Infections caused by the bacterial colonization of medical devices are a substantial problem to patients and healthcare. Biopassive polyoxazoline coatings are attracting attention in the biomedical ...field as one of the potential solutions to this problem. Here, we present an original and swift way to produce plasma-deposited oxazoline-based films for antifouling applications. The films developed via the plasma deposition of 2-methyl-2-oxazoline and 2-ethyl-2-oxazoline have tunable thickness and surface properties. Diverse film chemistries were achieved by tuning and optimizing the deposition conditions. Human-derived fibroblasts were used to confirm the biocompatibility of oxazoline derived coatings. The capacity of the coatings to resist biofilm attachment was studied as a function of deposition power and mode (i.e., continuous wave or pulsed) and precursor flow rates for both 2-methyl-2-oxazoline and 2-ethyl-2-oxazoline. After careful tuning of the deposition parameters films having the capacity to resist biofilm formation by more than 90% were achieved. The substrate-independent and customizable properties of the new generation of plasma deposited oxazoline thin films developed in this work make them attractive candidates for the coating of medical devices and other applications where bacteria surface colonization and biofilm formation is an issue.
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Pharmacotherapy of tuberculosis is potentially more efficient when delivered by the inhaled route than by the current oral and/or parenteral routes due to the higher concentration of ...drug reaching the primary region of infection in the lungs. This study investigated the influence of the amino acid l-leucine alone and in combination with the phospholipid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), on the aerosolization behaviour of the anti-TB drugs, pyrazinamide and moxifloxacin HCl. Spray dried powders of pyrazinamide (P), moxifloxacin (M) alone and in combination with 10% l-leucine (PL and ML) and 10% DPPC (PLD and MLD) were produced. The particle sizes of all powders except P were in the inhalable size range (<5 µm) but differ in their morphology in presence of the excipients. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed the migration of surface active l-leucine and DPPC onto the surface of the particles during the spray drying process. The aerosolization from a dry powder inhaler, Aerolizer®, using a Next Generation Impactor revealed fine particle fraction (FPF) values for P, PL and PLD of 18.7 ± 3.4%, 53.0 ± 3.2% and 74.5 ± 5.3% respectively while FPF values for M, ML and MLD were 55.6 ± 3.3%, 74.7 ± 4.7% and 74.1 ± 1.3% respectively. In conclusion, the differences in the aerosolization behaviours of the pyrazinamide and moxifloxacin spray dried powders with and without excipients was a combination of difference in the surface morphology and surface composition.
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Amorphous powders are thermodynamically unstable, significantly impacting the processing, storage and performance of a product. Therefore, stabilization of the amorphous contents is ...in demand. In this study, disodium cromoglycate (DSCG) powder was chosen as a model drug because it is amorphous and highly hygroscopic after spray drying. Sodium stearate (NaSt) was co-spray dried with DSCG at various concentrations (10, 50 and 90% w/w) to investigate its effect against moisture-induced deterioration on the in vitro aerosolization performance of DSCG. Particle size distribution and morphology were measured by laser diffraction and scanning electron microscopy (SEM). Physicochemical properties of the powders were analysed by X-ray powder diffraction (XRPD) and dynamic vapour sorption (DVS). Particle surface chemistry was analysed by the time-of-flight secondary ion mass spectrometry (ToF-SIMS). In vitro dissolution behaviours of the spray-dried (SD) powders were tested by the Franz cell apparatus. In vitro aerosolization performance of SD formulations stored at different relative humidity (RH) was evaluated by a multi-stage liquid impinger (MSLI), using an Osmohaler® at 100 L/min. Results showed that adding NaSt in the formulation not only increased the aerosolization performance of DSCG significantly, but also effectively reduced the deleterious impact of moisture. No significant difference was found in the fine particle fraction (FPF) of formulations containing NaSt before and after storage at both 60% and 75% RH for one week. However, after one month storage at 75% RH, SD formulation containing 10% NaSt showed a reduction in FPF, while formulations containing 50% or 90% NaSt showed no change. The underlying mechanism was that NaSt increased the crystallinity of the powders and its presence on the particle surface reduced particle aggregations and cohesiveness. However, NaSt at high concentration could reduce dissolution rate, which needs to be taken into consideration.
