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Recently, the number of water insoluble and poorly soluble drug compounds has increased significantly. Therefore, growing interest has been witnessed in different particle size reduction techniques to improve the dissolution rates, transport characteristics and bioavailability of drugs. Laser ablation has proven to be an alternative method to the production of nano- and micrometre-sized drug particles without considerable chemical damage. We present the nanosecond laser ablation of drug pastilles in distilled water, targeting meloxicam, a poorly water soluble nonsteroidal anti-inflammatory drug, at different laser wavelengths (248 nm, 532 nm and 1064 nm). Besides chemical characterization, crystallinity, morphology and particle size studies, the mechanism of the particle generation process was examined. The applicability of ablated particles in drug formulation was investigated by solubility, cytotoxicity and anti-inflammatory effect measurements. We showed that laser ablation is a clean, efficient and chemically non-damaging method to reduce the size of meloxicam particles to the sub-micrometre-few micrometre size range, which is optimal for pulmonary drug delivery. Complemented by the excellent solubility (four to nine times higher) and anti-inflammatory (four to five times better) properties of the particles compared to the initial drug, laser ablation is predicted to have wider applications in the development of drug formulations., (© 2022. The Author(s).)

Counterfeiting of the products for healing is as old as trading, and it is difficult to quantify the magnitude of the problem. It is known that substandard and/or falsified (SF) medicines are a growing global threat to health, and they cause serious social and economic damage. The EU has a strong legal framework for medicines, it is mandatory to meet the requirements of Directive 2011/62/EU. Serialisation prevents SF medicinal products from entering the legal distribution chain. The present study is an extension of the original idea and aims to develop a laser technology-based method to mark an individual traceable code on the surface of the tablet, which technology can also be used for marking personalized medicines. The method is based on the ablation of the upper layer of a double-layer, differently coloured coating. The 2D code should be formed without harming the functional layer, and anyone with a smartphone integrated with a camera should be able to authenticate these drugs with a suitable application. The present findings confirmed that KrF excimer laser and Ti:sapphire femtosecond laser are efficient and reliable for marking. These should be promising candidates for pharmaceutical companies that would like to have additional protection against drug counterfeiters., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Static scattering is detrimental to the accuracy of laser speckle contrast analysis (LASCA) measurements on skin when, instead of percentile change monitoring, absolute perfusion values are needed, e.g., for tissue injury examination. Perfusion values were calculated using two evaluation models, while changing the dynamic/static scattering ratio of monitored skin and tissue phantoms. Results were strongly affected by the significant increase of static contribution. Measurements on a modified tissue phantom showed that the changes in the measured perfusion values were mostly caused by the mixed scattering, which was omitted by the tested models. Dynamic ratio values obtained by multi-exposure LASCA could be used for perfusion data correction.

In pharmaceutical development, more and more drugs are classified as poorly water-soluble or insoluble. Particle size reduction is a common way to fight this trend by improving dissolution rate, transport characteristics and bioavailability. Pulsed laser ablation is a ground-breaking technique of drug particle generation in the nano- and micrometer size range. Meloxicam, a commonly used nonsteroidal anti-inflammatory drug with poor water solubility, was chosen as the model drug. The pastille pressed meloxicam targets were irradiated by a Ti:sapphire laser (τ = 135 fs, λ c = 800 nm) in air and in distilled water. Fourier transform infrared and Raman spectroscopies were used for chemical characterization and scanning electron microscopy to determine morphology and size. Additional particle size studies were performed using a scanning mobility particle sizer. Our experiments demonstrated that significant particle size reduction can be achieved with laser ablation both in air and in distilled water without any chemical change of meloxicam. The size of the ablated particles (~50 nm to a few microns) is approximately at least one-tenth of the size (~10-50 micron) of commercially available meloxicam crystals. Furthermore, nanoaggregate formation was described during pulsed laser ablation in air, which was scarcely studied for drug/organic molecules before.

