Utilizing Laser Activation of Photothermal Plasmonic Nanoparticles to Induce On-Demand Drug Amorphization inside a Tablet.

Poor aqueous drug solubility represents a major challenge in oral drug delivery. A novel approach to overcome this challenge is drug amorphization inside a tablet, that is, on-demand drug amorphization. The amorphous form is a thermodynamically instable, disordered solid-state with increased dissolution rate and solubility compared to its crystalline counterpart. During on-demand drug amorphization, the drug molecularly disperses into a polymer to form an amorphous solid at elevated temperatures inside a tablet. This study investigates, for the first time, the utilization of photothermal plasmonic nanoparticles for on-demand drug amorphization as a new pharmaceutical application. For this, near-IR photothermal plasmonic nanoparticles were tableted together with a crystalline drug (celecoxib) and a polymer (polyvinylpyrrolidone). The tablets were subjected to a near-IR laser at different intensities and durations to study the rate of drug amorphization under each condition. During laser irradiation, the plasmonic nanoparticles homogeneously heated the tablet. The temperature was directly related to the rate and degree of amorphization. Exposure times as low as 180 s at 1.12 W cm-2 laser intensity with only 0.25 wt % plasmonic nanoparticles and up to 50 wt % drug load resulted in complete drug amorphization. Therefore, near-IR photothermal plasmonic nanoparticles are promising excipients for on-demand drug amorphization with laser irradiation.

The Effect of the Molecular Weight of Polyvinylpyrrolidone and the Model Drug on Laser-Induced In Situ Amorphization.

Laser radiation has been shown to be a promising approach for in situ amorphization, i.e., drug amorphization inside the final dosage form. Upon exposure to laser radiation, elevated temperatures in the compacts are obtained. At temperatures above the glass transition temperature (Tg) of the polymer, the drug dissolves into the mobile polymer. Hence, the dissolution kinetics are dependent on the viscosity of the polymer, indirectly determined by the molecular weight (Mw) of the polymer, the solubility of the drug in the polymer, the particle size of the drug and the molecular size of the drug. Using compacts containing 30 wt% of the drug celecoxib (CCX), 69.25 wt% of three different Mw of polyvinylpyrrolidone (PVP: PVP12, PVP17 or PVP25), 0.25 wt% plasmonic nanoaggregates (PNs) and 0.5 wt% lubricant, the effect of the polymer Mw on the dissolution kinetics upon exposure to laser radiation was investigated. Furthermore, the effect of the model drug on the dissolution kinetics was investigated using compacts containing 30 wt% of three different drugs (CCX, indomethacin (IND) and naproxen (NAP)), 69.25 wt% PVP12, 0.25 wt% PN and 0.5 wt% lubricant. In perfect correlation to the Noyes-Whitney equation, this study showed that the use of PVP with the lowest viscosity, i.e., the lowest Mw (here PVP12), led to the fastest rate of amorphization compared to PVP17 and PVP25. Furthermore, NAP showed the fastest rate of amorphization, followed by IND and CCX in PVP12 due to its high solubility and small molecular size.

Customizable Fabrication of Photothermal Microneedles with Plasmonic Nanoparticles Using Low-Cost Stereolithography Three-Dimensional Printing.

Photothermal microneedle (MN) arrays have the potential to improve the treatment of various skin conditions such as bacterial skin infections. However, the fabrication of photothermal MN arrays relies on time-consuming and potentially expensive microfabrication and molding techniques, which limits their size and translation to clinical application. Furthermore, the traditional mold-and-casting method is often limited in terms of the size customizability of the photothermal array. To overcome these challenges, we fabricated photothermal MN arrays directly via 3D-printing using plasmonic Ag/SiO2 (2 wt % SiO2) nanoaggregates dispersed in ultraviolet photocurable resin on a commercial low-cost liquid crystal display stereolithography printer. We successfully printed MN arrays in a single print with a translucent, nanoparticle-free support layer and photothermal MNs incorporating plasmonic nanoaggregates in a selective fashion. The photothermal MN arrays showed sufficient mechanical strength and heating efficiency to increase the intradermal temperature to clinically relevant temperatures. Finally, we explored the potential of photothermal MN arrays to improve antibacterial therapy by killing two bacterial species commonly found in skin infections. To the best of our knowledge, this is the first time describing the printing of photothermal MNs in a single step. The process introduced here allows for the translatable fabrication of photothermal MN arrays with customizable dimensions that can be applied to the treatment of various skin conditions such as bacterial infections.

