An analytic and numerical study of intravascular thermography of vulnerable plaque.

Intravascular thermography has been proposed as a method for detecting vulnerable plaque. A marker of vulnerability in a plaque is inflammation, which is believed to reduce its mechanical stability. It has been hypothesized that this inflammation leads to a higher metabolic rate and therefore higher heat generation, causing increased temperature in the vicinity of the plaque. This temperature increase could be measured intravascularly using a temperature sensor, e.g., a thermistor or a thermocouple. The aim of this study is to present a thorough mathematical and physical analysis of the thermal distribution that can be expected in the plaque under various physiological conditions. To get reasonable predictions on the expected temperature distributions, idealized models with simple geometries are solved analytically. More realistic models, with more complex geometries, are solved numerically using the finite element method (FEM). Based on this analysis, the maximum temperature increase that can be expected in a plaque due to increased metabolism is less than 0.1 K.

In vivo spectroscopy of jaundiced newborn skin reveals more than a bilirubin index.

AIM: The aims of this study were to improve the algorithms for calculating a transcutaneous bilirubin index (TcB), to follow the bilirubin concentrations during phototherapy and to evaluate possible changes in skin optical parameters such as pigmentation and erythema during phototherapy. METHOD: Reflectance measurements were performed on 51 jaundiced newborns, of which 10 were subjected to phototherapy. The measurements were collected with a diode array spectrophotometer with an integrating sphere accessory, and a TcB was calculated from the measured spectra using algorithms based on diffusion theory. The newborns' birthweights were > or = 2000 g and their gestational age was > or = 35.5 wk. They had no substantial illnesses, and no newborns were submitted to the study until their second day. Heel prick blood samples were analysed for total serum bilirubin (Sbr) by the diazo reaction method. Phototherapy equipment was either an overhead lamp or lightbed. RESULTS: Measurements from the forehead gave the best correlation between TcB and Sbr (r = 0.81, p < 0.05). However, during phototherapy no significant correlation between TcB and Sbr was observed. A correlation (r = 0.45, p < 0.05) was found between phototherapy and melanin index obtained from the patients' back. CONCLUSIONS: Reflectance spectroscopy is useful in assessing bilirubin concentrations before phototherapy, and can also reveal changes in skin parameters such as pigmentation occurring as a result of phototherapy.

Methemoglobin formation during laser induced photothermolysis of vascular skin lesions.

BACKGROUND AND OBJECTIVE: Monitoring dynamic changes during laser induced photothermolysis of vascular skin lesions is essential for obtaining an optimal therapeutic result. Rapid photoinduced thermal damage occurs at a threshold temperature of about 70 degrees C. It is therefore, relevant to identify markers to indicate if this threshold temperature has been reached. Methemoglobin, which is formed by a photo-induced oxidation of hemoglobin, indicates that the temperature has reached this threshold value. This study presents a proof of concept of a method for monitoring the in vivo presence of methemoglobin immediately after laser exposure. STUDY DESIGN/MATERIALS AND METHODS: The present study was designed to investigate the in vivo temperature dependence of hemoglobin absorption in the 450-800 nm spectrum range. In vivo diffuse reflectance measurements of port-wine stain (PWS) and telangiectasia were performed prior to, and immediately after, laser treatment with a pulsed dye laser (PDL) at 585 nm wavelength. RESULTS: In vivo measurements following laser treatment of vascular skin lesions showed an immediate increase in the optical absorption of blood. This effect, caused by thermal stress, is a result of an increased dermal blood volume fraction and methemoglobin formation. The effect is light dose dependent, and reflectance spectra revealed methemoglobin formation in patients treated with fluences above 5 J/cm2 at 585 nm wavelength. CONCLUSIONS: It was proved that methemoglobin can be measured in vivo by reflectance spectroscopy. Measurements of the average methemoglobin concentrations immediately after laser exposure may be a valuable diagnostic tool to verify that the blood temperature has been sufficiently high to induce thermal damage to the vessel wall.

Cooling efficiency of cryogen spray during laser therapy of skin.

