposition of the J‐integral from DIC Displacement Data

This paper presents the implementation of the decomposition method on digital image correlation (DIC) obtained displacement fields to obtain J‐integral results (J) and respective stress intensity factors (SIFs). DIC is increasingly used with the J‐integral approach in experimental mechanics to obtain J estimates from complex fracture processes. In this approach, the decomposition method is applied to DIC displacement fields for the first time. Here, displacement fields are separated before stresses and strains are computed, so that subsequent computation of separate J or SIF components may follow the classical full‐field J‐integral approach. The sensitivity of the decomposition method to experimental errors is investigated using synthetically generated errors imposed on crack tip displacement fields (Williams' series), from which improvements to the procedure are proposed. The method is experimentally tested on PMMA Arcan specimens under mode I, II, and III, and mixed‐mode I–III loading. Test results were compared to fracture toughness values obtained from ASTM tests and literature with close agreement.     

Mechanically based models: Adaptive refinement for B‐spline finite element

This article presents two new methods for adaptive refinement of a B‐spline finite element solution within an integrated mechanically based computer aided engineering system. The proposed techniques for adaptively refining a B‐spline finite element solution are a local variant of np‐refinement and a local variant of h‐refinement. The key component in the np‐refinement is the linear co‐ordinate transformation introduced into the refined element. The transformation is constructed in such a way that the transformed nodal configuration of the refined element is identical to the nodal configuration of the neighbour elements. Therefore, the assembly proceeds as with classic finite elements, while the solution approximation conforms exactly along the inter‐element boundaries. For the h‐refinement, this transformation is introduced into a construction that merges the super element from the finite element world with the hierarchical B‐spline representation from the computational geometry. In the scope of developing sculptured surfaces, the proposed approach supports C⁰ as well as the Hermite B‐spline C¹ continuous shapes. For sculptured solids, C⁰ continuity only is considered in this article. The feasibility of the proposed methods in the scope of the geometric design is demonstrated by several examples of creating sculptured surfaces and volumetric solids. Numerical performance of the methods is demonstrated for a test case of the two‐dimensional Poisson equation. Copyright © 2003 John Wiley & Sons, Ltd.     

Coding of Experimental Conditions in Microfluidic Droplet Assays Using Colored Beads and Machine Learning Supported Image Analysis

To efficiently exploit the potential of several millions of droplets that can be considered as individual bioreactors in microfluidic experiments, methods to encode different experimental conditions in droplets are needed. The approach presented here is based on coencapsulation of colored polystyrene beads with biological samples. The decoding of the droplets, as well as content quantification, are performed by automated analysis of triggered images of individual droplets in‐flow using bright‐field microscopy. The decoding strategy combines bead classification using a random forest classifier and Bayesian inference to identify different codes and thus experimental conditions. Antibiotic susceptibility testing of nine different antibiotics and the determination of the minimal inhibitory concentration of a specific antibiotic against a laboratory strain of Escherichia coli are presented as a proof‐of‐principle. It is demonstrated that this method allows successful encoding and decoding of 20 different experimental conditions within a large droplet population of more than 10⁵ droplets per condition. The decoding strategy correctly assigns 99.6% of droplets to the correct condition and a method for the determination of minimal inhibitory concentration using droplet microfluidics is established. The current encoding and decoding pipeline can readily be extended to more codes by adding more bead colors or color combinations.     

Implicit boundary method for analysis using uniform B‐spline basis and structured grid

Several analysis techniques such as extended finite element method (X‐FEM) have been developed recently, which use structured grid for the analysis. Implicit boundary method uses implicit equations of the boundary to apply boundary conditions in X‐FEM framework using structured grids. Solution structures for test and trial functions are constructed using implicit equations such that the boundary conditions are satisfied even if there are no nodes on the boundary. In this paper, this method is applied for analysis using uniform B‐spline basis defined over a structured grid. Solution structures that are C¹ or C² continuous throughout the analysis domain can be constructed using B‐spline basis functions. As a structured grid does not conform to the geometry of the analysis domain, the boundaries of the analysis domain are defined independently using equations of the boundary curves/surfaces. Compared with conforming mesh, it is easier to generate structured grids that overlap the geometry and the elements in the grid are regular shaped and undistorted. Numerical examples are presented to demonstrate the performance of these B‐spline elements. The results are compared with analytical solutions as well as with traditional finite element solutions. Convergence studies for several examples show that B‐spline elements provide accurate solutions with fewer elements and nodes compared with traditional FEM. They also provide continuous stress and strain in the analysis domain, thus eliminating the need for smoothing stress/strain results. Copyright © 2008 John Wiley & Sons, Ltd.     