Silver/gold nanoalloy implant coatings with antibiofilm activity via pH-triggered silver ion release.

Implant infections are a major challenge for the healthcare system. Biofilm formation and increasing antibiotic resistance of common bacteria cause implant infections, leading to an urgent need for alternative antibacterial agents. In this study, the antibiofilm behaviour of a coating consisting of a silver (Ag)/gold (Au) nanoalloy is investigated. This alloy is crucial to reduce uncontrolled potentially toxic Ag+ ion release. In neutral pH environments this release is minimal, but the Ag+ ion release increases in acidic microenvironments caused by bacterial biofilms. We perform a detailed physicochemical characterization of the nanoalloys and compare their Ag+ ion release with that of pure Ag nanoparticles. Despite a lower released Ag+ ion concentration at pH 7.4, the antibiofilm activity against Escherichia coli (a bacterium known to produce acidic pH environments) is comparable to a pure nanosilver sample with a similar Ag-content. Finally, biocompatibility studies with mouse pre-osteoblasts reveal a decreased cytotoxicity for the alloy coatings and nanoparticles.

Antibiofilm activity of nanosilver coatings against Staphylococcus aureus.

Implant infections due to bacterial biofilms constitute a major healthcare challenge today. One way to address this clinical need is to modify the implant surface with an antimicrobial nanomaterial. Among such nanomaterials, nanosilver is arguably the most powerful one, due to its strong and broad antimicrobial activity. However, there is still a lack of understanding on how physicochemical characteristics of nanosilver coatings affect their antibiofilm activity. More specifically, the contributions of silver (Ag)+ ion-mediated vs. contact-based mechanisms to the observed antimicrobial activity are yet to be elucidated. To address this knowledge gap, we produce here nanosilver coatings on substrates by flame aerosol direct deposition that allows for facile control of the coating composition and Ag particle size. We systematically study the effect of (i) nanosilver content in composite Ag silica (SiO2) coatings from 0 (pure SiO2) up to 50 wt%, (ii) the Ag particle size and (iii) the coating thickness on the antibiofilm activity against Staphylococcus aureus (S. aureus), a clinically-relevant pathogen often present on the surface of surgically-installed implants. We show that the Ag+ ion concentration in solution largely drives the observed antibiofilm effect independently of Ag size and coating thickness. Furthermore, co-incubation of both pure SiO2 and nanosilver coatings in the same well also reveals that the antibiofilm effect stems predominantly from the released Ag+ ions, which is especially pronounced for coatings featuring the smallest Ag particle sizes, rather than direct bacterial contact inhibition. We also examine the biocompatibility of the developed nanosilver coatings in terms of pre-osteoblastic cell viability and proliferation, comparing it to that of pure SiO2. This study lays the foundation for the rational design of nanosilver-based antibiofilm implant coatings.

Tailored Biocompatible Polyurethane-Poly(ethylene glycol) Hydrogels as a Versatile Nonfouling Biomaterial.

