Efficiency of direct photoinduced generation of singlet oxygen at different wavelengths, power density and exposure time of laser irradiation.

This work investigates the influence of laser irradiation parameters (wavelength, power density and exposure time) on singlet oxygen (1O2) generation efficiency. Chemical trap (L-histidine) and fluorescent probe (Singlet Oxygen Sensor Green, SOSG) detection methods were used. Studies have been conducted for 1267, 1244, 1122 and 1064 nm laser wavelengths. 1267 nm had the highest efficiency of 1O2 generation, but 1064 nm demonstrated almost the same efficiency. We also observed that the 1244 nm wavelength can generate some amount of 1O2. It was demonstrated that laser exposure time can generate 1O2 more efficiently than an increase of power. Additionally, the SOSG fluorescence intensity measurements method for acute brain slices was studied. This allowed us to evaluate the approach's potential for in vivo detection of 1O2 concentrations.

Mechanisms of Photostimulation of Brain's Waste Disposal System: The Role of Singlet Oxygen.

There is strong evidence that augmentation of the brain's waste disposal system via stimulation of the meningeal lymphatics might be a promising therapeutic target for preventing neurological diseases. In our previous studies, we demonstrated activation of the brain's waste disposal system using transcranial photostimulation (PS) with a laser 1267 nm, which stimulates the direct generation of singlet oxygen in the brain tissues. Here we investigate the mechanisms underlying this phenomenon. Our results clearly demonstrate that PS-mediated stimulation of the brain's waste disposal system is accompanied by activation of lymphatic contractility associated with subsequent intracellular production of the reactive oxygen species and the nitric oxide underlying lymphatic relaxation. Thus, PS stimulates the brain's waste disposal system by influencing the mechanisms of regulation of lymphatic pumping.

Brillouin Interaction between Two Optical Modes Selectively Excited in Weakly Guiding Multimode Optical Fibers.

A multimode optical fiber supports excitation and propagation of a pure single optical mode, i.e., the field pattern that satisfies the boundary conditions and does not change along the fiber. When two counterpropagating pure optical modes are excited, they could interact through the stimulated Brillouin scattering (SBS) process. Here, we present a simple theoretical formalism describing SBS interaction between two individual optical modes selectively excited in an acoustically isotropic multimode optical fiber. Employing a weakly guiding step-index fiber approach, we have built an analytical expression for the spatial distribution of the sound field amplitude in the fiber core and explored the features of SBS gain spectra, describing the interaction between modes of different orders. In this way, we give a clear insight into the sound propagation effects accompanying SBS in multimode optical fibers, and demonstrate their specific contributions to the SBS gain spectrum.

Transcranial Photosensitizer-Free Laser Treatment of Glioblastoma in Rat Brain.

Over sixty years, laser technologies have undergone a technological revolution and become one of the main tools in biomedicine, particularly in neuroscience, neurodegenerative diseases and brain tumors. Glioblastoma is the most lethal form of brain cancer, with very limited treatment options and a poor prognosis. In this study on rats, we demonstrate that glioblastoma (GBM) growth can be suppressed by photosensitizer-free laser treatment (PS-free-LT) using a quantum-dot-based 1267 nm laser diode. This wavelength, highly absorbed by oxygen, is capable of turning triplet oxygen to singlet form. Applying 1267 nm laser irradiation for a 4 week course with a total dose of 12.7 kJ/cm2 firmly suppresses GBM growth and increases survival rate from 34% to 64%, presumably via LT-activated apoptosis, inhibition of the proliferation of tumor cells, a reduction in intracranial pressure and stimulation of the lymphatic drainage and clearing functions. PS-free-LT is a promising breakthrough technology in non- or minimally invasive therapy for superficial GBMs in infants as well as in adult patients with high photosensitivity or an allergic reaction to PSs.

Simulation of thermal field distribution in biological tissue and cell culture media irradiated with infrared wavelengths.