We studied the application of pulsed laser ablation (PLA) for particle size reduction in non-steroidal anti-inflammatory drugs (NSAIDs). Grinding of the poorly water-soluble NSAID crystallites can considerably increase their solubility and bioavailability, thereby the necessary doses can be reduced significantly. We used tablets of ibuprofen, niflumic acid and meloxicam as targets. Nanosecond laser pulses were applied at various wavelengths (KrF excimer laser, λ = 248 nm, FWHM = 18 ns and Nd:YAG laser, λ 1  = 532 nm/λ 2  = 1064 nm, FWHM = 6 ns) and at various fluences. FTIR and Raman spectra showed that the chemical compositions of the drugs had not changed during ablation at 532 nm and 1064 nm laser wavelengths. The size distribution of the ablated products was established using two types of particle size analyzers (SMPS and OPC) having complementary measuring ranges. The mean size of the drug crystallites decreased from the initial 30-80 µm to the submicron to nanometer range. For a better understanding of the ablation mechanism we made several investigations (SEM, Ellipsometry, Fast photography) and some model calculations. We have established that PLA offers a chemical-free and simple method for the size reduction of poorly water-soluble drugs and a possible new way for pharmaceutical drug preformulation for nasal administration.

Substandard and/or falsified medicines are a growing global threat for health and they cause serious social and economic damage. In low- and middle-income countries the failure rate of these medical products is approximately 10.5%. 50% of medicines purchased over the Internet may be fake. According to Directive 2011/62/EU as regards the prevention of falsified medicines from entering into the legal supply chain, a unique identification should be put on each box of drugs in the EU from 9th February 2019. The current project is focusing on the development of a laser technology to mark an individual traceable code on the surface of the tablet. Usually, coatings contain titanium dioxide for sufficient coverage, which makes precision laser coding more difficult. New naturally coloured films do not include those excipients. In this research, we would like to compare the physical-chemical properties of conventionally and naturally coloured coatings after the laser marking procedure by using two types of lasers. This unique identification technology can be used for marking personalized medicine with the doses tailored for each patient, too. To sum up, the present findings may contribute to efficient and reliable laser marking solutions in the unique identification procedure. Based on our measurement results, it can be stated that excimer UV lasers are promising candidates as marking instruments for the polymer film in both conventionally and naturally coloured coatings., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The amorphous to crystalline phase transformation of Ge2Sb2Te5 (GST) films by UV nanosecond (ns) and femtosecond (fs) single laser pulse irradiation at the same wavelength is compared. Detailed structural information about the phase transformation is collected by x-ray diffraction and high resolution transmission electron microscopy (TEM). The threshold fluences to induce crystallization are determined for both pulse lengths. A large difference between ns and fs pulse irradiation was found regarding the grain size distribution and morphology of the crystallized films. For fs single pulse irradiated GST thin films, columnar grains with a diameter of 20 to 60 nm were obtained as evidenced by cross-sectional TEM analysis. The local atomic arrangement was investigated by high-resolution Cs-corrected scanning TEM. Neither tetrahedral nor off-octahedral positions of Ge-atoms could be observed in the largely defect-free grains. A high optical reflectivity contrast (~25%) between amorphous and completely crystallized GST films was achieved by fs laser irradiation induced at fluences between 13 and 16 mJ/cm(2) and by ns laser irradiation induced at fluences between 67 and 130 mJ/cm(2). Finally, the fluence dependent increase of the reflectivity is discussed in terms of each photon involved into the crystallization process for ns and fs pulses, respectively.

The newborn pig is a widely accepted large animal model of hypoxic/ischemic (H/I) encephalopathy (HIE) of the term neonate appropriate for translational research. The methodology of the induction of H/I stress shows extensive variability of the literature, and little is known how these affect study outcome. The purpose of the present study was to determine the cerebrocortical microvascular effects of different H/I insults used in current HIE piglet models. For the semiquantitative study of cerebrocortical blood flow, we developed a methodological innovation: an operating microscope was converted into a custom-designed laser-speckle imager. Anesthetized, air-ventilated newborn pigs (n=7) were fitted with a closed cranial window. Speckle image series (2 ms, 1 Hz) were collected during baseline conditions, during transient bilateral carotid artery occlusion (BCAO), hypoxic (FiO(2)=0.1) hypoxia, hypoxia + BCAO, and asphyxia induced by suspending ventilation. Laser-speckle contrast analysis was performed off-line over parenchymal and arteriolar regions of interests, and pial arteriolar diameters were also determined for detailed analysis of cortical perfusion changes. Under normoxic conditions, transient BCAO did not affect parenchymal perfusion or pial arteriolar diameters. Hypoxia induced marked cortical hyperemia in 5 out of 7 piglets, with simultaneous increases in pial arteriolar diameters and arteriolar flow velocity, however, BCAO could not even affect these hypoxia-induced perfusion changes. In contrast to hypoxia or hypoxia + BCAO, asphyxia inevitably led also to severe cerebrocortical ischemia. In summary, acute reversible BCAO does not reduce cerebrocortical blood flow in the piglet, and thus it likely does not exacerbate the effect of hypoxic ventilation. Asphyxia elicits not only severe hypoxia, but also severe brain ischemia. These microcirculatory effects must be taken into consideration when assessing results obtained in the various HIE piglet models.

