SignificanceGlioblastoma (GBM) is a rare but deadly form of brain tumor with a low median survival rate of 14.6 months, due to its resistance to treatment. An independent simulation of the INtraoperative photoDYnamic therapy for GliOblastoma (INDYGO) trial, a clinical trial aiming to treat the GBM resection cavity with photodynamic therapy (PDT) via a laser coupled balloon device, is demonstrated.AimTo develop a framework providing increased understanding for the PDT treatment, its parameters, and their impact on the clinical outcome.ApproachWe use Monte Carlo radiative transport techniques within a computational brain model containing a GBM to simulate light path and PDT effects. Treatment parameters (laser power, photosensitizer concentration, and irradiation time) are considered, as well as PDT’s impact on brain tissue temperature.ResultsThe simulation suggests that 39% of post-resection GBM cells are killed at the end of treatment when using the standard INDYGO trial protocol (light fluence = 200 J/cm2 at balloon wall) and assuming an initial photosensitizer concentration of 5 μM. Increases in treatment time and light power (light fluence = 400 J/cm2 at balloon wall) result in further cell kill but increase brain cell temperature, which potentially affects treatment safety. Increasing the p hotosensitizer concentration produces the most significant increase in cell kill, with 61% of GBM cells killed when doubling concentration to 10 μM and keeping the treatment time and power the same. According to these simulations, the standard trial protocol is reasonably well optimized with improvements in cell kill difficult to achieve without potentially dangerous increases in temperature. To improve treatment outcome, focus should be placed on improving the photosensitizer.ConclusionsWith further development and optimization, the simulation could have potential clinical benefit and be used to help plan and optimize intraoperative PDT treatment for GBM.
Here we present a platform technology for the direct sintering of calcium phosphates on dental hard tissues using femtosecond lasers. Different parameters are investigated in order to obtain the optimum layers
Significance: Optical microscopy is characterized by the ability to get high resolution, below 1 μm, high contrast, functional and quantitative images. The use of shaped illumination, such as with lightsheet microscopy, has led to greater three-dimensional isotropic resolution with low phototoxicity. However, in most complex samples and tissues, optical imaging is limited by scattering. Many solutions to this issue have been proposed, from using passive approaches such as Bessel beam illumination to active methods incorporating aberration correction, but making fair comparisons between different approaches has proven to be challenging.
Aim: We present a phase-encoded Monte Carlo radiation transfer algorithm (φMC) capable of comparing the merits of different illumination strategies or predicting the performance of an individual approach.
Approach: We show that φMC is capable of modeling interference phenomena such as Gaussian or Bessel beams and compare the model with experiment.
Results: Using this verified model, we show that, for a sample with homogeneously distributed scatterers, there is no inherent advantage to illuminating a sample with a conical wave (Bessel beam) instead of a spherical wave (Gaussian beam), except for maintaining a greater depth of focus.
Conclusion: φMC is adaptable to any illumination geometry, sample property, or beam type (such as fractal or layered scatterer distribution) and as such provides a powerful predictive tool for optical imaging in thick samples.
In this paper we present on-chip mode-locked waveguide lasers fabricated in Yb-doped phosphate glass and Er, Ybdoped phosphate glass. At 1 micron wavelength, pulse repetition rates of up to 15 GHz with pulses ~800 fs were demonstrated and at 1.5 micron, picosecond pulses with a repetition rate up to 7 GHz were demonstrated. Dispersion was controlled in the cavity by varying the spacing between the waveguide and the SESAM, while the repetition rate could be controlled by varying the optical power. The average power can also be scaled using an integrated optical amplifier and on-chip gain of up to 10 dB was demonstrated. All these individual components can be integrated in a single platform to achieve a high-power on-chip multi-GHz optical frequency comb. Furthermore, we discuss an application of such laser sources in high-capacity telecommunications applications.
Photodynamic therapy (PDT) has been theoretically investigated using a Monte Carlo radiation transfer (MCRT)
model. By including complex three dimensional (3D) tumour models a more appropriate representation of the
treatment was achieved. The 3D clustered tumour model was compared to a smooth model, resulting in a
significantly deeper penetration associated with the clustered model. The results from the work presented here
indicates that light might penetrate deeper than suggested by 2D or simple layered models.
