Thomas Milner - Academia.edu (original) (raw)

Papers by Thomas Milner

Physics in Medicine and Biology, 1997

Successful laser treatment of haemangiomas requires selective photocoagulation of subsurface targ... more Successful laser treatment of haemangiomas requires selective photocoagulation of subsurface targeted blood vessels without thermal damage to the overlying epidermis. We present an in vivo experimental procedure, using a chicken comb animal model, and an infrared feedback system to deliver repetitive cryogen spurts (of the order of milliseconds) during continuous Nd:YAG laser irradiation. Gross and histologic observations show deep-tissue photocoagulation is achieved, while superficial structures are protected from thermal injury due to cryogen spray cooling. Experimental observation of epidermis protection in chicken comb animal models suggests selective photocoagulation of subsurface targeted blood vessels for successful treatment of haemangiomas can be achieved by repetitive applications of a cryogen spurt during continuous Nd:YAG laser irradiation.

SPIE Proceedings, 1994

Preliminary analysis of the applicability of IR FPAs to monitor temperature changes during variou... more Preliminary analysis of the applicability of IR FPAs to monitor temperature changes during various laser therapies has been performed at the Beckman Laser Institute. Temperature measurements of have been made implementing a high frame rate staring FPA. Extensive measurement skin surface temperature during pulsed laser exposure of port wine stain (PWS) were performed. Cursory experiments were performed on lung, teeth, and eye tissue during laser exposure.

Biomedical Optics Express, 2011

Non-invasive depth-resolved measurement of hemoglobin oxygen saturation (SaO 2) levels in discret... more Non-invasive depth-resolved measurement of hemoglobin oxygen saturation (SaO 2) levels in discrete blood vessels may have implications for diagnosis and treatment of various pathologies. We introduce a novel Dual-Wavelength Photothermal (DWP) Optical Coherence Tomography (OCT) for non-invasive depth-resolved measurement of SaO 2 levels in a blood vessel phantom. DWP OCT SaO 2 is linearly correlated with blood-gas SaO 2 measurements. We demonstrate 6.3% precision in SaO 2 levels measured a phantom blood vessel using DWP-OCT with 800 and 765 nm excitation wavelengths. Sources of uncertainty in SaO 2 levels measured with DWP-OCT are identified and characterized.

Laser Interaction with Hard and Soft Tissue, 1994

Individual blood vessels in the chick chorioallantoic membrane (CAM) were selectively coagulated ... more Individual blood vessels in the chick chorioallantoic membrane (CAM) were selectively coagulated through photothermolysis, using pulsed laser irradiation at 585 nm. Pulse durations were chosen to be 0.45 ms and 10 ms, which correspond to the thermal relaxation times in blood vessels of 30 pm and 150 tm diameter, respectively. The short pulses, at an energy density (or light dose) D=3 Jcm2, caused permanent occlusion of vessels of 40 p.m diameter or less, while larger caliber vessels (60-120 p.m) required D=4-5 Jcm2. The long-duration pulses, at D=7 Jcm2, coagulation of the larger diameter vessels; the small caliber vessels and capillaries showed resistance to photothermolysis and required multiple exposures to achieve coagulation. The dose vs diameter (D vs d) relationship for coagulation was calculated for the two pulse shapes. The energy deposited in a cylindrical absorber of diameter d by an optical field, incident perpendicular to the vessel, was expressed analytically and compared with the energy required to coagulate a blood vessel of the same lumen diameter. When thermal diffusion is incorporated into the model, our findings can be accounted for quantitatively. This information will be of use for improving the laser treatment of port wine stains and other vasculopathies. A surprising observation was that arterioles were damaged at lower incident energy densities than venules having the same lumen diameter, despite the fact that absorbance in oxygen-rich and oxygen-poor blood is the same for 585 nm radiation.

