Ultrashort lasers are typically utilized for tissue dissection by sequential application of tightly focused beam along a
scanning pattern. Each pulse creates a small (on the order of 1μm) zone of multiphoton ionization (optical breakdown).
At energies exceeding vaporization threshold cavitation bubble is formed around the focal volume. A continuous cut is
formed if the rupture zones produced by separate bubbles coalesce. We present an alternative approach, in which an
extended zone of tissue is cut by simultaneous application of laser energy in multiple foci. Simultaneous formation of
multiple cavitation bubbles results in hydrodynamic interactions that can lead to significant extension of the rupture zone
in tissue. Two simultaneously expanding bubbles compress and strain material between them, while simultaneously
collapsing bubbles can produce jets towards each other.
We calculated and experimentally imaged the flow dynamics of expanding and collapsing bubbles and obtained maps of
tissue deformation. With the measured tissue threshold strain, the deformation map allows predicting the rupture zone as
a function of maximum bubble size and distance between the bubbles.
We also demonstrate an optical system producing 1 mm long dissection with a single laser pulse. A combination of a
lens and an axicon produces a line of optical breakdown, with aspect ratio 250:1. The subsequent cavitation bubble has
aspect ratio 100:1 at early stage of expansion. We calculated an optimal laser beam intensity profile to create axiallyuniform
elongated ionization pattern.
Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulation time, increasing local concentration and reducing off-target effects. Controlled release from these formulations would increase their utility, and hyperthermia has been explored as a stimulus for targeted delivery of encapsulated drugs. Use of lasers as a thermal source could provide improved control over the release of the drug from the liposomes with minimal collateral tissue damage. Appropriate methods for assessing local release after systemic delivery would aid in testing and development of better formulations. We use in vivo bioluminescence imaging to investigate the spatiotemporal distribution of luciferin, used as a model small molecule, and demonstrate laser-induced release from liposomes in animal models after systemic delivery. These liposomes were tested for luciferin release between 37 and 45 °C in PBS and serum using bioluminescence measurements. In vivo studies were performed on transgenic reporter mice that express luciferase constitutively throughout the body, thus providing a noninvasive readout for controlled release following systemic delivery. An Nd:YLF laser was used (527 nm) to heat tissues and induce rupture of the intravenously delivered liposomes in target tissues. These data demonstrate laser-mediated control of small molecule delivery using thermally sensitive liposomal formulations.
We discuss the requirements for laser systems used in Coherent Anti-Stokes Raman Scattering (CARS) microscopy and
particularly in its wide-field modification. While such laser parameters as wavelength, spectral width and frequency
difference between pump and Stokes beams are similar for all CARS systems, requirements for pulse energy, repetition
rate, pulse length and mode structure might be significantly different for scanning and wide-field approaches. We will
present results obtained with a wide-field CARS microscope with non-phase matching illumination and compare its
performance with other CARS microscopes. Objectives for the design of future laser systems for CARS microscopy will
be outlined.
Induction of heat shock protein (Hsp) expression appears to correlate with a cytoprotective effect in cultured cells and with improved healing of damaged tissues in animal models and in humans. This family of proteins can also serve as indicators of thermal stress in cases of burn injury or surgical procedures that produce heat. Thus, a rapid in vivo readout for induction of Hsp transcription would facilitate studies of Hsp genes and their encoded proteins as mediators of therapeutic effects and as reporters of thermal damage to tissues. We created a transgenic reporter mouse where expression of luciferase is controlled by the regulatory region of the inducible 70 kDa Hsp, and assessed activation of Hsp70 transcription in live animals in response to rapid, high temperature stresses using in vivo bioluminescence imaging (BLI). This model can be used to noninvasively reveal levels of Hsp70 transcription in living tissues, and has utility in studies of the predictive and protective effects of Hsp70 expression, and of various stress responses in tissues.
