Photodynamic therapy (PDT) has been used intraoperatively to treat patients with malignant pleural mesothelioma. For the efficiency of PDT, it is crucial to deliver light doses uniformly. The current procedure utilizes eight light detectors placed inside the pleural cavity to monitor the light. An updated navigation system, combined with a novel scanning system, is developed to provide real-time guidance for physicians during pleural PDT to improve light delivery. The scanning system consists of two handheld three-dimensional (3D) scanners to capture the pleural cavity's surface topographies quickly and precisely before PDT so that the target surface can be identified for real-time light fluence distribution calculation during PDT. An algorithm is developed to further process the scanned volume to denoise for accurate light fluence calculation and rotate the local coordinate system into any desired direction for a clear visualization during the real-time guidance. The navigation coordinate system is registered to the patient coordinate system utilizing at least three markers to track the light source point position within the pleural cavity throughout the treatment. During PDT, the light source position, the scanned pleural cavity, and the light fluence distribution for the cavity's surface will be displayed in 3D and 2D, respectively. For validation, this novel system is tested using phantom studies with a large chest phantom and 3D-printed lung phantoms of different volumes based on a personal CT scan, immersed in a liquid tissue-simulating phantom with different optical properties, and treated with eight isotropic detectors and the navigation system.
We developed a simulation method for modeling the light fluence delivery in intracavity Photodynamic Therapy (icav-PDT) for pleural lung cancer using a moving light source. Due to the large surface area of the pleural lung cavity, the light source needs to be moved to deliver a uniform dose around the entire cavity. While multiple fixed detectors are used for dosimetry at a few locations, an accurate simulation of light fluence and fluence rate is still needed for the rest of the cavity. We extended an existing Monte Carlo (MC) based light propagation solver to support moving light sources by densely sampling the continuous light source trajectory and assigning the proper number of photon packages launched along the way. The performance of Simphotek GPU CUDA-based implementation of the method – PEDSy-MC – has been demonstrated on a life-size lung-shaped phantom, custom printed for testing icav-PDT navigation system at the Perlman School of Medicine (PSM) – calculations completed under a minute (for some cases) and within minutes have been achieved. We demonstrate results within a 5% error of the analytic solution for multiple detectors in the phantom. PEDSy-MC is accompanied by a dose-cavity visualization tool that allows real-time inspection of dose values of the treated cavity in 2D and 3D, which will be expanded to ongoing clinical trials at PSM. PSM has developed a technology to measure 8-detectors in a pleural cavity phantom using Photofrin-mediated PDT that has been used during validation.
We compare previously reported benzoporphyrin derivative (BPD)-mediated photodynamic therapy (PDT) results for reactive singlet oxygen concentration (also called singlet oxygen dose) on mice with simulations using a computational device, Dosie™, that calculates light transport and photokinetics for PDT in near real-time. The two sets of results are consistent and validate the use of the device in PDT treatment planning to predict BPD-mediated PDT outcomes in mice animal studies based on singlet oxygen dose, which showed a much better correlation with the cure index than the conventional light dose.
We compare previously reported 2-(1-hexyloxyethyl)-2-divinyl pyropheophorbide (HPPH) mediated photodynamic therapy (PDT) experimental results for singlet oxygen dose on mice with simulations using a new, integrated, hardware and software device, DosieTM, that calculates light transport and photokinetics for PDT. The two sets of results are consistent and validate the use of the device simulations to predict HPPH-mediated PDT results on mice animal studies.
Accurate light dosimery is critical to ensure consistent outcome for pleural photodynamic therapy (pPDT). Ellipsoid shaped cavities with different sizes surrounded by turbid medium are used to simulate the intracavity lung geometry. An isotropic light source is introduced and surrounded by turbid media. Direct measurements of light fluence rate were compared to Monte Carlo simulated values on the surface of the cavities for various optical properties. The primary component of the light was determined by measurements performed in air in the same geometry. The scattered component was found by submerging the air-filled cavity in scattering media (Intralipid) and absorbent media (ink). The light source was located centrally with the azimuthal angle, but placed in two locations (vertically centered and 2 cm below the center) for measurements. Light fluence rate was measured using isotropic detectors placed at various angles on the ellipsoid surface. The measurements and simulations show that the scattered dose is uniform along the surface of the intracavity ellipsoid geometries in turbid media. One can express the light fluence rate empirically as φ =4S/As*Rd/(1- Rd), where Rd is the diffuse reflectance, As is the surface area, and S is the source power. The measurements agree with this empirical formula to within an uncertainty of 10% for the range of optical properties studied. GPU voxel-based Monte-Carlo simulation is performed to compare with measured results. This empirical formula can be applied to arbitrary geometries, such as the pleural or intraperitoneal cavity.
