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Biomedical subjects

M S Patterson

Publications and source records attributed to M S Patterson.

At least 19 recordsLinked to original sources

Quantification of bioluminescence images of point source objects using diffusion theory models.

A simple approach for estimating the location and power of a bioluminescent point source inside tissue is reported. The strategy consists of using a diffuse reflectance image at the emission wavelength to determine the optical properties of the tissue. Following this, bioluminescence images are modelled using a single point source and the optical properties from the reflectance image, and the depth and power are iteratively adjusted to find the best agreement with the experimental image. The forward models for light propagation are based on the diffusion approximation, with appropriate boundary conditions. The method was tested using Monte Carlo simulations, Intralipid tissue-simulating phantoms and ex vivo chicken muscle. Monte Carlo data showed that depth could be recovered within 6% for depth 4-12 mm, and the corresponding relative source power within 12%. In Intralipid, the depth could be estimated within 8% for depth 4-12 mm, and the relative source power, within 20%. For ex vivo tissue samples, source depths of 4.5 and 10 mm and their relative powers were correctly identified.

Algorithms↗

Singlet oxygen luminescence as an in vivo photodynamic therapy dose metric: validation in normal mouse skin with topical amino-levulinic acid.

Although singlet oxygen ((1)O(2)) has long been proposed as the primary reactive oxygen species in photodynamic therapy (PDT), it has only recently been possible to detect it in biological systems by its luminescence at 1270 nm. Having previously demonstrated this in vitro and in vivo, we showed that cell survival was strongly correlated to the (1)O(2) luminescence in cell suspensions over a wide range of treatment parameters. Here, we extend this to test the hypothesis that the photobiological response in vivo is also correlated with (1)O(2) generation, independent of individual treatment parameters. The normal skin of SKH1-HR hairless mice was sensitised with 20% amino-levulinic acid-induced protoporophyrin IX and exposed to 5, 11, 22 or 50 J cm(-2) of pulsed 523 nm light at 50 mW cm(-2), or to 50 J cm(-2) at 15 or 150 mW cm(-2). (1)O(2) luminescence was measured during treatment and the photodynamic response of the skin was scored daily for 2 weeks after treatment. As observed by other authors, a strong irradiance dependence of the PDT effect was observed. However, in all cases the responses increased with the (1)O(2) luminescence, independent of the irradiance, demonstrating for the first time in vivo an unequivocal mechanistic link between (1)O(2) generation and photobiological response.

Aminolevulinic Acid↗

Coronary air embolism treated with aspiration catheter.

Coronary air embolism remains a recognised complication of coronary catheterisation despite a strong emphasis on prevention. Current treatment consists of supportive measures with 100% oxygen and analgesia. Recent case reports describe the use of mechanical treatments aimed at dispersing or removing the air embolus with variable success. A case of coronary air embolism causing an acute coronary syndrome is described that was definitively treated with an aspiration system. The effectiveness of the aspiration system in the distal section of an obtuse marginal artery indicates that such dedicated aspiration systems may prove useful in the standard treatment of air embolism.

Adult↗

A diffusion theory model of spatially resolved fluorescence from depth-dependent fluorophore concentrations.

A photon diffusion model has been developed to calculate the steady-state spatially resolved fluorescence from pencil beam excitation in layered tissue. The model allows the calculation of both the excitation reflectance and the fluorescence escape for an arbitrary continuous depth distribution of tissue optical properties and fluorophore concentration. The validity of this model was verified by comparison with Monte Carlo simulations and experimental measurements using phantoms with tissue-like optical properties. The potential usefulness of the spatially resolved fluorescence was explored using the model and simulations of realistic drug distributions. It was shown that using this technique it may be possible to quantify the diffusion of a topically administered drug into the skin, or the photobleaching of a sensitizer during photodynamic therapy.

Algorithms↗

Experimental verification of the effect of refractive index mismatch on the light fluence in a turbid medium.

Diffusion theory is often used to model the transport of light within tissue. It can be used to calculate the light fluence rate in tissue, for example, during photodynamic therapy, or to measure the absorption and scattering properties of tissue. For both of these applications, the influence of the interface between the tissue and the exterior medium on the fluence rate inside the tissue must be known in order to make accurate calculations. We present an experimental investigation of the effect of the refractive index mismatch at the tissue interface on the internal light fluence rate and on the spatially resolved diffuse reflectance as the boundary conditions of the tissue/external medium are changed. The effects of changing the relative refractive index at the boundary are compared to predictions of diffusion theory. The effect of the refractive index mismatch is predicted correctly by diffusion theory.