We report a wide-field Coherent Anti-Stokes Raman Scattering (CARS) microscopy technique based on non-phasematching
illumination and imaging systems. This technique is based on a non-collinear sample illumination by broad
laser beams and recording image of sample at anti-Stokes wavelength using full-frame image detector. An amplified
Ti:Sapphire laser and an Optical Parametric Amplifier (OPA) provided picosecond pump and Stokes beams with
energies sufficient for CARS generation in an area of 100 μm in diameter. The whole field of view of the microscope
was illuminated simultaneously by the pump and Stokes beams, and CARS signal was recorded onto a cooled CCD,
with resolution determined by the microscope objective. Several illumination schemes and several types of thin sample
preparations have been explored. We demonstrated that CARS image of a 100x100 μm sample can be recorded with
submicrometer spatial resolution using just a few laser pulses of microJoule energies.
The goal of this study was to investigate a Q-switched Er:YAG pumped ZGP crystal Optical Parametric Oscillator (OPO) as a potential alternative source to the Mark-III Free Electron Laser (FEL) for delivering 6.45 micron light for clinical applications. In addition, this research increased the understanding of the role of the unique pulse structure of the FEL with respect to the ablation of soft tissue at 6.45 microns, which has been shown to ablate with very minimal collateral damage (<40 microns).
The OPO operates from 6-8 microns in wavelength with a 100 ns pulse. Up to 250 micro-joules per pulse can be obtained with this laser. This provides up to three times the threshold energy for ablation given a diffraction limited spot of ~60 microns in diameter. The ablation threshold was determined using PROBIT analysis of 100 pulses on water at 6.1 and 6.45 microns in wavelength. The ablated crater depth was also measured on 90% w/w gelatin at both wavelengths for craters made with between 5 and 500 pulses.
The results obtained with the OPO were then compared with a Mark-III FEL with a similar spotsize (~90 microns) to determine if there were any differences due to the unique pulse structure of the FEL, which consists of a 2.85 GHz train of picosecond pulses within a five microsecond envelope. The results showed no difference with respect to the ablation threshold; while the ablated crater depth was reduced for the FEL pulse for equivalent parameters. In addition, bright-field imaging was performed at three times the ablation threshold for both lasers and will be presented.
Many laser therapies involve significant heating of tissue with pulses varying from picoseconds to minutes in duration. In some of the applications heating is a primary goal, while in others it is an undesirable side effect. In both cases, if a hyperthermia is involved, the knowledge about the threshold temperature leading to irreversible cellular damage is critically important. We study the dependence of the threshold temperature on duration of the heat exposure in the range of 0.3 ms to 5 seconds. Thin layer of cells cultured in a Petri dish was exposed to a pulsed CO2 laser radiation. Laser beam was focused onto sample providing Gaussian intensity distribution in the focal plane with a beam diameter (2w) 2-10 mm. Surface temperature in the central part of the focal spot (1mm in diameter) was measured by thermal infrared (IR) emission from the sample, recorded with a fast IR detector. For pulses shorter than 1 s the temperature profile across the focal spot was found to closely correspond to the radial distribution of the laser beam intensity, thus allowing for accurate determination of temperature at any given distance from the center of the spot. Immediate cellular damage was assessed using vital staining with the live/dead fluorescent assay. Threshold temperatures were found to vary from 65 °C at 5 s of heating to 160 °C at pulses of 0.3 ms in duration. The shorter end of this range was limited by vaporization, which occurs during the laser pulse and results in mechanical damage to cells. Dependence of the maximal temperature on pulse duration could be approximated by Arrhenius law with activation energy being about 1 eV.
KEYWORDS: Near field, Image acquisition, Refractive index, Near field optics, Microscopes, Microscopy, Near field scanning optical microscopy, Reflection, Infrared microscopy, Germanium
In this paper we discuss the mechanisms of image formation in the mid-IR of a transmission mode near-field microscope are studied. It is found that the amount of light propagating from a sub-wavelength aperture through a flat substrate strongly increases the tip nears the same. This effect tends to generate topographic artifacts in near-field images that can be eliminated through the use of flat sample preparation techniques. The transmitted power is strongly influenced by the refractive index of the sample, leading to a substantial difference between a near-field and a far- field spectrum. A phenomenological model, which makes predictions in good agreement with experiment, describing tunneling of light through a sub-wavelength aperture into a substrate is developed. The model predicts spectral sensitivity enhancement with decreasing aperture size.
