Hybrid microneedle arrays for antibiotic and near-IR photothermal synergistic antimicrobial effect against Methicillin-Resistant Staphylococcus aureus.

The rise of antibiotic-resistant skin and soft tissue infections (SSTIs) necessitates the development of novel treatments to improve the efficiency and delivery of antibiotics. The incorporation of photothermal agents such as plasmonic nanoparticles (NPs) improves the antibacterial efficiency of antibiotics through synergism with elevated temperatures. Hybrid microneedle (MN) arrays are promising local delivery platforms that enable co-therapy with therapeutic and photothermal agents. However, to-date, the majority of hybrid MNs have focused on the potential treatment of skin cancers, while suffering from the shortcoming of the intradermal release of photothermal agents. Here, we developed hybrid, two-layered MN arrays consisting of an outer water-soluble layer loaded with vancomycin (VAN) and an inner water-insoluble near-IR photothermal core. The photothermal core consists of flame-made plasmonic Au/SiO2 nanoaggregates and polymethylmethacrylate (PMMA). We analyzed the effect of the outer layer polymer, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), on MN morphology and performance. Hybrid MNs produced with 30 wt% PVA contain a highly drug-loaded outer shell allowing for the incorporation of VAN concentrations up to 100 mg g-1 and temperature increases up to 60 °C under near-IR irradiation while showing sufficient mechanical strength for skin insertion. Furthermore, we studied the combinatorial effect of VAN and heat on the growth inhibition of methicillin-resistant Staphylococcus aureus (MRSA) showing synergistic inhibition between VAN and heat above 55 °C for 10 min. Finally, we show that treatment with hybrid MN arrays can inhibit the growth of MRSA due to the synergistic interaction of heat with VAN reducing the bacterial survival by up to 80%. This proof-of-concept study demonstrates the potential of hybrid, two-layered MN arrays as a novel treatment option for MRSA-associated skin infections.

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.

Silica encapsulation of ZnO nanoparticles reduces their toxicity for cumulus cell-oocyte-complex expansion.

BACKGROUND: Metal oxide nanoparticles (NPs) are increasingly used in many industrial and biomedical applications, hence their impact on occupational and public health has become a concern. In recent years, interest on the effect that exposure to NPs may exert on human reproduction has grown, however data are still scant. In the present work, we investigated whether different metal oxide NPs interfere with mouse cumulus cell-oocyte complex (COC) expansion. METHODS: Mouse COCs from pre-ovulatory follicles were cultured in vitro in the presence of various concentrations of two types of TiO2 NPs (JRC NM-103 and NM-104) and four types of ZnO NPs (JRC NM-110, NM-111, and in-house prepared uncoated and SiO2-coated NPs) and the organization of a muco-elastic extracellular matrix by cumulus cells during the process named cumulus expansion was investigated. RESULTS: We show that COC expansion was not affected by the presence of both types of TiO2 NPs at all tested doses, while ZnO NM-110 and NM-111 induced strong toxicity and inhibited COCs expansion at relatively low concentration. Medium conditioned by these NPs showed lower toxicity, suggesting that, beside ion release, inhibition of COC expansion also depends on NPs per se. To further elucidate this, we compared COC expansion in the presence of uncoated or SiO2-coated NPs. Differently from the uncoated NPs, SiO2-coated NPs underwent slower dissolution, were not internalized by the cells, and showed an overall lower toxicity. Gene expression analysis demonstrated that ZnO NPs, but not SiO2-coated ZnO NPs, affected the expression of genes fundamental for COC expansion. Dosimetry analysis revealed that the delivered-to-cell mass fractions for both NPs was very low. CONCLUSIONS: Altogether, these results suggest that chemical composition, dissolution, and cell internalization are all responsible for the adverse effects of the tested NPs and support the importance of a tailored, safer-by-design production of NPs to reduce toxicity.

Evolution of biofilm-forming pathogenic bacteria in the presence of nanoparticles and antibiotic: adaptation phenomena and cross-resistance.