Polyurethane-based hydrogels are relatively inexpensive and mechanically robust biomaterials with ideal properties for various applications, including drug delivery, prosthetics, implant coatings, soft robotics, and tissue engineering. In this report, a simple method is presented for synthesizing and casting biocompatible polyurethane-poly(ethylene glycol) (PU-PEG) hydrogels with tunable mechanical properties, nonfouling characteristics, and sustained tolerability as an implantable material or coating. The hydrogels are synthesized via a simple one-pot method using commercially available precursors and low toxicity solvents and reagents, yielding a consistent and biocompatible gel platform primed for long-term biomaterial applications. The mechanical and physical properties of the gels are easily controlled by varying the curing concentration, producing networks with complex shear moduli of 0.82-190 kPa, similar to a range of human soft tissues. When evaluated against a mechanically matched poly(dimethylsiloxane) (PDMS) formulation, the PU-PEG hydrogels demonstrated favorable nonfouling characteristics, including comparable adsorption of plasma proteins (albumin and fibrinogen) and significantly reduced cellular adhesion. Moreover, preliminary murine implant studies reveal a mild foreign body response after 41 days. Due to the tunable mechanical properties, excellent biocompatibility, and sustained in vivo tolerability of these hydrogels, it is proposed that this method offers a simplified platform for fabricating soft PU-based biomaterials for a variety of applications.

Silica-Coated Nonstoichiometric Nano Zn-Ferrites for Magnetic Resonance Imaging and Hyperthermia Treatment.

Large-scale and reproducible synthesis of nanomaterials is highly sought out for successful translation into clinics. Flame aerosol technology with its proven capacity to manufacture high purity materials (e.g., light guides) up to kg h-1 is explored here for the preparation of highly magnetic, nonstoichiometric Zn-ferrite (Zn0.4 Fe2.6 O4 ) nanoparticles coated in situ with a nanothin SiO2 layer. The focus is on their suitability as magnetic multifunctional theranostic agents analyzing their T2 contrast enhancing capability for magnetic resonance imaging (MRI) and their magnetic hyperthermia performance. The primary particle size is closely controlled from 5 to 35 nm evaluating its impact on magnetic properties, MRI relaxivity, and magnetic heating performance. Most importantly, the addition of Zn in the flame precursor solution facilitates the growth of spinel Zn-ferrite crystals that exhibit superior magnetic properties over iron oxides typically made in flames. These properties result in strong MRI T2 contrast agents as shown on a 4.7 T small animal MRI scanner and lead to a more efficient heating with alternating magnetic fields. Also, by injecting Zn0.4 Fe2.6 O4 nanoparticle suspensions into pork tissue, MR-images are acquired at clinically relevant concentrations. Furthermore, the nanothin SiO2 shell facilitates functionalization with polymers, which improves the biocompatibility of the theranostic system.

Thermal decomposition of nano-enabled thermoplastics: Possible environmental health and safety implications.

Nano-enabled products (NEPs) are currently part of our life prompting for detailed investigation of potential nano-release across their life-cycle. Particularly interesting is their end-of-life thermal decomposition scenario. Here, we examine the thermal decomposition of widely used NEPs, namely thermoplastic nanocomposites, and assess the properties of the byproducts (released aerosol and residual ash) and possible environmental health and safety implications. We focus on establishing a fundamental understanding on the effect of thermal decomposition parameters, such as polymer matrix, nanofiller properties, decomposition temperature, on the properties of byproducts using a recently-developed lab-based experimental integrated platform. Our results indicate that thermoplastic polymer matrix strongly influences size and morphology of released aerosol, while there was minimal but detectable nano-release, especially when inorganic nanofillers were used. The chemical composition of the released aerosol was found not to be strongly influenced by the presence of nanofiller at least for the low, industry-relevant loadings assessed here. Furthermore, the morphology and composition of residual ash was found to be strongly influenced by the presence of nanofiller. The findings presented here on thermal decomposition/incineration of NEPs raise important questions and concerns regarding the potential fate and transport of released engineered nanomaterials in environmental media and potential environmental health and safety implications.

Plasmonic biocompatible silver-gold alloyed nanoparticles.

The addition of Au during scalable synthesis of nanosilver drastically minimizes its surface oxidation and leaching of toxic Ag(+) ions. These biocompatible and inexpensive silver-gold nanoalloyed particles exhibit superior plasmonic performance than commonly used pure Au nanoparticles, and as such these nanoalloys have great potential in theranostic applications.