Animals↗

Anisotropy of light propagation in human skin.

Using spatially resolved, steady state diffuse reflectometry, a directional dependence was found in the propagation of visible and near infrared light through human skin in vivo. The skin's reduced scattering coefficient mu(s)' varies by up to a factor of two between different directions of propagation at the same position. This anisotropy is believed to be caused by the preferential orientation of collagen fibres in the dermis, as described by Langer's skin tension lines. Monte Carlo simulations that examine the effect of partial collagen fibre orientation support this hypothesis. The observation has consequences for non-invasive diagnostic methods relying on skin optical properties, and it could be used non-invasively to determine the direction of lines of cleavage in order to minimize scars due to surgical incisions.

Algorithms↗

Improved continuous light diffusion imaging in single- and multi-target tissue-like phantoms.

The image reconstruction enhancement schemes of total variation minimization, dual meshing and iterative spatial filtering have been applied to laboratory data collected from continuous light illumination of tissue-like phantoms. Experiments include both single- and multi-target cases where variations in object size (4 mm to 20 mm), position (centred to near boundary) and contrast with the background (2:1 to 8:1) have been explored. The results show that dramatic improvements in image quality have been obtained in terms of geometric and spatial resolution measures relative to those previously reported for continuous light, but quantitative information on the actual optical properties of embedded heterogeneities is still lacking. Specifically, the geometric characteristics of object size, position and shape are generally accurate to 10-20% and the spatial resolution metrics of background-to-object size and neighbouring-edge separation are approximately 10:1. Direct comparisons are also made with images obtained with intensity-modulated light under identical experimental conditions. Images from intensity-modulated light are found to be superior to continuous light in several important ways, most notably in terms of the ability to quantitatively discriminate the optical property values of embedded targets from the surrounding background. Continuous-light images are also found to have centrally located artefacts in many instances which do not appear in the corresponding intensity-modulated cases.

Algorithms↗

Frequency-domain near-infrared photo diffusion imaging: initial evaluation in multitarget tissuelike phantoms.

In this paper, an initial evaluation of our finite element based frequency-domain image reconstruction algorithm is performed for experiments where multiple millimeter-sized heterogeneities are embedded within a tissue-equivalent (optically) background medium having multicentimeter dimensions. The cases considered consist of several interesting geometry and optical property contrast combinations including (i) two different-sized targets with the same contrast at three different separation distances; (ii) two different-sized targets with different contrasts at two different separation distances; and (iii) three targets with the same and different sizes and contrasts, respectively. The reconstruction algorithm that has been used is an enhanced version of our originally developed regularized least squares approach that now includes total variation minimization, dual meshing, and spatial low-pass filtering. Quantitative measures of image quality including the size, location, and shape of the embedded heterogeneities along with errors in their recovered optical property values are presented. The results show that multiple targets can be clearly detected for all combinations of locations, sizes, and contrast levels considered, but the quantitative nature of this detection is influenced by these parameters.

Algorithms↗

Comparison of the in vivo photodynamic threshold dose for photofrin, mono- and tetrasulfonated aluminum phthalocyanine using a rat liver model.

The photodynamic threshold dose in normal rat liver was determined from the measured depth of necrosis following surface irradiation. The threshold was determined for the photosensitizing drugs Photofrin and monosulfonated aluminum chlorophthalocyanine, AlPcS1, at 24 h postinjection and was found to be (3.4 x/divided by 1.3) x 10(18) and (8.2 x/divided by 1.5) x 10(18) photons cm-3, respectively, compared with the previously reported value of (38 +/- 2) x 10(18) photons cm-3 for the tri/tetrasulfonated phthalocyanine, AlPcS4. These values were independent of drug concentration or total light fluence. For all three drugs the depth of tissue necrosis decreased as the time between drug and light administration increased from 10 min to 72 h. This decrease can be attributed both to the change in the tissue drug concentration as well as to changes in the efficiency of photodynamic therapy for producing tissue damage, related to the photodynamic necrosis threshold. The threshold values for all three photosensitizers were lowest at 10 min post injection: (1.4 x/divided by 1.4) x 10(18), (1.6 x/divided by 1.3) x 10(18) and (23 x/divided by 1.3) x 10(18) photons cm-3 for Photofrin, AlPcS1 and AlPcS4, respectively. The changes in necrosis threshold with time may be due to an initial change from entirely vascular to a combination of vascular and cellular damage, with later redistribution of the photosensitizer to targets at the subcellular level.