The effects of ageing and skin type on Photodynamic Therapy (PDT) for different treatment methods have been theoretically investigated. A multilayered Monte Carlo Radiation Transfer model is presented where both daylight activated PDT and conventional PDT are compared. It was found that light penetrates deeper through older skin with a lighter complexion, which translates into a deeper effective treatment depth. The effect of ageing was found to be larger for darker skin types. The investigation further strengthens the usage of daylight as a potential light source for PDT where effective treatment depths of about 2 mm can be achieved.
In this work, we discuss mode-locking results obtained with low-loss, ion-exchanged waveguide lasers. With Yb3+-doped phosphate glass waveguide lasers, a repetition rate of up to 15.2 GHz was achieved at a wavelength of 1047 nm with an average power of 27 mW and pulse duration of 811 fs. The gap between the waveguide and the SESAM introduced negative group velocity dispersion via the Gires Tournois Interferometer (GTI) effect which allowed the soliton mode-locking of the device. A novel quantum dot SESAM was used to mode-lock Er3+, Yb3+-doped phosphate glass waveguide lasers around 1500 nm. Picosecond pulses were achieved at a maximum repetition rate of 6.8 GHz and an average output power of 30 mW. The repetition rate was tuned by more than 1 MHz by varying the pump power.
The ability to control the temporal output from a femtosecond laser can enable the same laser to be used for multiple
functions, for example, the laser used in an optical tweezers system could be used as a constant-intensity source to trap a
biological cell and then be temporarily switched to mode-locked operation to effect photoporation. Here, we report the
rapid switching of a Cr4+:forsterite laser between mode-locked and unmode-locked continuous wave (CW) regimes via
the optical pumping of an intracavity SESAM element. Mode-locking of the laser was initiated by an intracavity
quantum well (GaInAsN) SESAM having an anti-resonant design (ΔR~0.3%, λPL~1310nm) that yielded transform-limited
89fs pulses centered around 1296nm with a repetition rate of 162MHz at an average power of 64mW. Upon
excitation of the SESAM with 600mW of extra-cavity power from an 808nm semiconductor diode laser, switching could
be induced between the unmode-locked and mode-locked regimes. Transitions free of Q-switching or relaxation
oscillations were observed with <200μs switching times for both for the initiation and cessation of mode-locking.
Periods of mode-locked operation of custom duration could be produced by appropriate control of the SESAM pump
diode enabling the generation of bursts of pulses as short as 400μs. Switching was confirmed to originate from local
pump-induced heating of the SESAM by observing the laser going through identical regime switching when the chip
temperature of the 'unpumped' SESAM was raised by ~20°C.
We present a simple method applicable to common-path Fourier domain optical coherence tomography (OCT) in which the tissue surface is used as the reference arm. We propose using aluminium hydroxide powder as a potential tissue surface diffuser to allow wider application of this method. This technique allows one to avoid placing a reference arm reflective element, such as glass plate, on tissue, and intrinsically avoids both coherent and complex conjugate mirror artifacts associated with glass plates. Aluminium hydroxide can be sprayed onto tissue using spray nozzles commonly found in endoscopes. The sensitivity of the tissue reference arm common-path OCT image is 94 dB for a 50-µs charge-coupled device integration time, and 97.5 dB for a 200-µs CCD integration time.
We present protoporphyrin IX (PpIX) fluorescence measurements acquired from patients presenting with superficial basal cell carcinoma during photodynamic therapy (PDT) treatment, facilitating in vivo photobleaching to be monitored. Monte Carlo (MC) simulations, taking into account photobleaching, are performed on a three-dimensional cube grid, which represents the treatment geometry. Consequently, it is possible to determine the spatial and temporal changes to the origin of collected fluorescence and generated singlet oxygen. From our clinical results, an in vivo photobleaching dose constant, β of 5-aminolaevulinic acid-induced PpIX fluorescence is found to be 14 ± 1 J/cm2. Results from our MC simulations suggest that an increase from our typical administered treatment light dose of 75-150 J/cm2 could increase the effective PDT treatment initially achieved at a depth of 2.7-3.3 mm in the tumor, respectively. Moreover, this increase reduces the surface PpIX fluorescence from 0.00012 to 0.000003 of the maximum value recorded before treatment. The recommendation of administrating a larger light dose, which advocates an increase in the treatment time after surface PpIX fluorescence has diminished, remains valid for different sets of optical properties and therefore should have a beneficial outcome on the total treatment effect.