BACKGROUND: Treatment of bacterial biofilms are difficult and in many cases, expensive. Bacterial biofilms are naturally more resilient to antimicrobial agents than their free-living planktonic counterparts, rendering the community growth harder to control. The present work described the risks of long-term use of an important alternative antimicrobial, silver nanoparticles (NAg), for the first time, on the dominant mode of bacterial growth. RESULTS: NAg could inhibit the formation as well as eradicating an already grown biofilm of Pseudomonas aeruginosa, a pathogen notorious for its resilience to antibiotics. The biofilm-forming bacterium however, evolved a reduced sensitivity to the nanoparticle. Evidence suggests that survival is linked to the development of persister cells within the population. A similar adaptation was also seen upon prolonged exposures to ionic silver (Ag+). The persister population resumed normal growth after subsequent passage in the absence of silver, highlighting the potential risks of recurrent infections with long-term NAg (and Ag+) treatments of biofilm growth. The present study further observed a potential silver/antibiotic cross-resistance, whereby NAg (as well as Ag+) could not eradicate an already growing gentamicin-resistant P. aeruginosa biofilm. The phenomena is thought to result from the hindered biofilm penetration of the silver species. In contrast, both silver formulations inhibited biofilm formation of the resistant strain, presenting a promising avenue for the control of biofilm-forming antibiotic-resistant bacteria. CONCLUSION: The findings signify the importance to study the nanoparticle adaptation phenomena in the biofilm mode of bacterial growth, which are apparently unique to those already reported with the planktonic growth counterparts. This work sets the foundation for future studies in other globally significant bacterial pathogens when present as biofilms. Scientifically based strategies for management of pathogenic growth is necessary, particularly in this era of increasing antibiotic resistance.

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.

Ultrabright and Stable Luminescent Labels for Correlative Cathodoluminescence Electron Microscopy Bioimaging.

The mechanistic understanding of structure-function relationships in biological systems heavily relies on imaging. While fluorescence microscopy allows the study of specific proteins following their labeling with fluorophores, electron microscopy enables holistic ultrastructural analysis based on differences in electron density. To identify specific proteins in electron microscopy, immunogold labeling has become the method of choice. However, the distinction of immunogold-based protein labels from naturally occurring electron dense granules and the identification of several different proteins in the same sample remain challenging. Correlative cathodoluminescence electron microscopy (CCLEM) bioimaging has recently been suggested to provide an attractive alternative based on labels emitting characteristic light. While luminescence excitation by an electron beam enables subdiffraction imaging, structural damage to the sample by high-energy electrons has been identified as a potential obstacle. Here, we investigate the feasibility of various commonly used luminescent labels for CCLEM bioimaging. We demonstrate that organic fluorophores and semiconductor quantum dots suffer from a considerable loss of emission intensity, even when using moderate beam voltages (2 kV) and currents (0.4 nA). Rare-earth element-doped nanocrystals, in particular Y2O3:Tb3+ and YVO4:Bi3+,Eu3+ nanoparticles with green and orange-red emission, respectively, feature remarkably high brightness and stability in the CCLEM bioimaging setting. We further illustrate how these nanocrystals can be readily differentiated from morphologically similar naturally occurring dense granules based on optical emission, making them attractive nanoparticle core materials for molecular labeling and (multi)color CCLEM.

Flame-Made Calcium Phosphate Nanoparticles with High Drug Loading for Delivery of Biologics.

Nanoparticles exhibit potential as drug carriers in biomedicine due to their high surface-to-volume ratio that allows for facile drug loading. Nanosized drug delivery systems have been proposed for the delivery of biologics facilitating their transport across epithelial layers and maintaining their stability against proteolytic degradation. Here, we capitalize on a nanomanufacturing process famous for its scalability and reproducibility, flame spray pyrolysis, and produce calcium phosphate (CaP) nanoparticles with tailored properties. The as-prepared nanoparticles are loaded with bovine serum albumin (model protein) and bradykinin (model peptide) by physisorption and the physicochemical parameters influencing their loading capacity are investigated. Furthermore, we implement the developed protocol by formulating CaP nanoparticles loaded with the LL-37 antimicrobial peptide, which is a biological drug currently involved in clinical trials. High loading values along with high reproducibility are achieved. Moreover, it is shown that CaP nanoparticles protect LL-37 from proteolysis in vitro. We also demonstrate that LL-37 retains its antimicrobial activity against Escherichia coli and Streptococcus pneumoniae when loaded on nanoparticles in vitro. Therefore, we highlight the potential of nanocarriers for optimization of the therapeutic profile of existing and emerging biological drugs.

Nanofiller Presence Enhances Polycyclic Aromatic Hydrocarbon (PAH) Profile on Nanoparticles Released during Thermal Decomposition of Nano-enabled Thermoplastics: Potential Environmental Health Implications.