BACKGROUND AND OBJECTIVES: Cryogen spray cooling (CSC) is used extensively for epidermal protection during laser-induced photothermolysis of port wine stains and other vascular skin lesions. The efficacy of CSC depends critically on the heat transfer coefficient (H) at the skin surface for which, however, no reliable values exist. Reported values for H, based on tissue phantoms, vary from 1,600 to 60,000 W/m(2) K. STUDY DESIGN/MATERIALS AND METHODS: A simple experimental model was designed and constructed, consisting of a pure silver-measuring disk (diameter 10 mm, thickness approximately 1 mm), embedded in a thermal insulator. The disk was covered with a 10 microm thick stratum corneum layer, detached from in vivo human skin. The heat transfer coefficient of the stratum corneum/cryogen interface was measured during CSC with short spurts of atomized tetrafluoroethane. RESULTS: H was found to be dependent on the specific design of the cryogen valve and nozzle. With nozzles used in typical clinical settings, H was 11,500 W/m(2) K, when averaged over a 100 ms spurt, and 8,000 W/m(2) K when averaged over a 200 ms spurt. CONCLUSIONS: The presented model enables accurate prediction of H and thus improve control over temperature depth profile and cooling efficiency during laser therapy. Thereby, it may contribute to improvement of therapeutic outcome.

Cryogen spray cooling in laser dermatology: effects of ambient humidity and frost formation.

BACKGROUND AND OBJECTIVE: Dynamics of cryogen spray deposition, water condensation and frost formation is studied in relationship to cooling rate and efficiency of cryogen spray cooling (CSC) in combination with laser dermatologic surgery. STUDY DESIGN/MATERIALS AND METHODS: A high-speed video camera was used to image the surface of human skin during and after CSC using a commercial device. The influence of ambient humidity on heat extraction dynamics was measured in an atmosphere-controlled chamber using an epoxy block with embedded thermocouples. RESULTS: A layer of liquid cryogen may remain on the skin after the spurt termination and prolong the cooling time well beyond that selected by the user. A layer of frost starts forming only after the liquid cryogen retracts. Condensation of ambient water vapor and subsequent frost formation deposit latent heat to the target site and may significantly impair the CSC cooling rate. CONCLUSIONS: Frost formation following CSC does not usually affect laser dosage delivered for therapy of subsurface targets. Moreover, frost formation may reduce the risk of cryo-injury associated with prolonged cooling. The epidermal protection during CSC assisted laser dermatologic surgery can be further improved by eliminating the adverse influence of ambient humidity.

Influence of nozzle-to-skin distance in cryogen spray cooling for dermatologic laser surgery.

BACKGROUND AND OBJECTIVE: Cryogen sprays are used for cooling human skin during various laser treatments. Since characteristics of such sprays have not been completely understood, the optimal atomizing nozzle design and operating conditions for cooling human skin remain to be determined. MATERIALS AND METHODS: Two commercial cryogenic spray nozzles are characterized by imaging the sprays and the resulting areas on a substrate, as well as by measurements of the average spray droplet diameters, velocities, temperatures, and heat transfer coefficients at the cryogen-substrate interface; all as a function of distance from the nozzle tip. RESULTS: Size of spray cones and sprayed areas vary with distance and nozzle. Average droplet diameter and velocity increase with distance in the vicinity of the nozzle, slowly decreasing after a certain maximum is reached. Spray temperature decreases with distance due to the extraction of latent heat of vaporization. At larger distances, temperature increases due to complete evaporation of spray droplets. These three variables combined determine the heat transfer coefficient, which may also initially increase with distance, but eventually decreases as nozzles are moved far from the target. CONCLUSIONS: Sprayed areas and heat extraction efficiencies produced by current commercial nozzles may be significantly modified by varying the distance between the nozzle and the sprayed surface.

Optical property measurements of turbid media in a small-volume cuvette with frequency-domain photon migration.

A frequency-domain photon migration (FDPM) technique is developed for quantitative measurement of the absorption and reduced scattering coefficients of highly turbid samples in a small-volume (0.45-ml) reflective cuvette. We present both an analytical model for the FDPM cuvette and its experimental verification, using calibrated phantoms and suspensions of living cells. FDPM model fits to experimental data demonstrate that the reduced scattering (mu(s)?) and absorption (mu(a)) coefficients can be derived with accuracies of 5-10% and 10-15%, respectively. Changing the cuvette wall reflectivity alters the frequency-dependent behavior of photon density waves (PDWs). For highly reflective wall boundaries (R(eff) >/= 90-95%), PDW confinement leads to substantial enhancement in both amplitude and phase compared with identical samples in infinite media. Results from experiments on microsphere suspensions are compared with predictions from Mie theory to assess the potential of this method to interpret scattering properties in terms of scatterer size and density. Optical property measurements of biological cell suspensions are reported, and the possibility of optically monitoring cell physiology in a carefully controlled environment is demonstrated.

Quantifying the properties of two-layer turbid media with frequency-domain diffuse reflectance.