Skin Cancer Overview, 2011

Cutaneous malignant melanoma (CMM) is a serious type of cancer accounting for 75% of all deaths a... more Cutaneous malignant melanoma (CMM) is a serious type of cancer accounting for 75% of all deaths associated with skin cancer (Jerant et al., 2000). CMM incidence has dramatically increased in the past few decades and, recently, approximately 160,000 new cases of CMMs are diagnosed worldwide each year (Ries et al., 2003). In 2010, the American Cancer Society estimated that 68,130 cases of melanoma (38,870 males; 29,260 females) and 8,700 melanoma deaths (5,670 males; 3,030 females) were expected in the United States (American Cancer Society (ACS), 2010). In the United States, the lifetime risk for developing CMM has increased from 1 in 1500 in 1930 to 1 in 50 in 2010 (ACS, 2010; King, 2004). Proper staging of CMM is crucial for defining prognosis and for determining the optimal treatment approach. Several cancer staging systems are being used worldwide. One of the most common staging systems is the tumor-node-metastasis (TNM) classification established by the American Joint Committee on Cancer (AJCC) (Balch et al., 2001). The TNM system classifies CMM in three categories: (1) the size and extent of the primary tumor (T), (2) the involvement of regional lymph nodes (N) and, (3) the presence or absence of distant metastasis (M), determining CMM clinical Stage I, II, III, or IV. To remain current and relevant to clinical practice, the TNM classification is updated periodically based on advances in understanding of cancer prognosis. The latest revision of TNM (presented in the 7th edition of the AJCC Cancer Staging Manual) is applied for cases diagnosed on or after January 1, 2010 (Edge et al., 2010). The CMM invasion depth known as the Breslow thickness (Breslow, 1970) in T category is the single most important factor for CMM staging and closely related to survival rate (Mihm et al., 1988). The five-year survival rate is 95%-100% if CMM thickness is less than 1 mm, while the survival rate is reduced to 50% if the tumor thickness is greater than 4 mm (Figure 1). Current surgical treatment for primary CMM has often been an excision with a margin determined by CMM thickness (Table 1). Since the risk of local recurrence is dependent on CMM thickness, a narrow margin of 5 mm is recommended for in situ CMMs, 1 cm for tumors thinner than 1 mm, 1-2 cm for tumors between 1.01 and 2 mm, and 2 cm for tumors thicker than 2.01 mm (Sladden et al., 2009). Because sentinel lymph node highly correlates with the metastatic status of CMM, a sentinel lymph node dissection (SLND) procedure is also performed on patients with intermediate thickness (1-4 mm) lesions (Balch & Ross,

Proceedings - IEEE Ultrasonics Symposium, 2006

Photothermal therapy is a targeted, non-invasive thermal treatment of cancer. Up to 40 o C temper... more Photothermal therapy is a targeted, non-invasive thermal treatment of cancer. Up to 40 o C temperature increase is obtained in a small volume of malignant cells by using appropriate photoabsorbers and irradiating the tissue with a continuous wave laser. However, in order to ensure successful outcome of photothermal therapy, the tumor needs to be imaged before therapy, the temperature needs to be monitored during therapy and, finally, the tumor needs to be evaluated for necrosis during and after therapy. We investigated the feasibility of ultrasound imaging to track temperature changes during photothermal therapy and elasticity imaging to monitor tumor necrosis after treatment. The image-guided therapy was demonstrated on tissue mimicking phantoms and ex-vivo animal tissue with gold nanoparticles as photoabsorbers. Ultrasound-based thermal imaging effectively generates temperature maps during therapy while elasticity imaging monitors changes in the mechanical properties of tissue before and after therapy, allowing evaluation of treatment efficacy. Results of our study suggest that ultrasound can be used to guide photothermal therapy.

Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 2008

In photothermal therapy, a localized temperature increase is achieved by using a continuous wave ... more In photothermal therapy, a localized temperature increase is achieved by using a continuous wave laser and optically tuned metal nanoparticles. However, the successful outcome of therapy depends on identifying the presence of nanoparticles in the tumor before therapy and monitoring temperature rise during the photothermal procedure. In this paper, we investigate the utility of photoacoustic and ultrasound imaging to guide photothermal therapy. Differences in the optical properties of tissue, enhanced by the presence of nanoparticles, provide a contrast for photoacoustic imaging. Thus, an uptake of nanoparticles in the tumor can be detected by monitoring a photoacoustic image over time. A temperature rise causes the photoacoustic signal amplitude to increase. In addition, a temperature change also leads to time shifts in an ultrasound signal, primarily due to the change in speed of sound. Therefore, by measuring the change in the photoacoustic signal, and differential motion of ultrasound speckle, the temperature rise during photothermal therapy can be computed. Combined imaging was performed with a tunable pulsed laser and an array-based ultrasound transducer. Experiments were carried out on ex-vivo animal tissue injected with composite and broadly absorbing gold nanoparticles. The photoacoustic imaging identified the presence of nanoparticles in tissue. In addition, a localized temperature increase, obtained during therapy, was monitored using photoacoustic and ultrasound imaging. The temperature profiles, obtained by both imaging techniques, were spatially and temporally co-registered. Therefore, the experimental results suggest that photoacoustic and ultrasound imaging can be used to guide and monitor photothermal therapy.