Nano-enabled products are ultimately destined to reach end-of-life with an important fraction undergoing thermal degradation through waste incineration or accidental fires. Although previous studies have investigated the physicochemical properties of released lifecycle particulate matter (called LCPM) from thermal decomposition of nano-enabled thermoplastics, critical questions about the effect of nanofiller on the chemical composition of LCPM still persist. Here, we investigate the potential nanofiller effects on the profiles of 16 Environmental Protection Agency (EPA)-priority polycyclic aromatic hydrocarbons (PAHs) adsorbed on LCPM from thermal decomposition of nano-enabled thermoplastics. We found that nanofiller presence in thermoplastics significantly enhances not only the total PAH concentration in LCPM but most importantly also the high molecular weight (HMW, 4-6 ring) PAHs that are considerably more toxic than the low molecular weight (LMW, 2-3 ring) PAHs. This nano-specific effect was also confirmed during in vitro cellular toxicological evaluation of LCPM for the case of polyurethane thermoplastic enabled with carbon nanotubes (PU-CNT). LCPM from PU-CNT shows significantly higher cytotoxicity compared to PU which could be attributed to its higher HMW PAH concentration. These findings are crucial and make the case that nanofiller presence in thermoplastics can significantly affect the physicochemical and toxicological properties of LCPM released during thermal decomposition.

Enhanced Ag(+) Ion Release from Aqueous Nanosilver Suspensions by Absorption of Ambient CO2.

Nanosilver with closely controlled average particle diameter (7-30 nm) immobilized on nanosilica is prepared and characterized by X-ray diffraction, N2 adsorption, and transmission electron microscopy. The presence of Ag2O on the as-prepared nanosilver surface is confirmed by UV-vis spectroscopy and quantified by thermogravimetric analysis and mass spectrometry. The release of Ag(+) ions in deionized water is monitored electrochemically and traced quantitatively to the dissolution of a preexisting Ag2O monolayer on the nanosilver surface. During this dissolution, the pH of the host solution rapidly increases, suppressing dissolution of the remaining metallic Ag. When, however, a nanosilver suspension is exposed to a CO2-containing atmosphere, like ambient air during its storage or usage, then CO2 is absorbed by the host solution decreasing its pH and contributing to metallic Ag dissolution and further leaching of Ag(+) ions. So the release of Ag(+) ions from the above closely sized nanosilver solutions in the absence and presence of CO2 as well as under synthetic air containing 200-1800 ppm of CO2 is investigated along with the solution pH and related to the antibacterial activity of nanosilver.

Bioavailability, distribution and clearance of tracheally-instilled and gavaged uncoated or silica-coated zinc oxide nanoparticles.

BACKGROUND: Nanoparticle pharmacokinetics and biological effects are influenced by several factors. We assessed the effects of amorphous SiO2 coating on the pharmacokinetics of zinc oxide nanoparticles (ZnO NPs) following intratracheal (IT) instillation and gavage in rats. METHODS: Uncoated and SiO2-coated ZnO NPs were neutron-activated and IT-instilled at 1 mg/kg or gavaged at 5 mg/kg. Rats were followed over 28 days post-IT, and over 7 days post-gavage. Tissue samples were analyzed for 65Zn radioactivity. Pulmonary responses to instilled NPs were also evaluated at 24 hours. RESULTS: SiO2-coated ZnO elicited significantly higher inflammatory responses than uncoated NPs. Pulmonary clearance of both 65ZnO NPs was biphasic with a rapid initial t1/2 (0.2 - 0.3 hours), and a slower terminal t1/2 of 1.2 days (SiO2-coated ZnO) and 1.7 days (ZnO). Both NPs were almost completely cleared by day 7 (>98%). With IT-instilled 65ZnO NPs, significantly more 65Zn was found in skeletal muscle, liver, skin, kidneys, cecum and blood on day 2 in uncoated than SiO2-coated NPs. By 28 days, extrapulmonary levels of 65Zn from both NPs significantly decreased. However, 65Zn levels in skeletal muscle, skin and blood remained higher from uncoated NPs. Interestingly, 65Zn levels in bone marrow and thoracic lymph nodes were higher from coated 65ZnO NPs. More 65Zn was excreted in the urine from rats instilled with SiO2-coated 65ZnO NPs. After 7 days post-gavage, only 7.4% (uncoated) and 6.7% (coated) of 65Zn dose were measured in all tissues combined. As with instilled NPs, after gavage significantly more 65Zn was measured in skeletal muscle from uncoated NPs and less in thoracic lymph nodes. More 65Zn was excreted in the urine and feces with coated than uncoated 65ZnO NPs. However, over 95% of the total dose of both NPs was eliminated in the feces by day 7. CONCLUSIONS: Although SiO2-coated ZnO NPs were more inflammogenic, the overall lung clearance rate was not affected. However, SiO2 coating altered the tissue distribution of 65Zn in some extrapulmonary tissues. For both IT instillation and gavage administration, SiO2 coating enhanced transport of 65Zn to thoracic lymph nodes and decreased transport to the skeletal muscle.