In recent years, there has been a growing interest in the singlet form of oxygen as a regulator of the physiological functions of cells. One of the ways to generate singlet oxygen is direct optical excitation of the triplet oxygen form. Since molecular oxygen weakly absorbs light, high power is required to obtain sufficient concentrations of singlet oxygen. However, the increase in the radiation power of laser can induce a local temperature increase around the laser spot. This may be critical considering the temperature governs every biological reaction within living cells, in particular. Here, the interaction of laser radiation of infrared wavelengths, generating singlet oxygen, with biological tissues and cell culture media was simulated. Using the COMSOL Multiphysics software, the thermal field distribution in the volume of skin, brain tissue and cell culture media was obtained depending on the wavelength, power and exposure time. The results demonstrate the importance of taking temperature into account when conducting experimental studies at the cellular and organismal levels.

Photomodulation of Lymphatic Delivery of Bevacizumab to the Brain: The Role of Singlet Oxygen.

The blood-brain barrier (BBB) poses a significant challenge for drug delivery to the brain. Therefore, the development of safe methods for an effective delivery of medications to the brain can be a revolutionary step in overcoming this limitation. Using a quantum-dot-based 1267 nm laser (photosensitiser-free generation of singlet oxygen), we clearly show the photostimulation of lymphatic delivery of bevacizumab (BMZ) to the brain tissues and the meninges. These pilot findings open promising perspectives for photomodulation of a lymphatic brain drug delivery bypassing the BBB, and potentially enabling a breakthrough strategy in therapy of glioma using BMZ and other chemotherapy drugs.

Two-photon conversion of a bacterial phytochrome.

In nature, sensory photoreceptors underlie diverse spatiotemporally precise and generally reversible biological responses to light. Photoreceptors also serve as genetically encoded agents in optogenetics to control by light organismal state and behavior. Phytochromes represent a superfamily of photoreceptors that transition between states absorbing red light (Pr) and far-red light (Pfr), thus expanding the spectral range of optogenetics to the near-infrared range. Although light of these colors exhibits superior penetration of soft tissue, the transmission through bone and skull is poor. To overcome this fundamental challenge, we explore the activation of a bacterial phytochrome by a femtosecond laser emitting in the 1 µm wavelength range. Quantum chemical calculations predict that bacterial phytochromes possess substantial two-photon absorption cross sections. In line with this notion, we demonstrate that the photoreversible Pr ↔ Pfr conversion is driven by two-photon absorption at wavelengths between 1170 and 1450 nm. The Pfr yield was highest for wavelengths between 1170 and 1280 nm and rapidly plummeted beyond 1300 nm. By combining two-photon activation with bacterial phytochromes, we lay the foundation for enhanced spatial resolution in optogenetics and unprecedented penetration through bone, skull, and soft tissue.

Pulse dynamics in SESAM-free electrically pumped VECSEL.

Self-starting pulsed operation in an electrically pumped (EP) vertical-external-cavity surface-emitting-laser (VECSEL) without intracavity saturable absorber is demonstrated. A linear hemispherical cavity design, consisting of the EP-VECSEL chip and a 10% output-coupler, is used to obtain picosecond output pulses with energies of 2.8 pJ and pulse widths of 130 ps at a repetition rate of 1.97 GHz. A complete experimental analysis of the generated output pulse train and of the transition from continuous-wave to pulsed operation is presented. Numerical simulations based on a delay-differential-equation (DDE) model of mode-locked semiconductor lasers are used to reproduce the pulse dynamics and identify different laser operation regimes. From this, the measured single pulse operation is attributed to FM-type mode-locking. The pulse formation is explained by strong amplitude-phase coupling and spectral filtering inside the EP-VECSEL.

Femtosecond Alexandrite laser passively mode-locked by an InP/InGaP quantum-dot saturable absorber.

An Alexandrite laser passively mode-locked using an InP/InGaP quantum-dot semiconductor saturable absorber mirror (QD-SESAM) was demonstrated. The laser was pumped at 532 nm and generated pulses as short as 380 fs at 775 nm with an average output power of 295 mW. To the best of our knowledge, this is the first report on a passively mode-locked femtosecond Alexandrite laser using a SESAM in general and a QD-SESAM in particular.

Tunable single- and dual-wavelength SHG from diode-pumped PPKTP waveguides.

A compact, all-room-temperature, widely tunable, continuous wave laser source in the green spectral region (502.1-544.2 nm) with a maximum output power of 14.7 mW is demonstrated. This was made possible by utilizing second-harmonic generation (SHG) in a periodically poled potassium titanyl phosphate (PPKTP) crystal waveguide pumped by a quantum-well external-cavity fiber-coupled diode laser and exploiting the multimode-matching approach in nonlinear crystal waveguides. The dual-wavelength SHG in the wavelength region between 505.4 and 537.7 nm (with a wavelength difference ranging from 1.8 to 32.3 nm) and sum-frequency generation in a PPKTP waveguide is also demonstrated.