Noncontact, frequency-domain measurements of diffusely reflected light are used to quantify optical properties of two-layer tissuelike turbid media. The irradiating source is a sinusoidal intensity-modulated plane wave, with modulation frequencies ranging from 10 to 1500 MHz. Frequency-dependent phase and amplitude of diffusely reflected photon density waves are simultaneously fitted to a diffusion-based two-layer model to quantify absorption (mu(a)) and reduced scattering (mu(s)') parameters of each layer as well as the upper-layer thickness (l). Study results indicate that the optical properties of two-layer media can be determined with a percent accuracy of the order of +/-9% and +/-5% for mu(a) and mu(s)', respectively. The accuracy of upper-layer thickness (l) estimation is as good as +/-6% when optical properties of upper and lower layers are known. Optical property and layer thickness prediction accuracy degrade significantly when more than three free parameters are extracted from data fits. Problems with convergence are encountered when all five free parameters (mu(a) and mu(s)' of upper and lower layers and thickness l) must be deduced.

Collimated light sources in the diffusion approximation.

Collimated light sources in turbid media are difficult to describe within the diffusion approximation, because they do not meet the requirement of near isotropy. For precise calculation of light intensities close to the source, alternative descriptions of the light source are necessary. In this paper the transition of collimated light into diffusivity is studied by Monte Carlo simulations. On the basis of these simulations and the diffusion approximation a hybrid approach is designed and used to analyze approaches based on analytic source terms. The influence of boundaries to air is studied. The benefits of increased approximation orders are investigated. It is shown that, even in the presence of strong absorption, the diffusion approach can give satisfactory results if only the source terms are suitably chosen.

Reflectance measurements of layered media with diffuse photon-density waves: a potential tool for evaluating deep burns and subcutaneous lesions.

The basic principles of a non-contact, near-infrared technique for the mapping of layered tissues are discussed theoretically and verified experimentally. The propagation properties of diffuse photon-density waves in tissues depend on the optical properties of the tissue. When a layered medium is irradiated by amplitude modulated light, the difference in optical properties between the layers is evident in the phase and amplitude of the diffuse reflection coefficient, which is a result of the interference of the partial waves propagating in the different layers. Thus, diffuse photon-density waves are applicable to the analysis of the structure of layered tissue. The probing depth is determined by the modulation frequency of the incident light. For modulation frequencies between several hundred megahertz and a few gigahertz, this allows us to analyse the properties of muscle tissue of up to 4-8 mm below the surface. Experimental results based on chicken breast muscle are given. As an example, the technique might be of use for evaluating the depth of necrosis and the blood volume fraction in deep burns.

Pigmentary changes after pulsed dye laser treatment in 125 northern European patients with port wine stains.

We investigated the occurrence of pigmentary changes after flash lamp pumped dye laser treatment in 125 Norwegian patients. Post-treatment hyperpigmentation occurred with equal frequency during summer and winter (23%), and the facial regions did not exhibit higher occurrence than lesions located elsewhere. The patients that achieved hyperpigmented skin were not exposed to any higher fluence than those without this complication. On the contrary, we found that during the summer period from April to September the patients with post-treatment hyperpigmentation had been exposed to a significantly lower dose than those without pigmentary changes. These results indicate that the epidermal melanin content is not the only criterion for obtaining post-treatment hyperpigmentation. There might also be a constitutional disposition. In predisposed individuals the threshold dose for hyperpigmentation might be reduced in summer when the skin is more pigmented.

The origin and role of erythema after carbon dioxide laser resurfacing. A clinical and histological study.

BACKGROUND: Transient erythema, which can last up to 3 months after carbon dioxide (CO2) laser skin resurfacing, is a usual side effect with pulsed or rapidly scanned CO2 lasers. OBJECTIVE: We evaluated the cause of erythema in the clinical setting and by histology in order to determine if and how we may decrease it, or even eliminate it. METHODS: Ten patients who underwent resurfacing were recruited to this study. Skin punch biopsies were taken at 0, 7, 21, and 90 days and analyzed by light microscopy. RESULTS: Erythema was noticed from about day 8, when the crusting on the skin surface was exfoliated. It reached its maximum intensity after 14 days, and had disappeared by 60-90 days. Histology showed an early inflammatory response, with an immature neopithelium, and rich vascularization. The normal epidermis had returned by 90 days, and during this period there was reduced optical scattering and absorption in melanin. CONCLUSION: Although the erythema is an unwanted side effect in the patient's eyes, it is to be expected and thus represents the effects of a combination of epidermal immaturity, reduced melanin absorption of light, reduced dermal optical scattering, and increased blood flow secondary to the surgically induced inflammatory response.

Purpura without vessel structural damage.