Paper-based colorimetric hyperammonemia sensing by controlled oxidation of plasmonic silver nanoparticles.

High concentrations of ammonia in the human body can occur due to a wide variety of underlying causes such as liver cirrhosis and the symptoms of high ammonia concentrations are diffuse and hard to diagnose. The measurement of blood ammonia levels is an important diagnostic tool but is challenging to perform at the patient's bedside. Here, we present a plasmonic Ag nanoparticle-based ammonia sensor which provides a colorimetric optical readout and does not require specialised equipment. This is achieved using plasmonic Ag/SiO2 nanoparticles with the sensing mechanism that in the presence of OCl- they rapidly degrade reducing their plasmonic extinction and losing their characteristic colour. However, if ammonia is also present in the system, it neutralises the OCl- and thus the silver nanoparticles retain their plasmonic colour as can be measured by the naked eye or using a spectrometer. This sensing was further developed to enable measurements with animal serum as well as a implementing a facile "dip-stick" style paper-based sensor.

Prevention of uropathogenic E. coli biofilm formation by hydrophobic nanoparticle coatings on polymeric substrates.

Biofilms in infections are a major health-care challenge and strategies to reduce their formation on medical devices are crucial. Fabrication of superhydrophobic coatings based on hydrocarbon adsorption on rare-earth oxides constitutes an attractive strategy, but their capacity to prevent biofilm formation has not been studied. Here, we explore a scalable and reproducible nanofabrication process for the manufacture of such superhydrophobic coatings and study their antibiofilm activity against clinically-relevant uropathogenic E. coli. These coatings reduce bacterial biofilm formation and prevent biofouling with potential applications preventing medical device related infections.

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.

Toxicity of silver nanoparticles in macrophages.

Silver nanoparticles (nanosilver) are broadly used today in textiles, food packaging, household devices and bioapplications, prompting a better understanding of their toxicity and biological interactions. In particular, the cytotoxicity of nanosilver with respect to mammalian cells remains unclear, because such investigations can be biased by the nanosilver coatings and the lack of particle size control. Here, nanosilver of well-defined size (5.7 to 20.4 nm) supported on inert nanostructured silica is produced using flame aerosol technology. The cytotoxicity of the prepared nanosilver with respect to murine macrophages is assessed in vitro because these cells are among the first to confront nanosilver upon its intake by mammals. The silica support facilitates the dispersion and stabilization of the prepared nanosilver in biological suspensions, and no other coating or functionalization is applied that could interfere with the biointeractions of nanosilver. Detailed characterization of the particles by X-ray diffraction and electron microscopy reveals that the size of the nanosilver is well controlled. Smaller nanosilver particles release or leach larger fractions of their mass as Ag⁺ ions upon dispersion in water. This strongly influences the cytotoxicity of the nanosilver when incubated with murine macrophages. The size of the nanosilver dictates its mode of cytotoxicity (Ag⁺ ion-specific and/or particle-specific). The toxicity of small nanosilver (<10 nm) is mostly mediated by the released Ag⁺ ions. The influence of such ions on the toxicity of nanosilver decreases with increasing nanosilver size (>10 nm). Direct silver nanoparticle-macrophage interactions dominate the nanosilver toxicity at sizes larger than 10 nm.

Quantifying the origin of released Ag+ ions from nanosilver.

Nanosilver is most attractive for its bactericidal properties in modern textiles, food packaging, and biomedical applications. Concerns, however, about released Ag(+) ions during dispersion of nanosilver in liquids have limited its broad use. Here, nanosilver supported on nanostructured silica is made with closely controlled Ag size both by dry (flame aerosol) and by wet chemistry (impregnation) processes without any surface functionalization that could interfere with its ion release. It is characterized by electron microscopy, atomic absorption spectroscopy, and X-ray diffraction, and its Ag(+) ion release in deionized water is monitored electrochemically. The dispersion method of nanosilver in solutions affects its dissolution rate but not the final Ag(+) ion concentration. By systematically comparing nanosilver size distributions to their equilibrium Ag(+) ion concentrations, it is revealed that the latter correspond precisely to dissolution of one to two surface silver oxide monolayers, depending on particle diameter. When, however, the nanosilver is selectively conditioned by either washing or H(2) reduction, the oxide layers are removed, drastically minimizing Ag(+) ion leaching and its antibacterial activity against E. coli . That way the bactericidal activity of nanosilver is confined to contact with its surface rather than to rampant ions. This leads to silver nanoparticles with antibacterial properties that are essential for medical tools and hospital applications.

Electrochemical crystallization of plasmonic nanostructures.