Picosecond pulse amplification up to a peak power of 42 W by a quantum-dot tapered optical amplifier and a mode-locked laser emitting at 1.26 µm.

We experimentally study the generation and amplification of stable picosecond-short optical pulses by a master oscillator power-amplifier configuration consisting of a monolithic quantum-dot-based gain-guided tapered laser and amplifier emitting at 1.26 µm without pulse compression, external cavity, gain- or Q-switched operation. We report a peak power of 42 W and a figure-of-merit for second-order nonlinear imaging of 38.5 W2 at a repetition rate of 16 GHz and an associated pulse width of 1.37 ps.

Efficient yellow-green light generation at 561 nm by frequency-doubling of a QD-FBG laser diode in a PPLN waveguide.

A compact high-power yellow-green continuous wave (CW) laser source based on second-harmonic generation (SHG) in a 5% MgO doped periodically poled congruent lithium niobate (PPLN) waveguide crystal pumped by a quantum-dot fiber Bragg grating (QD-FBG) laser diode is demonstrated. A frequency-doubled power of 90.11 mW at the wavelength of 560.68 nm with a conversion efficiency of 52.4% is reported. To the best of our knowledge, this represents the highest output power and conversion efficiency achieved to date in this spectral region from a diode-pumped PPLN waveguide crystal, which could prove extremely valuable for the deployment of such a source in a wide range of biomedical applications.

Self-mode-locked quantum-dot vertical-external-cavity surface-emitting laser.

We present the first self-mode-locked optically pumped quantum-dot semiconductor disk laser. Our mode-locked device emits sub-picosecond pulses at a wavelength of 1040 nm and features a record peak power of 460 W at a repetition rate of 1.5 GHz. In this work, we also investigate the temperature dependence of the pulse duration as well as the time-bandwidth product for stable mode locking.

Wireless Dynamic Light Scattering Sensors Detect Microvascular Changes Associated With Ageing and Diabetes.

This article presents clinical results of wireless portable dynamic light scattering sensors that implement laser Doppler flowmetry signal processing. It has been verified that the technology can detect microvascular changes associated with diabetes and ageing in volunteers. Studies were conducted primarily on wrist skin. Wavelet continuous spectrum calculation was used to analyse the obtained time series of blood perfusion recordings with respect to the main physiological frequency ranges of vasomotions. In patients with type 2 diabetes, the area under the continuous wavelet spectrum in the endothelial, neurogenic, myogenic, and cardio frequency ranges showed significant diagnostic value for the identification of microvascular changes. Aside from spectral analysis, autocorrelation parameters were also calculated for microcirculatory blood flow oscillations. The groups of elderly volunteers and patients with type 2 diabetes, in comparison with the control group of younger healthy volunteers, showed a statistically significant decrease of the normalised autocorrelation function in time scales up to 10 s. A set of identified parameters was used to test machine learning algorithms to classify the studied groups of young controls, elderly controls, and diabetic patients. Our conclusion describes and discusses the classification metrics that were found to be most effective.

Low-Level Laser Treatment Induces the Blood-Brain Barrier Opening and the Brain Drainage System Activation: Delivery of Liposomes into Mouse Glioblastoma.

The progress in brain diseases treatment is limited by the blood-brain barrier (BBB), which prevents delivery of the vast majority of drugs from the blood into the brain. In this study, we discover unknown phenomenon of opening of the BBBB (BBBO) by low-level laser treatment (LLLT, 1268 nm) in the mouse cortex. LLLT-BBBO is accompanied by activation of the brain drainage system contributing effective delivery of liposomes into glioblastoma (GBM). The LLLT induces the generation of singlet oxygen without photosensitizers (PSs) in the blood endothelial cells and astrocytes, which can be a trigger mechanism of BBBO. LLLT-BBBO causes activation of the ABC-transport system with a temporal decrease in the expression of tight junction proteins. The BBB recovery is accompanied by activation of neuronal metabolic activity and stabilization of the BBB permeability. LLLT-BBBO can be used as a new opportunity of interstitial PS-free photodynamic therapy (PDT) for modulation of brain tumor immunity and improvement of immuno-therapy for GBM in infants in whom PDT with PSs, radio- and chemotherapy are strongly limited, as well as in adults with a high allergic reaction to PSs.