We report the first use of a Semiconductor Disk Laser (SDL) as a pump source for ~2μm-emitting Tm3+ (,Ho3+)-doped
dielectric lasers. The ~1213nm GaInNAs/GaAs SDL produces >1W of CW output power, a maximum power transfer net
slope efficiency of 18.5%, and a full width half maximum wavelength tuning range of ~24nm. Free-running operation of
a Tm3+-doped tellurite glass laser under 1213nm SDL pumping generated up to 60mW output power with 22.4% slope
efficiency. Wavelength tunable output is also obtained from 1845 to 2043nm. Improved performance with output powers
of ~200mW and a slope efficiency of ~35% are achieved by replacing the Tm3+-doped glass with a Tm3+-doped KYW
active medium. Emission of a Tm3+,Ho3+-codoped tellurite glass laser is also reported with maximum output power of
~12mW and a ~7% slope efficiency. Finally, preliminary investigations of 1213nm-pumping of a Tm3+,Ho3+-codoped
silica fibre laser lead to 36mW output power with ~19.3% slope efficiency.
Efficient DNA delivery into single living cells would be a very powerful capability for cell biologists for elucidating basic cellular functions but also in other fields such as applied drug discovery and gene therapy. The ability to gently permeate the cell membrane and introduce foreign DNA with the assistance of lasers is a powerful methodology but requires exact focusing due to the required two-photon power density. Here, we demonstrate a laser-mediated delivery method of the red fluorescent protein DS-RED into Chinese hamster Ovary (CHO) cells. We used an elongated beam of light created by a Bessel beam (BB) which obviates the need to locate precisely the cell membrane, permitting two-photon excitation along a line leading to cell transfection. Assuming a threshold for transfection of 20%, the BB gives us transfection over twenty times the axial distance compared to the Gaussian beam of equivalent core diameter. In addition, by exploiting the BB property of reconstruction, we demonstrate successful transfection of CHO cells which involves the BB passing through an obstructive layer and re forming itself prior to reaching the cell membrane. In the light of this exciting result, one can envisage the possibility of achieving transfection through multiple cell monolayer planes and tissues using this novel light field, eliminating this way the stringent requirements for tight focusing.
Progress in the development of efficient and reliable diode-pumped ytterbium femtosecond laser systems based on Kerr-lens
mode locking effect is reported. Average output power of up to 1 W is demonstrated in a Kerr-lens mode locked
Yb:YVO4 laser with pulse durations as short as 80 fs at a pulse repetition frequency of 79 MHz. Measurements of the
nonlinear refractive indexes of the Yb3+:YVO4 crystal, n2, were performed and were determined to be 39×10-16 cm2/W
and 49×10-16 cm2/W for E||c and E⊥c polarizations, respectively. These results were found to be in a good agreement
with those calculated using both the Kramers-Krönig relation and Boling, Glass and Owyoung formula.
Keywords: Mode-locked lasers, diode-pumped lasers
1.
Progress in the development of efficient and reliable diode-pumped femtosecond laser systems based on both Kerr-lens
and saturable-absorber mode locking is reported. Efficient Kerr-lens mode locking in diode pumped ytterbium-doped
lasers, namely Yb:KY(WO4)2 (Yb:KYW) and Yb:YVO4, is demonstrated with average output powers in excess of 1W, pulse durations around 100fs and electrical-to-optical efficiencies that exceed 15%. Novel semiconductor saturable
absorbers based on InAs/InGaAs quantum dots are described and their applicability for efficient femtosecond pulse
generation from near-infrared solid-state lasers is discussed. Efficient passive mode locking in the spectral regions
around 1.3&mgr;m and 1.55&mgr;m in Cr:forsterite and the more recently developed Er, Yb:YAl3(BO4)3 crystalline lasers has been demonstrated using low-loss InGaNAs saturable absorbers. A few examples of applications for this category of robust and efficient femtosecond lasers have been included. Specifically, the characteristics of a femtosecond visible
light source producing pulses as short as 200fs at 520nm are outlined.