We report the experimental results on production of multilayer soft x-ray and EUV mirrors and their application in x-ray spectroscopy and fluorescence analysis, as well as for development of EUV lithographic and x-ray microscopic devices and soft x-ray point sources. The problem of the production and the investigation of short-period x-ray multilayers and multilayer (gamma) -filters is discussed.
A novel method of filtering out atoms and small particulates, emitted from a laser plasma EUV radiation source, has been developed and experimentally characterized. The method consists of elimination of debris species by an optically transparent assembly of foils positioned in a buffer gas environment near the source. A high trapping efficiency is achieved due to retardation and scattering of particles in the gas and subsequent deposition on the foils. The method imposes no limitations of the radiation acceptance angle. The foil trap technique, a debris suppression method universally applicable for different EUVL radiation sources, has been investigated in combination with a fast rotating laser plasma target. A target unit with a disk edge velocity of up to 500 m/s enabling nearly full elimination of large particulates, served as a source of different debris components for experiments on foil trapping atoms and sub-micron particulates. An integrated suppression coefficient of 500 has been measured for debris with sizes of up to a micrometer using a pilot trap cooled down to -90 degrees C. Extrapolation of this data to conditions when debris of sub-micron size only is produced, resulted in a suppression coefficient of 2000.
Results on laser plasma EUV characteristics for various target materials and irradiation conditions are presented. Spectra of high-Z elements in the 12.5-15.4 nm range from plasmas generated with a high-power KrF laser at 2 X 1012 W/cm2 were measured. The highest conversion efficiency (CE) of 0.85% in 2% BW was found for Re near 13.6 nm, corresponding to a maximal EUV power of 550 mW in 2% BW at 50 Hz. The use of two successive laser pulses, investigated with 2.5 ns pulses of 0.53 micrometers radiation at (0.5-1) X 1013, resulted in an increase of the CE by a factor of 1.8-2.3 for the second pulse at specific delay values (6 and 12 ns for W). The total CE gain amounted to 1.4-2. The first demonstration of an alternative concept of a laser plasma raget for EUVL was performed, based on the usage of a centrufugal force for elimination of particluates. The principle of the approach is generation of laser plasmas at the edge of a fastly-rotating disc. The effect of re- direction of particulates was observed in experiments with a (phi) 50 mm Ta disc at 36.000 rpm at laser power densitites between 109 and 1011 W/cm2.
Absolute calibrated multichannel devices based on plane and spherical multilayer mirrors and transparent filters have been used for spectral investigation of high-temperature plasma in a soft X-ray range. Possibility of optimization of the multilayers and filters to obtain maximum values of the channel transmittance and contrast are discussed.
Deposition possibility of the small d-spacing (d approximately 1 - 2 nm) multilayers on the basis of the material combinations W/Sb, W/B4C, Cr/Sb, Cr/Sc, Fe/Sc, and their utilization as dispersive and focusing elements for the photon energy range E > 0.3 keV have been investigated. The employment of the normal incidence spherical multilayers W/Sb and Cr(Fe)/Sc for imaging of a high-temperature laser-produced plasma within the `water window' spectral range (0.3 < E < 0.5 keV) are presented.
In this work a further investigation of characteristics of the LPP-MLM combination at (lambda) approximately equals 48 angstrom has been performed. A system, consisting of the LPP source generated by Nd-glass laser ((lambda) equals 0.53 micrometers ) and a focusing MLM, was evaluated from the standpoint of reaching the highest power density of the focused SXR radiation. A dependence of the conversion coefficient for the laser-SXR energy transformation was studied, with spatial and time parameters of the source determined for low-Z and high-Z targets.
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