Surface nanotopograpy has been recognized as an important regulator of cellular responses including those of immune cells, the latter being of particular importance for implantable materials since ...these can determine biomaterial fate. In this paper, evidence is provided that the scale of surface nanotopography modulates the conformation of attached serum proteins, which in turn controls immune cell adhesion and activation. Model surfaces of tailored nanotopography of heights of 16, 38, and 68 nm are created by covalent immobilization of gold nanoparticles to an oxazoline‐rich plasma polymer film. This strategy not only produces surfaces of tailored nanofeature density but allows control of the outermost surface chemistry. Circular dichroism spectroscopy and Mac‐1 positive THP‐1 monocytes studies demonstrate distinct protein unfolding patterns, which upregulate or downregulate the expression of proinflammatory cytokines and cells attachment. The findings presented in this paper shed light on the missing relationship between surface nanotopography, protein unfolding, and the immune response. On the other hand, this work demonstrates the possibility to use specifically tailored surface nanotoporaphy scales to modulate and achieve desired immune responses.
This study provides the missing link between surface nanotopography, protein unfolding, and immune responses. Precisely engineered surfaces demonstrate nanotopography size‐dependent fibrinogen unfolding and exposure of hidden peptide sequences, which activate the Mac‐1 receptor of inflammatory cells. Nanofeatures of ≈38 nm lead to minimal protein unfolding and reduced expression of proinflammatory cytokines.
Nanoparticles are widely used for biomedical applications such as vaccine, drug delivery, diagnostics, and therapeutics. This study aims to reveal the influence of nanoparticle surface ...functionalization on protein corona formation from blood serum and plasma and the subsequent effects on the innate immune cellular responses. To achieve this goal, the surface chemistry of silica nanoparticles of 20 nm diameter was tailored via plasma polymerization with amine, carboxylic acid, oxazolines, and alkane functionalities. The results of this study show significant surface chemistry-induced differences in protein corona composition, which reflect in the subsequent inflammatory consequences. Nanoparticles rich with carboxylic acid surface functionalities increased the production of pro-inflammatory cytokines in response to higher level of complement proteins and decreased the number of lipoproteins found in their protein coronas. On another hand, amine rich coatings led to increased expressions of anti-inflammatory markers such as arginase. The findings demonstrate the potential to direct physiological responses to nanomaterials via tailoring their surface chemical composition.
This study aimed to develop a high payload dry powder inhalation formulation containing a combination of the first line anti-tubercular drug, pyrazinamide, and the second line drug, moxifloxacin HCl. ...Individual powders of pyrazinamide (PSD) and moxifloxacin (MSD) and combination powders of the two drugs without (PM) and with 10% l-leucine (PML) and 10% DPPC (PMLD) were produced by spray drying. PSD contained >10 μm crystalline particles and showed poor aerosolization behaviour with a fine particle fraction (FPF) of 18.7 ± 3.4%. PM produced spherical hollow particles with aerodynamic diameter < 5 μm and PML showed improved aerosolization with a high FPF of ~70%. However, PMLD showed a significantly reduced FPF (p > 0.05) compared to PML. Solid state studies and surface elemental analysis by X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry confirmed the surface coating of particles contained amorphous moxifloxacin and both l-leucine and DPPC over crystalline pyrazinamide. Furthermore, pyrazinamide, moxifloxacin, PML and PMLD were found to display low toxicity to both A549 and Calu-3 cell lines even at a concentration of 100 μg/mL. In conclusion, a combination powder formulation of PML has the potential to deliver a high drug dose to the site of infection resulting in efficient treatment.