Smooth contact strategies with emphasis on the modeling of balloon angioplasty with stenting

Critical to the simulation of balloon angioplasty is the modeling of the contact between the artery wall and the medical devices. In standard approaches, the 3D contact surfaces are described by means of C⁰‐continuous facet‐based techniques, which may lead to numerical problems. This work introduces a novel contact algorithm where the target surfaces are described by polynomial expressions with C²‐continuity. On the basis of uniform cubic B‐splines, two different parametrization techniques are presented and compared, while the related implementation of the algorithm into a finite element analysis program is described. Two numerical examples are selected to demonstrate the special merits of the proposed contact formulation. The first example is a benchmark contact problem selected to point out the special features of the proposed strategies. The second example is concerned with the simulation of balloon angioplasty and stenting, where the contact between the balloon, the stent and the artery wall is numerically modeled. A patient‐specific 3D model of a stenotic femoral artery serves as a basis. The study concludes by identifying the changes in the mechanical environment of the artery in terms of contact forces and strains by considering two different stent designs. Copyright © 2008 John Wiley & Sons, Ltd.     

A Biomimetic Non‐Antibiotic Approach to Eradicate Drug‐Resistant Infections

The chronic infections by pathogenic Pseudomonas aeruginosa (P. aeruginosa) remain to be properly addressed. In particular, for drug‐resistant strains, limited medication is available. An in vivo pneumonia model induced by a clinically isolated aminoglycoside resistant strain of P. aeruginosa is developed. Tobramycin clinically treating P. aeruginosa infections is found to be ineffective to inhibit or eliminate this drug‐resistant strain. Here, a newly developed non‐antibiotics based nanoformulation plus near‐infrared (NIR) photothermal treatment shows a remarkable antibacterial efficacy in treating this drug‐resistant pneumonia. The novel formulation contains 50–100 nm long nanorods decorated with two types of glycomimetic polymers to specifically block bacterial LecA and LecB lectins, respectively, which are essential for bacterial biofilm development. Such a 3D display of heteromultivalent glycomimetics on a large scale is inspired by the natural strengthening mechanism for the carbohydrate–lectin interaction that occurs when bacteria initially infects the host. This novel formulation shows the most efficient bacteria inhabitation and killing against P. aeruginosa infection, through lectin blocking and the near‐infrared‐light‐induced photothermal effect of gold nanorods, respectively. Collectively, the novel biomimetic design combined with the photothermal killing capability is expected to be an alternative treatment strategy against the ever‐threatening drug‐resistant infectious diseases when known antibiotics have failed.     

Second‐order defeaturing error estimation for multiple boundary features

A posteriori estimation of defeaturing error, that is, engineering analysis error caused by defeaturing, remains a key challenge in computer‐aided design/computer‐aided engineering integration; indeed, it is essential if analysis based on automatic simplification of the geometry of a complex design is to be reliable. Previous work has mainly focused on removing a single, negative, internal design feature (i.e. a void within the model's interior); effects of removal of multiple features are found by simple summation. In this paper, we give a second‐order defeaturing error estimator that can handle multiple boundary features, either positive or negative (cutouts or additions on the model's boundary). This is the first such method to take into account interactions between different features. (Removing internal holes in 2D or through holes in 3D will change the model's topology and is not addressed here.) The proposed estimator is also the first to handle positive features without heuristics. Our approach uses second‐order shape sensitivity, on the basis of reformulating defeaturing as a shape transformation process. The reference model used for sensitivity computation is carefully chosen, as is the associated shape variation velocity, to ensure efficient computation and simple sensitivity expressions. Mixed partial derivatives in a second‐order Taylor expansion are used to account for interaction between features. The advantages of our approach are demonstrated using various numerical examples. Copyright © 2014 John Wiley & Sons, Ltd.     

Low‐cycle fatigue life behaviour of BS 460B and BS B500B steel reinforcing bars

This paper investigates the low‐cycle fatigue resistance of BS 460B and BS B500B steel reinforcing bars and proposes models for predicting their fatigue life based on plastic‐strain (?_ap) and total‐strain (?_a) amplitudes. Constant‐amplitude, strain‐controlled low‐cycle fatigue tests were carried out on these bars under cyclic load with a frequency of 0.05 Hz. The maximum applied axial strain amplitude (?_s,max) ranges from 3 to 10% with zero and non‐zero mean strains. The strain ratios (R = ?_s,min/?_s,max) used are R =?1, ?0.5 and 0. Hysteresis loops were recorded and plastic and total strain amplitudes were related to the number of reversals (2N_f) to fatigue failure and models for predicting the number of reversals to fatigue failure were proposed. It is concluded that the predicted fatigue life of these bars is very accurate when compared with the measured experimental fatigue life results for wide range of values of strain ratios. It is also observed that based on plastic‐strain amplitude, BS B500B consistently has a longer life (higher number of cycles to failure) than those of BS 460B for all R values; however, at low plastic‐strain amplitudes they tend to behave similarly, irrespective of R value. Other observations and conclusions were also drawn.     