We show how gold recrystallizes when under the influence of electrochemical potentials. This "cold annealing" occurs without charge transfer reactions and preserves nanoscale structural features. By performing the process on plasmonic nanostructures, grain growth is monitored noninvasively by optical spectroscopy. In this way, the influence from crystal structure on plasmon resonances can be investigated independently. Observed spectral changes are in excellent agreement with analytical models and changes in electron relaxation time and plasma frequency are calculated.

Highly Efficient Near-IR Photothermal Microneedles with Flame-Made Plasmonic Nanoaggregates for Reduced Intradermal Nanoparticle Deposition.

Near-infrared (NIR) photothermal therapy by microneedles (MNs) exhibits high potential against skin diseases. However, high costs, photobleaching of organic agents, low long-term stability, and potential nanotoxicity limit the clinical translation of photothermal MNs. Here, photothermal MNs are developed by utilizing Au nanoaggregates made by flame aerosol technology and incorporated in water-insoluble polymer matrix to reduce intradermal nanoparticle (NP) deposition. The individual Au interparticle distance and plasmonic coupling within the nanoaggregates are controlled by the addition of a spacer during their synthesis rendering the Au nanoaggregates highly efficient NIR photothermal agents. In situ aerosol deposition of Au nanoaggregates on MN molds results in the fabrication of photothermal MNs with thin plasmonic layers. The photothermal performance of these MN arrays is compared to ones made by three methods utilizing NP dispersions, and it is found that similar temperatures are reached with 28-fold lower Au mass due to reduced light scattering losses of the thin layers. Finally, all developed photothermal MN arrays here cause clinically relevant hyperthermia at benign laser intensities while reducing intradermal NP deposition 127-fold compared to conventional MNs made with water-soluble polymers. Such rational design of photothermal MNs requiring low laser intensities and minimal NP intradermal accumulation sets the basis for their safe clinical translation.

SERS Hotspot Engineering by Aerosol Self-Assembly of Plasmonic Ag Nanoaggregates with Tunable Interparticle Distance.

Surface-enhanced Raman scattering (SERS) is a powerful sensing technique. However, the employment of SERS sensors in practical applications is hindered by high fabrication costs from processes with limited scalability, poor batch-to-batch reproducibility, substrate stability, and uniformity. Here, highly scalable and reproducible flame aerosol technology is employed to rapidly self-assemble uniform SERS sensing films. Plasmonic Ag nanoparticles are deposited on substrates as nanoaggregates with fine control of their interparticle distance. The interparticle distance is tuned by adding a dielectric spacer during nanoparticle synthesis that separates the individual Ag nanoparticles within each nanoaggregate. The dielectric spacer thickness dictates the plasmonic coupling extinction of the deposited nanoaggregates and finely tunes the Raman hotspots. By systematically studying the optical and morphological properties of the developed SERS surfaces, structure-performance relationships are established and the optimal hot-spots occur for interparticle distance of 1 to 1.5 nm among the individual Ag nanoparticles, as also validated by computational modeling, are identified for the highest signal enhancement of a molecular Raman reporter. Finally, the superior stability and batch-to-batch reproducibility of the developed SERS sensors are demonstrated and their potential with a proof-of-concept practical application in food-safety diagnostics for pesticide detection on fruit surfaces is explored.

Laser-Induced Forward Transfer Printing on Microneedles for Transdermal Delivery of Gemcitabine.

Cancer treatment with chemotherapeutic drugs remains to be challenging to the physician due to limitations associated with lack of efficacy or high toxicities. Typically, chemotherapeutic drugs are administered intravenously, leading to high drug concentrations that drive efficacy but also lead to known side effects. Delivery of drugs through transdermal microneedles (MNs) has become an important alternative treatment approach. Such delivery options are well suited for chemotherapeutic drugs in which sustained levels would be desirable. In the context of developing a novel approach, laser-induced forward transfer (LIFT) was applied for bioprinting of gemcitabine (Gem) to coat polymethylmethacrylate MNs. Gem, a chemotherapeutic agent used to treat various types of cancer, is a good candidate for MN-assisted transdermal delivery to improve the pharmacokinetics of Gem while reducing efficiency limitations. LIFT bioprinting of Gem for coating of MNs with different drug amounts and successful transdermal delivery in mice is presented in this study. Our approach produced reproducible, accurate, and uniform coatings of the drug on MN arrays, and on in vivo transdermal application of the coated MNs in mice, dose-proportional concentrations of Gem in the plasma of mice was achieved. The developed approach may be extended to several chemotherapeutics and provide advantages for metronomic drug dosing.