Animals↗

Determination of the optical properties of semi-infinite turbid media from frequency-domain reflectance close to the source.

We investigate theoretically the errors in determining the reduced scattering and absorption coefficients of semi-infinite turbid media from frequency-domain reflectance measurements made at small distances between the source and the detector(s). The errors are due to the uncertainties in the measurement of the phase, the modulation and the steady-state reflectance as well as to the diffusion approximation which is used as a theoretical model to describe light propagation in tissue. Configurations using one and two detectors are examined for the measurement of the phase and the modulation and for the measurement of the phase and the steady-state reflectance. Three solutions of the diffusion equation are investigated. We show that measurements of the phase and the steady-state reflectance at two different distances are best suited for the determination of the optical properties close to the source. For this arrangement the errors in the absorption coefficient due to typical uncertainties in the measurement are greater than those resulting from the application of the diffusion approximation at a modulation frequency of 200 MHz. A Monte Carlo approach is also examined; this avoids the errors due to the diffusion approximation.

Biophysical Phenomena↗

Accuracy of noninvasive in vivo measurements of photosensitizer uptake based on a diffusion model of reflectance spectroscopy.

This study compares the photosensitizer concentration measured noninvasively in vivo by diffuse reflectance spectroscopy with the results of postmortem tissue solubilization and fluorometric assay. The reflectance spectrometer consists of a fiber optic surface probe, spectrometer and charge-coupled device (CCD) array detector. The surface probe has eight detection fibers separated from the light source fiber by distances ranging from 0.85 to 10 mm. The imaging spectrometer disperses the light from each detector fiber onto the two-dimensional CCD array, while maintaining spatial separation of each individual spectrum. A single exposure of the CCD therefore captures the reflectance spectrum ar eight distances and over a range of 300 nm. From the spectra, the tissue's optical scattering and absorption coefficients are determined using a diffusion model of light propagation. Changes in the tissue absorption are used to estimate the photosensitizer concentration. Normal New Zealand White rabbits were injected with aluminum phthalocyanine tetrasulfonate (AlPcS4) and probe measurements made 24 h after injection on the dorsal skin, on muscle after surgically turning the skin back and on liver. For skin, the noninvasive estimate to proportional to the true concentration but low by a factor of 3. Based on Monte Carlo modeling of multilayered systems, this underestimate is attributed to the layered structure of the skin and nonuniform AlPcS4 distribution. A comparison of the noninvasive concentration estimates to the postmortem assay results finds good agreement for liver tissue even though application of the diffusion model is not strictly justified.

Animals↗

Improved solutions of the steady-state and the time-resolved diffusion equations for reflectance from a semi-infinite turbid medium.

Improved solutions of the diffusion equation for time-resolved and steady-state spatially resolved reflectance are investigated for the determination of the optical coefficients of semi-infinite turbid media such as tissue. These solutions are derived for different boundary conditions at the turbid-medium-air interface and are compared with Monte Carlo simulations. Relative reflectance data are fitted in the time domain, whereas relative and absolute reflectance are investigated in the steady-state domain. It is shown that the error in deriving the optical coefficients is, especially for steady-state spatially resolved reflectance, considerably smaller for the solutions under study than for the commonly used solutions. Analysis of experimental measurements of absolute steady-state spatially resolved reflectance confirms these results.

Diffusion↗

Changes in in vivo optical properties and light distributions in normal canine prostate during photodynamic therapy.

The optical absorption and transport scattering coefficients of normal prostate tissue have been measured in vivo in dogs. The measurements were made at 630 nm before and during treatment by Photofin photodynamic therapy using interstitial optical fiber fluence-rate detectors. Corresponding measurements were made ex vivo, at 1 week after treatment, in the contralateral lobe. The optical properties were derived by applying a diffusion theory model to the fluence rates measured at two different source-detector fiber distances. While the in vivo pretreatment and in vivo contralateral post-treatment absorption and scattering values are self-consistent and in agreement with published data, significant changes were observed in the light fluence rates, and hence in the derived optical properties, during light irradiation. The possible causes of such changes are considered, and the implications for light dosimetry in photodynamic therapy are discussed.