Controlled release antibiotics for dry powder lung delivery

Introduction: Two controlled release (CR) antibiotics intended for inhalation therapy were evaluated. Material and Methods: Ciprofloxacin and doxycycline (both hydrochlorides) were selected as model drugs. Microparticles containing 90:10 ratio of polyvinyl alcohol (PVA) and single antibiotics or combinations were obtained via spray drying. The microparticles were evaluated in terms of particle size, morphology, thermal properties, aerosol performance, and in vitro release. Results and Discussion: Analysis of the microparticle morphology indicated comparable size distributions (2.04 ± 0.06, 2.15 ± 0.01, and 2.21 ± 0.01 μm for ciprofloxacin, doxycycline, and co-spray-dried antibiotic formulations, respectively). Thermal analysis of the microparticles suggested similar responses, which were dominated by the endothermic peaks observed for PVA alone. Analysis of the aerosol performance suggested that the individual antibiotic formulations had different aerosol profiles that were dependent on the antibiotic used. In comparison, the combination CR antibiotics had identical aerosol profiles, suggesting that the microparticles were homogeneous. The release of antibiotics from the CR microparticles showed that ≤50% was released over a 6-hour period in comparison to ≥90% being released in the first hour for microparticles containing no PVA. Conclusions: The potential for antibiotic therapy, and specifically CR antibiotic therapy using dry powder inhalers, provides a promising route for the treatment of pulmonary infection.     

Diffusing‐Wave Spectroscopy Contribution to Strain Analysis

Abstract: We present a new full‐field strain measurement method based on diffusing‐wave spectroscopy. Our technique makes it possible to measure strains in the vicinity of the surface of highly light‐scattering materials. Its main feature is an extreme sensitivity: the range of deformations measured is 10^?5–10^?3. To validate the measurements, experimental results from several plane stress configurations are compared with theoretical and numerical calculations. Furthermore, we propose an extension of the method for non‐scattering materials.     

Highly stable,protein capped gold nanoparticles as effective drug delivery vehicles for amino-glycosidic antibiotics

A method for the production of highly stable gold nanoparticles (Au NP) was optimized using sodium borohydride as reducing agent and bovine serum albumin as capping agent. The synthesized nanoparticles were characterized using UV–visible spectroscopy, transmission electron microscopy, X‐ray diffraction (XRD) and dynamic light scattering techniques. The formation of gold nanoparticles was confirmed from the appearance of pink colour and an absorption maximum at 532 nm. These protein capped nanoparticles exhibited excellent stability towards pH modification and electrolyte addition. The produced nanoparticles were found to be spherical in shape, nearly monodispersed and with an average particle size of 7.8 ± 1.7 nm. Crystalline nature of the nanoparticles in face centered cubic structure is confirmed from the selected‐area electron diffraction and XRD patterns. The nanoparticles were functionalized with various amino-glycosidic antibiotics for utilizing them as drug delivery vehicles. Using Fourier transform infrared spectroscopy, the possible functional groups of antibiotics bound to the nanoparticle surface have been examined. These drug loaded nanoparticle solutions were tested for their antibacterial activity against Gram-negative and Gram-positive bacterial strains, by well diffusion assay. The antibiotic conjugated Au NP exhibited enhanced antibacterial activity, compared to pure antibiotic at the same concentration. Being protein capped and highly stable, these gold nanoparticles can act as effective carriers for drugs and might have considerable applications in the field of infection prevention and therapeutics.     

Artificial Channels in an Infectious Biofilm Created by Magnetic Nanoparticles Enhanced Bacterial Killing by Antibiotics

The poor penetrability of many biofilms contributes to the recalcitrance of infectious biofilms to antimicrobial treatment. Here, a new application for the use of magnetic nanoparticles in nanomedicine to create artificial channels in infectious biofilms to enhance antimicrobial penetration and bacterial killing is proposed. Staphylococcus aureus biofilms are exposed to magnetic‐iron‐oxide nanoparticles (MIONPs), while magnetically forcing MIONP movement through the biofilm. Confocal laser scanning microscopy demonstrates artificial channel digging perpendicular to the substratum surface. Artificial channel digging significantly (4–6‐fold) enhances biofilm penetration and bacterial killing efficacy by gentamicin in two S. aureus strains with and without the ability to produce extracellular polymeric substances. Herewith, this work provides a simple, new, and easy way to enhance the eradication of infectious biofilms using MIONPs combined with clinically applied antibiotic therapies.     