Experiments on an animal model for vascular lesions, the chicken comb model, have demonstrated a bluish-grey discoloration phenomenon similar to that observed immediately after pulsed dye laser treatment of port wine stains. In the model, erythrocytes and cell nuclei are found in the extravascular matrix even where there is no sign of vessel wall rupture. It is believed that the vapour pressure of the boiling blood forces erythrocytes through passages in an elastically expanding vessel wall.

Non-invasive determination of port wine stain anatomy and physiology for optimal laser treatment strategies.

The treatment of port wine stains (PWSs) using a flashlamp-pumped pulsed dye laser is often performed using virtually identical irradiation parameters. Although encouraging clinical results have been reported, we propose that lasers will only reach their full potential provided treatment parameters match individual PWS anatomy and physiology. The purpose of this paper is to review the progress made on the technical development and clinical implementation of (i) infrared tomography (IRT), optical reflectance spectroscopy (ORS) and optical low-coherence reflectometry (OLCR) to obtain in vivo diagnostic data on individual PWS anatomy and physiology and (ii) models of light and heat propagation, predicting irreversible vascular injury in human skin, to select optimal laser wavelength, pulse duration, spot size and radiant exposure for complete PWS blanching in the fewest possible treatment sessions. Although non-invasive optical sensing techniques may provide significant diagnostic data, development of a realistic model will require a better understanding of relevant mechanisms for irreversible vascular injury.

Clinical effects of dynamic cooling during pulsed laser treatment of port-wine stains.

Pulsed dye lasers permit effective treatment of port-wine stains without a significant risk of complications. However, epidermal damage manifested by weeping or crusting of the treated area have been reported in 48-83% of patients, and transient hyperpigmentation after treatment is observed in 10-57%. Theoretically, the epidermis can be protected from thermal damage with the use of the concept of selective epidermal cooling.This study examined the clinical effects of rapid cooling of the epidermis with a liquid refrigerant R-134a (boiling point - 26.5 double daggerC) during pulsed dye laser therapy. In 23 patients with port-wine stains, a 50-ms-long cooling pulse delivered immediately prior to laser irradiation with a fluence of 6.0 J cm(-2) significantly reduced the pain, and shortened the period with purpura without compromising the clinical blanching. Cooling periods longer than 60 ms, as well as additional cooling pulses immediately after laser exposure, reduced the blanching in areas irradiated with 6.0 J cm(-2).Post-treatment hyperpigmentation was not prevented with dynamic cooling.

Possible mechanisms for an irregular vessel coagulation when long laser pulses are used in the treatment of port-wine stains.

The laser treatment of port-wine stains (PWS) has as a main aim the irreversible damage of ectatic vessels. Blood content of the subcutaneous venous plexus in PWS can be increased by a factor of seven or more, compared to that of the normal skin. The venous blood velocity ranges from 0.1-1 mm/s in capillaries to approximately 22 mm/s in larger vessels of about 300 microns in diameter. A PWS, selected for study, was irradiated with a multiline argon laser 488/515 nm wavelength, 1.5 W power, 200 ms pulse duration, 0.5 mm beam diameter and repetition frequency up to 5 Hz. Laser shots were placed adjacently in an area of 1 cm2. Using these parameters, in the case of dilated PWS vessels with an optical penetration depth and thermal diffusion length less than the diameter of the vessel, together with a transit time of blood across the irradiated spot less than the pulse duration, and estimating that during a pulsed laser emission of 200 ms, the blood has travelled a distance of 3-4 mm, there is a strong indication that hemodynamics during irradiation may influence the pattern of coagulation and agglutination. Thrombosis should occur in the case of small vessels and, in larger vessels, the coagulated blood will only partly fill the lumen. The structure developed in the vessel interior may also change continuously with time, as the coagulated material is progressively replaced by fibrotic tissue and the irregular agglutination pattern may be due to inhomogeneity in the absorbed optical energy.

Photothermally induced vessel-wall necrosis after pulsed dye laser treatment: lack of response in port-wine stains with small sized or deeply located vessels.