Animals↗

The sensitivity of normal brain and intracranially implanted VX2 tumour to interstitial photodynamic therapy.

The applicability and limitations of a photodynamic threshold model, used to describe quantitatively the in vivo response of tissues to photodynamic therapy, are currently being investigated in a variety of normal and malignant tumour tissues. The model states that tissue necrosis occurs when the number of photons absorbed by the photosensitiser per unit tissue volume exceeds a threshold. New Zealand White rabbits were sensitised with porphyrin-based photosensitisers. Normal brain or intracranially implanted VX2 tumours were illuminated via an optical fibre placed into the tissue at craniotomy. The light fluence distribution in the tissue was measured by multiple interstitial optical fibre detectors. The tissue concentration of the photosensitiser was determined post mortem by absorption spectroscopy. The derived photodynamic threshold values for normal brain are significantly lower than for VX2 tumour for all photosensitisers examined. Neuronal damage is evident beyond the zone of frank necrosis. For Photofrin the threshold decreases with time delay between photosensitiser administration and light treatment. No significant difference in threshold is found between Photofrin and haematoporphyrin derivative. The threshold in normal brain (grey matter) is lowest for sensitisation by 5 delta-aminolaevulinic acid. The results confirm the very high sensitivity of normal brain to porphyrin photodynamic therapy and show the importance of in situ light fluence monitoring during photodynamic irradiation.

Aminolevulinic Acid↗

Determination of the optical properties of turbid media from a single Monte Carlo simulation.

We describe a fast, accurate method for determination of the optical coefficients of 'semi-infinite' and 'infinite' turbid media. For the particular case of time-resolved reflectance from a biological medium, we show that a single Monte Carlo simulation can be used to fit the data and to derive the absorption and reduced scattering coefficients. Tests with independent Monte Carlo simulations showed that the errors in the deduced absorption and reduced scattering coefficients are smaller than 1% and 2%, respectively.

Animals↗

Initial assessment of a simple system for frequency domain diffuse optical tomography.

Diffuse optical tomography is an imaging technique whereby spatial maps of absorption and scattering coefficients are derived from the characteristics of multiply scattered light transmitted through the object. The system described here used four intensity-modulated light sources and measurements of the intensity and phase (relative to each source) at 16 or 20 detectors on the surface of a 10 cm diameter cylinder. An iterative Newton-Raphson algorithm was used to estimate the absorption and scattering coefficients at each pixel in a 17 x 17 array minimizing the difference between measured and calculated values of the intensity and phase at the measurement sites. Forward calculations of the intensity and phase were based on a multigrid finite-difference solution of the frequency domain diffusion equation. Numerical simulations were used to examine the resolution, contrast, and accuracy of the reconstructions as well as the effects of measurement noise, systematic uncertainties in source-detector location, and accuracy of the initial estimates for the optical properties. Experimental tests also confirmed that the system could identify and locate both scattering and absorbing inhomogeneities in a tissue-simulating phantom.

Algorithms↗

Frequency-domain optical absorption spectroscopy of finite tissue volumes using diffusion theory.

The goal of frequency-domain optical absorption spectroscopy is the non-invasive determination of the absorption coefficient of a specific tissue volume. Since this allows the concentration of endogenous and exogenous chromophores to be calculated, there is considerable potential for clinical application. The technique relies on the measurement of the phase and modulation of light, which is diffusely reflected or transmitted by the tissue when it is illuminated by an intensity-modulated source. A model of light propagation must then be used to deduce the absorption coefficient. For simplicity, it is usual to assume the tissue is either infinite in extent (for transmission measurements) or semi-infinite (for reflectance measurements). The goal of this paper is to examine the errors introduced by these assumptions when measurements are actually performed on finite volumes. Diffusion-theory calculations and experimental measurements were performed for slabs, cylinders and spheres with optical properties characteristic of soft tissues in the near infrared. The error in absorption coefficient is presented as a function of object size as a guideline to when the simple models may be used. For transmission measurements, the error is almost independent of the true absorption coefficient, which allows absolute changes in absorption to be measured accurately. The implications of these errors in absorption coefficient for two clinical problems--quantitation of an exogenous photosensitizer and measurement of haemoglobin oxygenation--are presented and discussed.

Algorithms↗