Capture, isolation and electrochemical detection of industrially-relevant engineered aerosol nanoparticles using poly (amic) acid, phase-inverted, nano-membranes.

Workplace exposure to engineered nanoparticles (ENPs) is a potential health and environmental hazard. This paper reports a novel approach for tracking hazardous airborne ENPs by applying online poly (amic) acid membranes (PAA) with offline electrochemical detection. Test aerosol (Fe2O3, TiO2 and ZnO) nanoparticles were produced using the Harvard (Versatile Engineered Generation System) VENGES system. The particle morphology, size and elemental composition were determined using SEM, XRD and EDS. The PAA membrane electrodes used to capture the airborne ENPs were either stand-alone or with electron-beam gold-coated paper substrates. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were used to conceptually illustrate that exposure levels of industry-relevant classes of airborne nanoparticles could be captured and electrochemically detected at PAA membranes filter electrodes. CV parameters showed that PAA catalyzed the reduction of Fe2O3 to Fe(2+) with a size-dependent shift in reduction potential (E(0)). Using the proportionality of peak current to concentration, the amount of Fe2O3 was found to be 4.15×10(-17)mol/cm(3) PAA electrodes. Using EIS, the maximum phase angle (Φmax) and the interfacial charge transfer resistance (Rct) increased significantly using 100µg and 1000µg of TiO2 and ZnO respectively. The observed increase in Φmax and Rct at increasing concentration is consistent with the addition of an insulating layer of material on the electrode surface. The integrated VENGES/PAA filter sensor system has the potential to be used as a portable monitoring system.

Optically stable biocompatible flame-made SiO2-coated Y2O3:Tb3+ nanophosphors for cell imaging.

Nanophosphors are light-emitting materials with stable optical properties that represent promising tools for bioimaging. The synthesis of nanophosphors, and thus the control of their surface properties, is, however, challenging. Here, flame aerosol technology is exploited to generate Tb-activated Y(2)O(3) nanophosphors (∼25 nm) encapsulated in situ by a nanothin amorphous inert SiO(2) film. The nanocrystalline core exhibits a bright green luminescence following the Tb(3+) ion transitions, while the hermetic SiO(2)-coating prevents any unspecific interference with cellular activities. The SiO(2)-coated nanophosphors display minimal photobleaching upon imaging and can be easily functionalized through surface absorption of biological molecules. Therefore, they can be used as bionanoprobes for cell detection and for long-term monitoring of cellular activities. As an example, we report on the interaction between epidermal growth factor (EGF)-functionalized nanophosphors and mouse melanoma cells. The cellular uptake of the nanophosphors is visualized with confocal microscopy, and the specific activation of EGF receptors is revealed with biochemical techniques. Altogether, our results establish SiO(2)-coated Tb-activated Y(2)O(3) nanophosphors as superior imaging tools for biological applications.

Oxygen sensing using microrobots.

We present a luminescence oxygen sensor incorporated in a wireless intraocular microrobot for minimally-invasive diagnosis. This microrobot can be accurately controlled in the intraocular cavity by applying magnetic fields. The microrobot consists of a magnetic body susceptible to magnetic fields and a sensor coating. This coating embodies Pt(II) octaethylporphine (PtOEP) dyes as the luminescence material and polystyrene as a supporting matrix, and it can be wirelessly excited and read out by optical means. The sensor works based on quenching of luminescence in the presence of oxygen. The excitation and emission spectrum, response time, and oxygen sensitivity of the sensor were characterized using a spectrometer. A custom device was designed and built to use this sensor for intraocular measurements with the microrobot. Due to the intrinsic nature of luminescence lifetimes, a frequency-domain lifetime measurement approach was employed. An alternative sensor implementation using poly(styrene-co-maleic anhydride) (PS-MA) and PtOEP was successfully demonstrated with nanospheres to increase sensor performance.