A new laser speckle-contrast analysis (LASCA) technique based on multi-exposure imaging was employed to simultaneously study pial arteriolar responses with cerebrocortical perfusion changes to various vasodilator (5-10% CO(2) ventilation, bradykinin (1-10 μM), N-methyl-D-aspartate (100 μM)) vasoconstrictor (10-100 μM noradrenaline, 1M KCl), or neutral (2.1% H(2) ventilation) stimuli as well as to asphyxia in the newborn piglet. Anesthetized, ventilated animals (n=20) were fitted with closed cranial windows. Multiple exposure laser-speckle image series (1-100 ms) were obtained using a near infrared diode laser (λ=808 nm). The autocorrelation decay time (τ) of speckle fluctuations was determined over pial arterioles and parenchymal areas to express 1/τ being proportional to blood flow velocity by two different LASCA techniques: our novel multi-exposure or a single exposure (2 and 20 ms) approach. 1/τ values yielded by different LASCA techniques were not significantly different at most points. LASCA easily detected both increases and decreases in cortical blood flow (CoBF). Cortical 1/τ changes to hypercapnia closely matched quantitative CoBF data determined previously, and were also in accordance with increases of pial arteriolar blood flow, calculated from arteriolar flow velocity and cross sectional area changes. In summary, LASCA emerges as an appealing method to simultaneously study microvascular reactivity and cortical perfusion changes in the piglet., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Urease thin films have been immobilized using matrix-assisted pulsed laser evaporation for biosensor applications in clinical diagnostics. The targets exposed to laser radiation were made of frozen composites that had been manufactured by dissolving urease in distilled water. An UV KrF* (lambda = 248 nm, tauFWHM congruent with 30 ns, nu = 10 Hz) excimer source was used for the multipulse laser irradiation of the targets that were cooled down to solidification using Peltier elements. The incident laser fluence was set at 0.4 J/cm2. The surface morphology and chemical bonding states of the laser immobilized urease thin films were investigated by atomic force microscopy and Fourier transform infrared spectroscopy. The enzymatic activity and kinetics of the immobilized urease were assayed by the Worthington method, which monitors urea hydrolysis by coupling ammonia production to a glutamate dehydrogenase reaction. Decreased absorbance was found at 340 nm and correlated with the enzymatic activity of urease., (Copyright 2008 Wiley Periodicals, Inc.)

In laser speckle contrast analysis (LASCA) used for imaging of blood flow, besides the moving blood cells, the speckle pattern is also influenced by the imaging system and scattering properties of the laser-illuminated static surface. A latex microsphere (650 nm size) emulsion was covered with scattering semitransparent materials (Teflon foils, tracing paper). Speckle images were recorded with different exposure times (0.2 ms-500 ms), and correlation times were determined by parameterizing the theoretical contrast-exposure time function. The correlation times obtained for covered and uncovered microsphere emulsions were in good agreement. The possibility of obtaining comparable, setup-independent results in blood perfusion monitoring can contribute to better applicability of LASCA.

The survival, proliferation, and differentiation of freshly isolated and cultured cells were studied after absorbing film-assisted laser-induced forward transfer. Rat Schwann and astroglial cells and pig lens epithelial cells were used for transfer and the cells were cultured for 2 weeks after laser-pulsed transfer. All three cell types survived, proliferated, and differentiated under cell culture conditions and regained their original phenotype a few days after cell transfer. Time resolution studies have shown that the time required to accelerate the jets and droplets containing the cells was less than 1 micros and that the estimated minimum average acceleration of those ejected cells that reached a constant velocity was approximately 10(7) x g. This suggests that the majority of studied cells tolerated the extremely high acceleration at the beginning of the ejection and the deceleration during impact on the acceptor plate without significant damage to the original phenotype. These results suggest that the absorbing film-assisted laser-induced forward transfer technique appears to be suitable for several potential applications in tissue engineering and the biomedical tissue repair technologies.