Physics in Medicine and Biology, 1998

Pulsed photothermal radiometry (PPTR) is a non-contact method for determining the temperature inc... more Pulsed photothermal radiometry (PPTR) is a non-contact method for determining the temperature increase in subsurface chromophore layers immediately following pulsed laser irradiation. In this paper the inherent limitations of PPTR are identified. A time record of infrared emission from a test material due to laser heating of a subsurface chromophore layer is calculated and used as input data for a non-negatively constrained conjugate gradient algorithm. Position and magnitude of temperature increase in a model chromophore layer immediately following pulsed laser irradiation are computed. Differences between simulated and computed temperature increase are reported as a function of thickness, depth and signal-to-noise ratio (SNR). The average depth of the chromophore layer and integral of temperature increase in the test material are accurately predicted by the algorithm. When the thickness/depth ratio is less than 25%, the computed peak temperature increase is always significantly less than the true value. Moreover, the computed thickness of the chromophore layer is much larger than the true value. The accuracy of the computed subsurface temperature distribution is investigated with the singular value decomposition of the kernel matrix. The relatively small number of right singular vectors that may be used (8% of the rank of the kernel matrix) to represent the simulated temperature increase in the test material limits the accuracy of PPTR. We show that relative error between simulated and computed temperature increase is essentially constant for a particular thickness/depth ratio.

Physics in Medicine and Biology, 1995

?be ability to control the degree and spatial distribution of cwling in biological tissues during... more ?be ability to control the degree and spatial distribution of cwling in biological tissues during a thermally mediated therapeutic procedure would be useful for several biomedical applications of lasers. We present a theory based on the solution of the heat conduction equation that demonshates the feasibility of selectively cooling biological tissues. Model predictions are compared with infrared thermal measurements of in vivo human skin in response to cooling by a c'yogen spun. The presence of B boundary layer, undergoing a liquid-vapour phase transition, is associated with a relatively &e thermal convection coefficient (= 40 kW m-* K-'), which gives rise to the observed surface temperature reductions (30-40 "C). The degree and the spatialtemporal distribution of cooling are shown to be directly related to the cryogen spurt duration.

Lasers in Medical Science, 1997

The epidermal melanin content affects most dermatologic treatments involving light, and can limit... more The epidermal melanin content affects most dermatologic treatments involving light, and can limit the therapeutic success significantly. Therefore, knowledge of the optical properties of skin is required. This study investigates how the concentration of melanin influences visible reflectance spectra of skin and the relationship to threshold radiant energy fluence for melanosomal or melanocyte destruction. Reflectance spectra were measured at 28 pigmented human skin sites in vivo. For Asian and Caucasian subjects, measured reflectance values varied over the same range, while significantly lower values were recorded for African individuals. Epidermal melanin absorption coeMcients measured at 694 nm were about 2500 m-1 for African, and 300-1200 m-1 for Caucasian and Asian skin. Twenty-five skin sites were exposed to ruby laser pulses (694 rim), where the pulse duration was long enough to allow heat diffusion between melanosomes. Hypopigmentation occurred, on average, at 12 and 26 J cm 2 for sun-exposed and sun-protected white skin, respectively, while slightly lower threshold values resulted from the measured spectra. As visible reflectance spectra reveal information regarding skin pigmentation and individual threshold doses for melanosomal damage, a use as a diagnostic tool in various dermatological laser treatments is apparent.