P-i-n junction quantum dot saturable absorber mirror: electrical control of ultrafast dynamics.

We report on nonlinear optical properties of a p-i-n junction quantum dot saturable absorber based on InGaAs/GaAs. Absorption recovery dynamics and nonlinear reflectivity are investigated for different reverse bias and pump power conditions. A decrease in absorption recovery time of nearly two orders of magnitude is demonstrated by applying a voltage between 0 and -20 V. The saturable absorber modulation depth and saturation fluence are found to be independent from the applied reverse bias.

Intranasal Delivery of Liposomes to Glioblastoma by Photostimulation of the Lymphatic System.

The blood-brain barrier (BBB) limits the delivery of majority of cancer drugs and thereby complicates brain tumor treatment. The nasal-brain-lymphatic system is discussed as a pathway for brain drug delivery overcoming the BBB. However, in most cases, this method is not sufficient to achieve a therapeutic effect due to brain drug delivery in a short distance. Therefore, it is necessary to develop technologies to overcome the obstacles facing nose-to-brain delivery of promising pharmaceuticals. In this study, we clearly demonstrate intranasal delivery of liposomes to the mouse brain reaching glioblastoma (GBM). In the experiments with ablation of the meningeal lymphatic network, we report an important role of meningeal pathway for intranasal delivery of liposomes to the brain. Our data revealed that GBM is characterized by a dramatic reduction of intranasal delivery of liposomes to the brain that was significantly improved by near-infrared (1267 nm) photostimulation of the lymphatic vessels in the area of the cribriform plate and the meninges. These results open new perspectives for non-invasive improvement of efficiency of intranasal delivery of cancer drugs to the brain tissues using nanocarriers and near-infrared laser-based therapeutic devices, which are commercially available and widely used in clinical practice.

Fiber coupling to BaTiO3 glass microspheres in an aqueous environment.

Compact microspheres with high-quality (Q) whispering gallery modes are required for many applications involving liquid immersion, such as sensing nanoparticles and studying resonant radiative pressure effects. We show that high-index (1.9 and 2.1) barium titanate glass (BTG) microspheres are perfect candidates for these applications due to their high-Q (∼10(4) in the 1100-1600 nm range) resonances evanescently excited in spheres with diameters of 4-15 µm. By reattaching the spheres at different positions along a tapered optical fiber, we show that the coupling constant exponentially increases with thinner fiber diameters. We demonstrate the close to critical coupling regime with intrinsic Q=3×10(4) for water immersed 14 µm BTG spheres.

Singlet oxygen stimulates mitochondrial bioenergetics in brain cells.

Oxygen, in form of reactive oxygen species (ROS), has been shown to participate in oxidative stress, one of the major triggers for pathology, but also is a main contributor to physiological processes. Recently, it was found that 1267 nm irradiation can produce singlet oxygen without photosensitizers. We used this phenomenon to study the effect of laser-generated singlet oxygen on one of the major oxygen-dependent processes, mitochondrial energy metabolism. We have found that laser-induced generation of 1O2 in neurons and astrocytes led to the increase of mitochondrial membrane potential, activation of NADH- and FADH-dependent respiration, and importantly, increased the rate of maximal respiration in isolated mitochondria. The activation of mitochondrial respiration stimulated production of ATP in these cells. Thus, we found that the singlet oxygen generated by 1267 nm laser pulse works as an activator of mitochondrial respiration and ATP production in the brain.

Conical refraction Nd:KGd(WO4)2 laser.

In 1832 Hamilton predicted conical refraction, concluding that if a beam propagates along an optic axis of a biaxial crystal, a hollow cone of light will emerge. Nearly two centuries on, cascade conical refraction involving multiple crystals has not been investigated. We empirically investigate a unique two-crystal configuration, and use this to demonstrate an ultra-efficient conical refraction Nd:KGd(WO(4))(2) laser providing multi-watt output with excellent beam quality independent of resonator design with a slope efficiency close to the theoretical maximum, offering a new route for power and brightness-scaling in solid-state bulk lasers.