We demonstrate the use of supercontinuum radiation to provide enhanced guiding distances of microscopic particles
compared to the standard continuous wave or femtosecond lasers. Our technique relies on the chromatic aberration of the
lens used to form an elongated focal region within which guiding takes place. The resulting beam profile has been
modelled and shows that for a Gaussian input beam, the intensity profile after the lens can be considered as a sum of
Gaussians, one for each wavelength but with varying focal position due to dispersion. Our experimental investigations
compare radiation from continuous wave (bandwidth <1nm) and femtosecond pulsed (bandwidth > 100nm) lasers as
well as supercontinuum radiation (bandwidth > 450nm) and show good agreement with theory.
The development of femtosecond (fs) lasers has continued rapidly since the demonstration of fs Ti:Sapphire systems in 1989. Recent research has yielded lasers which offer greatly enhanced performance in all areas. In this document we describe the development of femtosecond lasers with electrical to optical efficiency > 14%, pulse repetition frequencies > 4GHz and compact and stable cavities. We further outline the use of such lasers for the generation of high power visible femtosecond pulses and their application within systems environments for ultrahigh speed data communications, ultrafast optical switching and optical analogue to digital conversion. We also describe progress in the development of femtosecond lasers based on both active and passive semiconductor quantum dot components.
The introduction of naked DNA or other membrane impermeable substances into a cell (transfection) is a ubiquitous
problem in cell biology. This problem is particularly challenging when it is desired to load membrane impermeable
substances into specific cells, as most transfection technologies (such as liposomal transfection) are based on treating a
global population of cells. The technique of optical transfection, using a focused laser to open a small transient hole in
the membrane of a biological cell (photoporation) to load membrane impermeable DNA into it, allows individual cells
to be targeted for transfection, while leaving neighbouring cells unaffected. Unlike other techniques used to perform
single cell transfection, such as microinjection, optical transfection can be performed in an entirely closed system,
thereby maintaining sterility of the sample during treatment. Here, we are investigating the introduction and subsequent
expression of foreign DNA into living mammalian cells by laser-assisted photoporation with a femtosecond-pulsed
titanium sapphire laser at 800 nm, in cells that are adherent.
Optical guiding of microscopic particles in femtosecond and continuous wave Bessel light beams is studied and compared. We confirm that optical guiding is an average power effect and observe no difference in the guiding velocities of non-fluorescing polymer spheres. Furthermore, we observe second harmonic generation of guided KTP crystallites in femtosecond Bessel light beams. This observation opens up the prospect of using multi-photon effects in optical manipulation for applications such as optical identification of guided cells for sorting purposes.
We report a highly efficient diode-pumped femtosecond Yb:KYW laser having a compact three-element resonator that incorporates a prismatic output coupler. Near-transform limited pulses of 107fs duration at a centre wavelength of 1056nm are produced at repetition pulse frequency of 294MHz by utilising soft-aperture Kerr-lens mode locking. The femtosecond operation had a mode-locking threshold at a pump power of 250mW and the laser was tunable from 1042nm to 1075nm. The optical-to-optical conversion efficiency exceeded 50% in this femtosecond-pulse regime.
We demonstrate a highly efficient and low threshold passively mode-locked femtosecond Yb:KYW laser pumped by an InGaAs narrow-stripe laser diode and which incorporates a semiconductor saturable absorber mirror. Near-transform limited pulses of 123fs at 1047nm were produced at an average mode-locked power of 107mW for only 308mW of incident pump power. An optical-to-optical conversion efficiency of 35% was achieved and the corresponding electrical-to-optical efficiency exceeded 14%.
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