Effective photodynamic therapy (PDT) treatment planning and treatment monitoring requires computer simulations of
both light transport in tissue and photosensitizer (PS) photophysics to accurately estimate singlet oxygen. Simply using
fixed prescribed values of light dose (fluence) or PDT dose (the time integral of ‘PS concentration’ times the ‘fluence
rate’) – one value for all patients – does not account for differences in the amount of singlet oxygen formed when
fluence rates change or patient tissue parameters change. We will focus on singlet oxygen dose which is calculated by
solving the photokinetics rate equations and which determines the effectiveness of the subsequent reactions of singlet
oxygen with the cancer target and the negative effect of PS photobleaching.
Using a novel numerical method we show how to optimize the resolution enhancement of stimulated emission depletion
(STED) by simulating the entire process including the absorption, overlapping multiple beams and stimulated emission.
We provide calculations showing that for fixed donut pulse energy, a longer donut pulse length can result in greater
resolution enhancement than a shorter donut pulse length. These results show how it is possible to use our simulations to
design the best experimental conditions for STED resolution enhancement and illustrate the importance of having a
software program that includes both multiple beams and stimulated emission.
Many techniques in biological and clinical science use multiphoton absorbers for fluorescence. The applications include medical imaging for living cells, diagnostic techniques for disease and spectroscopy. The intrinsic value of the multiphoton absorber coefficients is therefore of the utmost importance. Additionally, the laser intensity at which the absorber saturates can determine which absorber, dye or protein is useful for a particular application.
Yet, experimental methods for determining the optical coefficients often yield different results. We describe several common methods of 2PA measurements and describe their features. As an example of the importance of applying the correct analysis to measurements, we fit experimental data and obtain values for multiphoton absorbers and accurately obtain their intrinsic values. Finally, we present the optical properties of several multiphoton materials used in biology.
Multiple fluorescent probes (multi-dyes) and single or multi-laser configurations can significantly extend the applications and accuracy of microscopy. Multiple fluorescent probes enable the user to identify more than one target, but difficulties can arise due to overlapping spectral emissions of the different probes. In particular, spectral overlapping of fluorescent and/or phosphorescent emission signals can lead to incorrect analysis. We present a method to numerically calculate overlapping spectra. An accurate modeling tool would be valuable to predict the best laser-probes combinations for selection and screening stages.
We use a numerical method that simulates both time and space so that we can calculate on a near-instantaneous basis the absorption of laser light and electron populations. We can then calculate the intensity of the emitted signal and determine the overlap of the spectra.
Traditional numerical analyses of laser beam transmission through “active” nonlinear materials have involved many assumptions that narrow their general applicability. As more complex optical phenomena are widely employed in research and industry, it is necessary to expand the use of numerical simulation methods. Historically, laser-matter interactions have involved calculations of “classical” wave propagation by Maxwell’s equations and photon absorption through rate equations using numerous approximations. We describe a novel numerical modeling framework that adapts itself for simulation of different types of active materials provided by a simple graphical input. Our framework combines classical electric field propagation with “active” photon absorption kinetics using computational active photonic building blocks (APBB). It allows investigating a plane electromagnetic wave propagating through generic organic or inorganic photoactive materials; while, “active” photo-transitions are implemented using the APBB algorithm on the user interface. To date we have used the method in multiphoton absorbers, upconversion, semiconductor quantum dots, rare earth ions, organic chromophores, singlet oxygen formation, energy transfer, and optically-induced chemical reactions. We will demonstrate the method with applications of amplification in rare-earth ions and multiple two-photon absorbers materials in tandem.
Many traditional investigations of saturation in multiphoton absorbers with the z-scan method use an approximate
analytical formula that assumes a steady-state approximation. Using a numerical simulation for Maxwell’s equations for
laser propagation including diffraction and coupled electron population dynamics, we show that the commonly used
analytical formula for determining saturation in multiphoton absorbers is often incorrect, even when the sample thickness
is only one diffraction length. Using published experimental data on an organic chromophore, we show that saturation, in
fact, does not occur at the laser intensity values predicted for these two and three photon absorbers. We numerically fit
the published experimental z-scan data and obtain new absorption coefficients for multiphoton absorbers that accurately
reflect their intrinsic values. The new values are from three to ten times larger than the published values.
Because multiphoton absorbers are being used more extensively in many applications such as optical limiter, medical
diagnostics and two photon microscopy, it is important to have accurate values for the two and three-photon absorption
coefficients. Knowing the real value of the multiphoton absorber coefficients, even for a single diffraction length, is
therefore of the utmost importance. In particular, the laser intensity at which the absorber saturates can determine which
absorber is useful for a particular application.
Advances in biophotonic medicine require new information on photodynamic mechanisms. In photodynamic therapy (PDT), a photosensitizer (PS) is injected into the body and accumulates at higher concentrations in diseased tissue compared to normal tissue. The PS absorbs light from a light source and generates excited-state triplet states of the PS. The excited triplet states of the PS can then react with ground state molecular oxygen to form excited singlet - state oxygen or form other highly reactive species. The reactive species react with living cells, resulting in cel l death. This treatment is used in many forms of cancer including those in the prostrate, head and neck, lungs, bladder, esophagus and certain skin cancers. We developed a novel numerical method to model the photophysical and photochemical processes in the PS and the subsequent energy transfer to O2, improving the understanding of these processes at a molecular level. Our numerical method simulates light propagation and photo-physics in PS using methods that build on techniques previously developed for optical communications and nonlinear optics applications.
