C. Tom A. Brown

Monte Carlo modeling of in vivo protoporphyrin IX fluorescence and singlet oxygen production during photodynamic therapy for patients presenting with superficial basal cell carcinomas

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/cm(2). Results from our MC simulations suggest that an increase from our typical administered treatment light dose of 75-150 J/cm(2) 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.

A quantitative comparison of 5-aminolaevulinic acid- and methyl aminolevulinate-induced fluorescence, photobleaching and pain during photodynamic therapy.

The characteristics of protoporphyrin IX (PPIX) fluorescence in superficial basal cell carcinoma (sBCC) and carcinoma in situ (Bowen’s Disease, BD) following application of 5‐aminolaevulinic acid (5‐ALA) and its methyl ester (methyl aminolevulinate [MAL]) before, during and after photodynamic therapy (PDT) were investigated in 40 patients. Photosensitizer prodrug penetration can limit PDT efficacy and understanding the characteristics of PPIX fluorescence through fluorescence spectroscopy, may improve knowledge of photosensitizer delivery. Fluorescence intensity was assessed quantitatively, and the rate of photobleaching was determined by fitting an exponential decay. As a secondary end‐point, PDT‐induced pain was also measured continuously during treatment using a novel hand‐held device, known as a pain logger. In vivo PPIX fluorescence was shown to decrease during irradiation, allowing the in vivo photobleaching of PPIX to be monitored. No significant difference was found between ALA‐ or MAL‐induced PPIX fluorescence in lesions of sBCC and BD (P > 0.05), indicating no detectable difference in PPIX kinetics for the two prodrugs as assessed by these measures. Pain, as assessed by the logger device, showed high interindividual variability and pain levels tended to be higher initially, decreasing during treatment. No difference was seen in pain experienced during ALA‐or MAL‐PDT (P > 0.05).

Suppression of amplitude-to-phase noise conversion in balanced optical-microwave phase detectors

We demonstrate an amplitude-to-phase (AM-PM) conversion coefficient for a balanced optical-microwave phase detector (BOM-PD) of 0.001 rad, corresponding to AM-PM induced phase noise 60 dB below the single-sideband relative intensity noise of the laser. This enables us to generate 8 GHz microwave signals from a commercial Er-fibre comb with a single-sideband residual phase noise of -131 dBc Hz(-1) at 1 Hz offset frequency and -148 dBc Hz(-1) at 1 kHz offset frequency.

Ultrafast High-Repetition-Rate Waveguide Lasers

We report on progress in the field of integrated mode-locked waveguide lasers with an emphasis on compact monolithic designs producing picosecond and femtosecond optical pulses at multi-GHz repetition rates.

Caged AG10: new tools for spatially predefined mitochondrial uncoupling

The study of mitochondria and mitochondrial Ca2+ signalling in localised regions is hampered by the lack of tools that can uncouple the mitochondrial membrane potential (DeltaPsi(m)) in a spatially predefined manner. Although there are a number of existing mitochondrial uncouplers, these compounds are necessarily membrane permeant and therefore exert their actions in a spatially unselective manner. Herein, we report the synthesis of the first caged (photolabile protected) mitochondrial uncouplers, based on the tyrphostin AG10. We have analysed the laser photolysis of these compounds, using (1)H NMR and HPLC, and demonstrate that the major product of caged AG10 photolysis is AG10. It is shown that photolysis within single smooth muscle cells causes a collapse of DeltaPsi(m) consistent with photorelease of AG10. Furthermore, the effect of the photoreleased AG10 is localised to a subcellular region proximal to the site of photolysis, demonstrating for the first time spatially predefined mitochondrial uncoupling.

Broad tunability from a compact, low-threshold Cr: LiSAF laser incorporating an improved birefringent filter and multiple-cavity Gires-Tournois interferometer mirrors

We demonstrate prismless tuning of a compact femtosecond Cr:LiSAF laser. The employed technique, which uses a specially designed birefringent filter in combination with dispersion compensation from a pair of multiple-cavity Gires-Tournois interferometer mirrors, provides tuning over 20 nm. We give the results of theoretical modeling of the tuning velocity and the spectral width of the central passband. We show, both experimentally and theoretically, that a single birefringent plate can be used to control the oscillating bandwidth of the laser. The effect this has on the output-pulse duration has also been investigated.

3D Monte Carlo radiation transfer modelling of photodynamic therapy

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.

Problem-based labs and group projects in an introductory university physics course

This article describes problem-based labs and analytical and computational project work we have been running at the University of St Andrews in an introductory physics course since 2008/2009. We have found the choice of topics, scaffolding of the process, timing in the year and facilitator guidance decisive for the success of these activities. Instructors can email the corresponding author to obtain the problem texts and instructor resources for all the activities described here.

A novel light source with tuneable uniformity of light distribution for artificial daylight photodynamic therapy

OBJECTIVES Implementation of daylight photodynamic therapy (dPDT) is somewhat limited by variable weather conditions. Light sources have been employed to provide artificial dPDT indoors, with low irradiances and comparable treatment times to dPDT. Uniform light distribution across the target area is desirable in effective treatment planning, particularly for large areas. A novel light source is developed with tuneable direction of light emission in order to meet this challenge. METHODS Wavelength composition of the novel light source is controlled such that the protoporphyrin-IX (PpIX) weighted spectra of both the light source and daylight match. The uniformity of the light distribution is characterised on a flat surface, a model head and a model leg. For context, a typical conventional PDT light source is also characterised. Additionally, the wavelength uniformity across the treatment site is characterised. RESULTS The PpIX-weighted spectrum of the novel light source matches the PpIX-weighted daylight spectrum, with irradiance values within the bounds for effective dPDT. By tuning the direction of light emission, improvements are seen in the uniformity across large anatomical surfaces. Wavelength uniformity is discussed. CONCLUSIONS We have developed a light source that addresses the challenges in uniform, multiwavelength light distribution for large area artificial dPDT across curved anatomical surfaces.

A Quantitative Study of In Vivo Protoporphyrin IX Fluorescence Build Up During Occlusive Treatment Phases

BACKGROUND Topical photodynamic therapy (PDT) is a non-invasive light based therapy used to treat non-melanoma skin cancer (NMSC) and dysplasia. During PDT, the light sensitive molecule protoporphyrin IX (PpIX) is activated, resulting in the production of singlet oxygen, which subsequently leads to cell death. PpIX is metabolised from a topically applied pro-drug and the strong fluorescence signal associated with PpIX can be utilised as an indicator of the amount of PpIX present within the tumour tissue. In this work we measure the build up PpIX during the occlusive treatment phase and investigate how the PpIX production rate is affected by different lesion and patient characteristics. METHODS Fluorescence measurements were used to investigate the build up of PpIX within the tumour tissue during the 3h long occlusive treatment prior to irradiation. The study included in vivo measurements of 38 lesions from 38 individual patients. Actinic keratosis (AK) and basal cell carcinoma (BCC) were the lesion types included in this study. The resulting data from the study was analysed using generalised linear mixed effects models. RESULTS It was found that the surface fluorescence signal linearly increased with occlusive treatment time. The predictive models suggest that there is a significant difference in PpIX production between lesion location, however no significant difference is demonstrated between different lesion types, gender and skin type. CONCLUSIONS The study extends and supports previous knowledge of PpIX production during the occlusive treatment phase.