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Bacterial infections are continuing to pose a significant threat to human health. Coatings with inherent antibacterial properties are becoming increasingly common as an infection preventative ...measure. The aim of this review is to highlight recent progress in development of "smart" and responsive antibacterial surfaces. The review describes various strategies utilized for generation of such surfaces and the specific stimuli that are used to trigger antibacterial action. It also provides a critical discussion of the advantages and drawbacks of different approaches. The review concludes with a perspective about the future of the field and outlines the challenges and obstacles that need to be overcome in order to make future advances.
The development of enzyme‐responsive hyaluronic acid methacrylate (HYAMA)‐coated porous silicon (pSi) films and their application in electrochemical diagnostic devices for the in situ detection of ...the enzyme hyaluronidase (hyal), which is secreted by Staphylococcus aureus (S. aureus) bacteria, are reported. The approach relies on a HYAMA‐pSi electrode made of thermally hydrocarbonized pSi (pSi‐THC) that is impregnated with crosslinked HYAMA/polyethylene glycol diacrylate (PEGDA) hydrogels. The enzymatic degradation of HYAMA by bacterial hyal is monitored by differential pulse voltammetry (DPV) utilizing pSi‐THC as a working electrode and ferro/ferricyanide (FF) as external redox probe. The degradation of HYAMA results in reduced diffusion of the redox probe through the partially charged film, thereby enabling the detection of hyal by DPV. In addition to the determination of the concentration‐dependent response in NaOAc buffer (pH 5.2), the detection of hyal as indicator for the presence of S. aureus bacteria above a threshold level in bacterial supernatants and artificial wound fluid is highlighted.
Enzyme‐responsive hyaluronic acid methacrylate (HYAMA)‐coated porous silicon (pSi) films and their application in electrochemical diagnostic devices for the in situ detection of Staphylococcus aureus bacteria through the enzymatic activity of secreted hyaluronidase are reported. The HYAMA‐pSi electrode is made of thermally hydrocarbonized pSi (pSi‐THC) impregnated with crosslinked HYAMA/polyethylene glycol diacrylate (PEGDA) hydrogels.
In a spray drying operation, a two-fluid nozzle (2FN) with a single channel is commonly used for atomizing the feed solution. However, the less commonly used three-fluid nozzle (3FN) has two separate ...channels, which allow spray drying of materials in two incompatible solution systems. Although amorphous solid dispersions (ASDs) prepared using a 3FN have been reported to deliver comparable drug dissolution performance relative to those prepared using a 2FN, few studies have systematically examined the effect of 3FN on the physical stability. Therefore, the goal of this work is to systematically study the physical stability of ASDs that are spray-dried using a 3FN compared to those prepared using the traditional 2FN. For the 2FN, a single solution of naproxen and polyvinylpyrrolidone (PVP) was prepared in a mixture of acetone and water at a 1:1 volume ratio because 2FN allows for only one solution inlet. For the 3FN, naproxen and PVP were dissolved individually in acetone and water, respectively, because 3FN allows simultaneous entry of two solutions. Upon storage of the formulated ASDs at different humidity levels (25%, 55% and 75% RH), naproxen crystallized more quickly from the 3FN ASDs as compared with the 2FN ASDs. 3FN ASDs crystallized after 5 days of storage at all conditions, whereas 2FN ASDs did not crystallize even at 55% RH for two months. This relatively higher crystallization tendency of 3FN ASDs was attributed to the inhomogeneity of drug and polymers as identified by the solid-state Nuclear Magnetic Resonance findings, specifically due to poor mixing of water- and acetone-based solutions at the 3FN nozzle. When only acetone was used as a solvent to prepare drug-polymer solutions for 3FN, the formulated ASD was found to be stable for >3 months of storage (at 75% RH), which suggests that instability of the 3FN ASD was due to the insufficient mixing of water and acetone solutions. This study provides insights into the effects of solvent and nozzle choices on the physical stability of spray-dried ASDs.
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