Lasers in Medical Science, 1996

Specifying the distribution of laser energy within a tissue is the first step towards understandi... more Specifying the distribution of laser energy within a tissue is the first step towards understanding and capitalizing on a variety of laser-tissue interactions. Whether photothermal, photochemical or photomechanical in nature, laser-tissue interactions begin with the absorption of photon energy. The spatial distribution of photon absorption specifies the required laser exposure to be delivered and the extent of subsequent therapeutic action. Using infra-red ~omography (IRT), the broad long-term objective of this research is the development of a ~omographic reconstruction algorithm as a means to determine: (1) the depths and physical dimensions of discrete subsurface port-wine-stain (PWS) blood vessels in human skin; and (2) the initial space-dependent temperature increase in PWS blood vessels immediately following pulsed laser exposure. In this reportl prelimingry studies are described which demonstrate the potential Rpplieation of IRT in the etinieal management of' PWS patients.

Journal of Investigative Dermatology, 1994

Journal of Biomedical Optics, 1997

Optical low-coherence reflectometry and confocal microscopy images were taken of the rat dorsal s... more Optical low-coherence reflectometry and confocal microscopy images were taken of the rat dorsal skin flap window model. Blood vessel depths and diameters measured with the two techniques, and preparation thickness determined from reflectometry images, are in reasonable agreement with measurements from histologic sections. Blood vessels appear as areas of low signal when constant-depth reflectometry images are taken at a depth near the center of a vessel, whereas they appear bright when taken close to the blood-dermis boundary. Doppler shift plus increased light absorption in blood, and the blood-dermis index of refraction mismatch, are discussed as possible causes of the dark-and bright-appearing vessels, respectively. One reflectometry image was used to generate an input grid for a novel Monte Carlo analysis program that is capable of determining the light distribution and heat generation ͓J/m 3 ͔ within complex blood vessel geometries. The feasibility of imaging skin blood vessel accurately with optical low-coherence tomography, and using the acquired knowledge of blood vessels structure to create more realistic Monte Carlo analyses is demonstrated by the results of the study.

Journal of Biomedical Optics, 2008

Photothermal therapy is a noninvasive, targeted, laserbased technique for cancer treatment. Durin... more Photothermal therapy is a noninvasive, targeted, laserbased technique for cancer treatment. During photothermal therapy, light energy is converted to heat by tumor-specific photoabsorbers. The corresponding temperature rise causes localized cancer destruction. For effective treatment, however, the presence of photoabsorbers in the tumor must be ascertained before therapy and thermal imaging must be performed during therapy. This study investigates the feasibility of guiding photothermal therapy by using photoacoustic imaging to detect photoabsorbers and to monitor temperature elevation. Photothermal therapy is carried out by utilizing a continuous wave laser and metal nanocomposites broadly absorbing in the near-infrared optical range. A linear array-based ultrasound imaging system is interfaced with a nanosecond pulsed laser to image tissue-mimicking phantoms and ex-vivo animal tissue before and during photothermal therapy. Before commencing therapy, photoacoustic imaging identifies the presence and spatial location of nanoparticles. Thermal maps are computed by monitoring temperature-induced changes in the photoacoustic signal during the therapeutic procedure and are compared with temperature estimates obtained from ultrasound imaging. The results of our study suggest that photoacoustic imaging, augmented by ultrasound imaging, is a viable candidate to guide photoabsorber-enhanced photothermal therapy.

Journal of Biomedical Optics, 2013

A swept-source dual-wavelength photothermal (DWP) optical coherence tomography (OCT) system is de... more A swept-source dual-wavelength photothermal (DWP) optical coherence tomography (OCT) system is demonstrated for quantitative imaging of microvasculature oxygen saturation. DWP-OCT is capable of recording three-dimensional images of tissue and depth-resolved phase variation in response to photothermal excitation. A 1,064-nm OCT probe and 770-nm and 800-nm photothermal excitation beams are combined in a single-mode optical fiber to measure microvasculature hemoglobin oxygen saturation (SO 2) levels in phantom blood vessels with a range of blood flow speeds (0 to 17 mm∕s). A 50-μm-diameter blood vessel phantom is imaged, and SO 2 levels are measured using DWP-OCT and compared with values provided by a commercial oximeter at various blood oxygen concentrations. The influences of blood flow speed and mechanisms of SNR phase degradation on the accuracy of SO 2 measurement are identified and investigated.