In flow cytometry a group of cells labeled with a fluorescent probe molecule or dye is focused into a single cell stream
passing through a laser light source. The fluorescent light is filtered and sampled by an array of detectors. In many cases
a single light source and one probe/dye molecule have been used. But additional information can be obtained if several
different laser wavelengths and multiple probes fluorescing at other wavelengths are used. We consider four lasers at
488nm, 532nm, 640nm and 785nm which occur near the peak absorptions of common fluorescent probes, Alexa488,
Alexa532, Alexa647 and Alexa750, respectively. In some cases overlapping of the various fluorescent spectra occur.
This effect can be mitigated by checking the emitted signals in individual wavelength channels and subtracting them, a
practice known as compensation. But residual amounts of fluorescence as well as phosphorescence may not be
completely taken into account because of the photodetector sensitivity. Using our unique numerical we calculated both
the fluorescence and phosphorescence intensities in a multi-laser and multi-probe configuration. The total intensities of
the fluorescent state and phosphorescent state are calculated for a range of laser powers from 5mW to 100mW. We
found that there can be significant overlap between fluorescence and phosphorescence emission from multiple dyes.
We describe a general numerical method for calculating short-pulse laser propagation in rare-earth-doped materials,
which are very important as gain materials for solid-state lasers, fiber lasers and optical amplifiers. The split-step, finite
difference method simultaneously calculates changes in the laser pulse as it propagates through the material and
calculates the dynamic populations of the rare-earth energy levels at any position within the material and for times during
and after the laser pulse has passed through the material. Many traditional theoretical and numerical analyses of laser
pulse propagation involve approximations and assumptions that limit their applicability to a narrow range of problems.
Our numerical method, however, is more comprehensive and includes the processes of single- and multi-photon
absorption, excited state absorption (ESA), energy transfer, upconversion, stimulated emission, cross relaxation,
radiative relaxation and non-radiative relaxation. In the models, the rare-earth dopants can have an arbitrary number of
energy levels. We are able to calculate the electron population density of every electronic level as a function of, for
example, pulse energy, dopant concentration and sample thickness. We compare our theoretical results to published
experimental results for rare-earth ions such as Er3+, Yb3+, Tm3+ and Ho3+.
We describe a unique mathematical/numerical model to analyze ultrafast laser experimental data and obtain two-photon
(TPA) and multi-photon (MPA) absorption parameter(s). The material used to demonstrate the numerical method is a
hybrid organic-inorganic nano-structured semiconductor quantum dot-polymer composite. Chemical, biological and
engineering studies require advancements in TPA/MPA absorbers for microscopy, fluorescence, imaging, and microprocessing
of materials. We illustrate the numerical method by fitting data from the well-known z-scan experimental
method. Often an analytical model is used to analyze data from such experiments, which is limited in scope with
certain restrictions on laser intensity and material thickness.
A more general mathematical/numerical method that includes TPA/MPA and can be extended to free carrier absorption
and stimulated emission is described. Under certain circumstances, we can also calculate the electron population
density on every electronic level to demonstrate physical effects such as saturation. Additionally, we include
diffraction in our numerical calculation so that the TPA/MPA can be obtained even for thick optical samples. We use
the numerical method to calculate published z-scan measurements on quantum-dot CdS-polymer composites, and show
excellent agreement with published analytical results.
We have developed a mathematical/numerical framework based on computational transition modules and measured
ultrafast laser light propagating through nonlinear materials. The numerical framework can be applied to a broad set of
photo-activated materials and lasers, and can optimize photo-physical parameters in multi-photon absorbers. Two
photon (TPA) processes are particularly useful in many applications including fluorescence imaging, optical data
storage, micro-fabrication, and nanostructured quantum dots for optical limiters. Laser transmission measurements of
the organic molecular chromophore, AF455-known TPA material-were taken with a 175 fs, λ0=780nm, plane-polarized
light pulses from Ti:S regenerative amplifier into a 5.1mm thick PMMA slab doped with the chromophore. The range of
input energies (intensities) in this experiment was 0.01μJ (0.97 GW/cm2) to 25 μJ (2.4 x103 GW/cm2). Experiments
showed that for intensities beyond several μJ, the material did not saturate as predicted by traditional theory. We
included excited-state absorption (ESA), as demonstrated by the absorption spectrum, which still could not account for
the deviation. To understand this result we used our framework to show that an unexpected/unknown higher energy
level was being populated. We calculated the entire experimental curve from 0.01μJ (0.97 GW/cm2) to 25 μJ (2.4 x103
GW/cm2) and found excellent agreement with the experimental data.
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