The optimal treatment of port-wine stains is laser-induced selective photothermolysis. Lesion color and location and the age of the patient are reported to influence the therapeutic outcome. This study was initiated to analyze the outcome not only by the clinical response of lightening, but also in terms of photothermally induced necrosis to the vessel wall. Punch biopsy specimens were taken from 51 patients before treatment. Post-treatment biopsies were taken after exposure to a pulsed dye laser (585-nm wavelength, 0.45-ms pulse length) with an irradiant fluence of 6.5 J/cm2. Vessel diameter, depth, and wall thickness were measured in all histologic slides. The viability of the vessel walls was evaluated using an enzyme histochemical method. Port-wine stains with good blanching had significantly more superficially located vessels than the moderate and poor responders (p < 0.000). The moderate and good responding lesions consisted of moderate-sized vessels with diameters of 38 +/- 17 micrometers and 38 +/- 19 micrometers (mean +/- SD), respectively. The lesions showing poor blanching had significantly smaller vessels, with a diameter of 19 +/- 6.5 micrometers < 0.000). Analyses of the post-treatment specimens showed that coagulated vessels were superficially located and of moderate size, whereas the viable vessels were small with a median diameter of 14 micrometers. The probability of coagulation correlated with the thickness of the vessel wall. These data indicate that the therapeutic outcome of port-wine stains can be improved by using the lesional vessel parameters to select the optimal laser wavelength, pulse duration, and dose.

Structural and functional effects of endometrial photodynamic therapy in a rat model.

OBJECTIVE: Our purpose was to determine the optical dose required for irreversible endometrial destruction and prevention of implantation by photodynamic therapy with topical 5-aminolevulinic acid. STUDY DESIGN: Three hours after drug application 74 female Sprague-Dawley rats received varying doses of 630 nm of light delivered by an intrauterine cylindric diffusing fiber. RESULTS: A 64 J/cm2 in situ optical dose resulted in long-term irreversible endometrial destruction; 43 J/cm2 damaged endometrial stroma and myometrium but not glandular epithelium 1 day after photodynamic therapy. At this lower light dose endometrium regenerated to full thickness within 3 weeks; however, implantation sacs were significantly reduced. CONCLUSIONS: Photodynamic destruction of glandular epithelium accompanies irreversible endometrial ablation, whereas isolated stromal damage leads to reproductive impairment only. The optical dose required for endometrial ablation is approximately 1.5-fold higher than for reproductive impairment (functional damage) because of differential cell photosensitivity.

Laser treatment of port wine stains: therapeutic outcome in relation to morphological parameters.

Thirty patients were treated with a flashlamp-pumped pulsed dye laser, with 0.45 ms pulse width and 585 nm wavelength. Punch biopsies were taken prior to treatment, and the biopsies were examined morphometrically. Three different test sites were exposed to laser light of fluence 5.25, 6.50 and 7.75 J/cm2. The degree of blanching was examined 6-8 weeks after treatment, and each site was retreated four times. Six patients (20%) achieved poor blanching, eight patients (27%) obtained moderate lightening and 16 patients (53%) showed good response. The vessels of the good responders were located significantly more superficially than the vessels of the moderate and poor responders (P < 0.05). The poor responders had significantly smaller vessels than the moderate and good responders (P < 0.01). The moderate responders had deeper, but larger vessels, than the poor responders. Hence, an increasing vessel diameter reduces the negative outcome of increasing vessel depth. The vessel diameter was correlated to the colour (P < 0.01), e.g. the mean vessel diameter was increasing from 16.5 microns in pink lesions to 51.2 microns in purple lesions. The vessel depth was partly reflected in the lesional colour, as the pink and purple lesions had significantly deeper vessels than the red ones (P = 0.02). These results indicate that pink lesions predict poor blanching due to deeply located small vessels, while red lesions predict a good therapeutic result because of more superficially located vessels.

A mathematical model for light dosimetry in photodynamic destruction of human endometrium.

We are involved in the development of photodynamic therapy (PDT) as a minimally invasive method for treating dysfunctional uterine bleeding, one of the primary clinical indications for hysterectomy. In this paper, we analyse light propagation through the uterus in order to specify the requirements for a light delivery system capable of effectively performing endometrial PDT. Our approach involves developing an analytical model based on diffusion theory to predict optical fluence rate distributions when cylindrical and spherical optical applicators are placed in the uterine cavity. We apply the results of our model calculations to estimate the thermal effects of optical irradiation and the effective photodynamic optical dose. Theoretical fluence rate calculations are compared to fluence rate measurements made in fresh, surgically removed human uteri. Our results show that a trifurcated cylindrical optical applicator inserted into the human uterus can provide a light dose that is sufficient to cause photodynamic destruction of the entire endometrium. When the optical power per unit length of each cylindrical applicator is 100 mW cm-1 (at 630 nm), a fluence rate of 40 mW cm-2 is delivered to the boundary layer between the endometrium and the myometrium (a depth of about 4-6 mm). The optical fluence delivered to the boundary layer after 20 min of exposure is 50 J cm-2, a level that is generally accepted to cause tissue damage throughout the endometrium in most patients.