IEEE Journal of Selected Topics in Quantum Electronics, 1996

Information regarding energy deposition during laser irradiation of structurally complex biologic... more Information regarding energy deposition during laser irradiation of structurally complex biological tissue is needed to understand and improve the results of clinical procedures. A modular adaptive geometry numerical model capable of simulating the propagation of laser light in a wide variety of multiple component tissues has been developed and tested. A material grid array is generated by assigning a value representing a tissue type to each of a large number of small voxels. The grid array is used to indicate optical properties in an existing variable step size, weighted-photon Monte Carlo algorithm that has been modified to account for voxels-to-voxels changes in optical properties. To test the model, simple geometric shapes and optical low coherence reflectometry images of rat skin have been used to create material grids consisting of epidermis, dermis, and blood. The model assumes 1-J/cm 2 irradiation of the tissue samples with a 1.0-mm diameter uniform beam at 585 nm. Computed results show good quantitative and qualitative agreement with published data. Various effects due to shading and scattering, similar to those suggested in the literature, are noted. This model provides a way to achieve more realistic representation of anatomical geometry as compared to other models, and produces accurate results.

IEEE Journal of Selected Topics in Quantum Electronics, 1999

Optical Doppler tomography (ODT) is an imaging modality that takes advantage of the short coheren... more Optical Doppler tomography (ODT) is an imaging modality that takes advantage of the short coherence length of a broad-band light sources to perform micrometer-scale, crosssectional imaging of tissue structure and blood flow dynamics simultaneously. We review in this paper the principal of ODT and its applications. Results from in vitro and in vivo model studies demonstrated that ODT can map the blood flow velocity profile with high spatial resolution in scattering medium. ODT detection mechanisms are illustrated using Monte Carlo simulations. The application of ODT to image brain hemodynamics is demonstrated. Finally, we discuss the limitations of the current technology and application of a phase resolved technique to improve image speed and quality.

Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 2002

Differential phase optical low coherence reflectometry (OLCR) was used to detect sub-wavelength d... more Differential phase optical low coherence reflectometry (OLCR) was used to detect sub-wavelength displacements in the infrared-sensitive thoracic pit organ of Melanophila acuminata (Coleoptera: Buprestidae) upon absorption of infrared radiation at 3.39 mm. The displacement had more complex morphology but similar amplitude (;100 nm at 1 W cm) y2 when compared to the displacement measured from the exocuticle in an alternate region on the beetle's body. In addition, a simplified finite difference model was developed to predict the temperature distribution and resultant thermal expansion in the pit organ tissue. The experimental and model results were interpreted to help clarify the mechanism by which the sensilla in the pit organ convert infrared radiation to neural signals. The results of this paper are discussed in relation to the photo-thermal-mechanical transduction hypothesis. This is the first experimental examination of the transduction mechanism in Melanophila acuminata.

ACS Nano, 2009

The ability of 20-50 nm nanoparticles to target and modulate the biology of specific types of cel... more The ability of 20-50 nm nanoparticles to target and modulate the biology of specific types of cells will enable major advancements in cellular imaging and therapy in cancer and atherosclerosis. A key challenge is to load an extremely high degree of targeting, imaging, and therapeutic functionality into small, yet stable particles. Herein we report ~30 nm stable uniformly sized near-infrared (NIR) active, superparamagnetic nanoclusters formed by kinetically controlled self-assembly of goldcoated iron oxide nanoparticles. The controlled assembly of nanocomposite particles into clusters with small primary particle spacings produces collective responses of the electrons that shift the absorbance into the NIR region. The nanoclusters of ~70 iron oxide primary particles with thin gold coatings display intense NIR (700-850 nm) absorbance with a cross section of ~10 −14 m 2. Because of the thin gold shells with an average thickness of only 2 nm, the r 2 spin-spin magnetic relaxivity is 219 mM −1 s −1 , an order of magnitude larger than observed for typical iron oxide particles with thicker gold shells. Despite only 12% by weight polymeric stabilizer, the particle size and NIR absorbance change very little in deionized water over 8 months. High uptake of the nanoclusters by macrophages is facilitated by the dextran coating, producing intense NIR contrast in dark field and hyperspectral microscopy, both in cell culture and an in vivo rabbit model of atherosclerosis. Small nanoclusters with optical, magnetic, and therapeutic functionality, designed by assembly of