The Binary Effect on Methicillin‐Resistant Staphylococcus aureus of Polymeric Nanovesicles Appended by Proline‐Rich Amino Acid Sequences and Inorganic Nanoparticles

Prevalent research underscores efforts to engineer highly sophisticated nanovesicles that are functionalized to combat antibiotic‐resistant bacterial infections, especially those caused by methicillin‐resistant Staphylococcus aureus (MRSA), and that aid with wound healing or immunomodulation. This is especially relevant for patients who are susceptible to Staphylococcus aureus infections postoperatively. Here, antibacterial formulations are incorporated into polymeric, biocompatible vesicles called polymersomes (PsNPs) that self‐assemble via hydrophobic interactions of admixed aqueous and organic substances. Nano‐PsNPs are synthesized using a high molecular weight amphiphilic block copolymer, and are conjugated to include antimicrobial peptides (AMPs) along the peripheral hydrophilic region and silver nanoparticles (AgNPs) inside their hydrophobic corona. In vitro testing on bacterial and human cell lines indicates that finely tuned treatment concentrations of AMP and AgNPs in PsNPs synergistically inhibits the growth of MRSA without posing significant side effects, as compared with other potent treatment strategies. A ratio of silver‐to‐AMP of about 1:5.8 corresponding to ≈11.6 µg mL^?1 of silver nanoparticles and 14.3 × 10^?6 m of the peptide, yields complete MRSA inhibition over a 23 h time frame. This bacteriostatic activity, coupled with nominal cytotoxicity toward native human dermal fibroblast cells, extends the potential for AMP/AgNP polymersome therapies to replace antibiotics in the clinical setting.     

Performance Measures for ―X Charts with Asymmetric Control Limits

Theoretical and empirical justification is given for using asymmetric control limits for certain types of production processes. The following are also discussed: the sensitivity of the performance measures to the process and control parameters, the advantages and disadvantages of using asymmetric control limits, and the construction of tradeoff curves to characterize performance. The justification is given in terms of a collection of quantitative performance measures for ―X charts with asymmetric control limits. The performance measures quantify the false‐alarm frequency, the sensitivity to out‐of‐control conditions, and the resources required for sampling. Copyright © 2005 John Wiley & Sons, Ltd.     

Reliability and maintenance strategy for systems with aging‐dependent components

An innovative approach is presented for the reliability analysis of aging multistate systems that considers the subsystems and their components' dependency. A reliability function is determined for an aging series system with the component dependency following the local load‐sharing rule, and a reliability function is determined for an aging “m out of n” system with the component dependency following the equal load‐sharing rule. Linking the results of those load‐sharing models, a mixed‐dependency model for multistate “m out of l”‐series systems is constructed by assuming the dependence between subsystems connected in series under the local load‐sharing rule and the dependence between their components under the equal load‐sharing rule. As a special case, the reliability of this system, modeled using piecewise exponential reliability functions, is considered, and the results are applied to characterize shipyard rope elevator reliability. Finally, the maintenance of this elevator as a repairable multistate system is analyzed with the time of renovation ignored.     

Dynamic response of intrinsic continua for use in biological and molecular modeling: Explicit finite element formulation

An intrinsic beam formulation has recently appeared (AIAA J. 2003; 41 (6):1131–1137), which presents the three‐dimensional equations of motion governing spatial and temporal changes in a one‐dimensional continua's curvature, strain, rectilinear velocity, and angular velocity. The formulation would suggest several computational advantages over more‐traditional displacement‐based continua approaches: low‐order interpolation functions can describe generally curved and twisted continua configurations; inter‐element displacements, slopes, strains, and curvatures can be matched; and finite rotational variables and their complexities are absent. Here, we present a completed intrinsic continua finite element development and critical analysis, which follows from an earlier preliminary treatment as applied to carbon nanotubes (Int. J. Solids Struct. 2007; 44 :874–894). Modeling of nodal displacements and rotations are included. Explicit time stepping, with desired high‐frequency damping, is accomplished using an implementation of the generalized‐α method. Zero‐energy modes inherent in the formulation are also identified and rectified. Finally, we document very good agreement between results predicted with the intrinsic continua finite element simulator and results generated using more‐traditional finite element simulations. Copyright © 2009 John Wiley & Sons, Ltd.