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.
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 present recent significant progress in the fabrication of polymer Bragg gratings suitable for telecom applications. We demonstrate that polymer Bragg gratings can be thermally tuned over 20nm with polarization sensitivity less than 0.05nm. Experimental data are presented to address issues of long-term performance stability, propagation loss, polarization sensitivity and practical wavelength tuning. Polymer Bragg gratings are shown to survive very stringent accelerated aging tests and exhibit long-term stability in both material properties and grating performance. The spectral performance of the gratings and example telecom applications employing polymer Bragg gratings are also discussed.
A key property that differentiates optical polymers from more conventional optical materials such as glass, is the rapid variation of the refractive index with temperature. This large difference in dn/dT can be leveraged to produce efficient thermo-optically active optical components. An advanced polymeric waveguide technology was developed for affordable thermo-optically active integrated optical devices that address the needs of the telecom industry. We engineered high-performance organic polymers that can be readily made into single-mode waveguide structures of controlled geometries and of modal profiles that closely match standard telecom glass fibers. These materials are formed from highly-crosslinked halogenated acrylate monomers with specific linkages that determined properties such as flexibility, toughness, optical loss, thermal stability, and humidity resistance. These monomers are intermiscible, providing for precise continuous adjustment of the refractive index over a wide range. In polymer form, they exhibit state-of-the-art loss values, suppressed polarization effects, and exceptional environmental stability. The devices we describe include thermally tunable Bragg-grating-based wavelength filters, thermally tunable arrayed-waveguide gratings, and digital optical switches.
All-optical networks that exhibit high speed, high capacity, scalability, configurability, and transparency are becoming a reality through the exploitation of the unique properties of fiber and integrated optics. An advanced polymeric waveguide technology was developed for affordable passive and active integrated optical elements that address the needs of these networks. We engineered high-performance organic polymers that can be readily made into photonic circuits of controlled numerical apertures and geometries. These materials are formed from highly-crosslinked acrylate monomers with specific linkages that determine properties such as flexibility, robustness, optical loss, thermal stability, and humidity resistance. These monomers are intermiscible, providing for precise continuous adjustment of the refractive index over a wide range. In polymer form, they exhibit state-of-the-art optical loss values, suppressed polarization effects, and exceptional environmental stability. A wide range of rigid and flexible substrates can be used. The devices we describe include demultiplexers, tunable wavelength filters, digital optical switches, and variable optical attenuators.
We have investigated the photochemistry and optical properties of an azo dye-based electro- optic (EO) copolymer, methacrylate-bound Disperse Red 1/methylmethacrylate (MA1). We present a complete picture of the optical properties of the copolymer at wavelengths ranging from 200 nm to 1800 nm with detection sensitivity over 6 orders of magnitude. We describe intrinsic measurements of absorption loss and also describe how temperature and radiation affect absorption loss. Photochemical investigations reveal details concerning photodelineation of waveguides in MA1. Irreversible photodegradation of the azo chromophore proceeds with both visible and ultra-violet radiation and a quantum yield of 2 X 10-5 is found for 475 nm radiation in MA1.
Practical applications of electro-optic polymers require thermally stable materials with high electro-optic coefficients and low absorption loss. In this report, we first review the properties of some azo-based electro-optic polymer materials and devices. We then describe a new class of electro-optic cardo polymers with glass transition temperatures greater than 200$DEGC.
We describe a laser-writing technique for fabricating polymeric optical waveguides by photo- crosslinking acrylate monomer materials. We report loss measurements as low as 0.01 dB/cm in straight laser-written photopolymer waveguides and describe changes in waveguide losses at temperatures up to 250 degree(s)C. Loss measurements are also summarized for 90 degree(s) bends and laser-written 8 X 8 star couplers.
We report loss measurements in polymer-bound Disperse Red I slab and photodelineated channel waveguides. Losses resulting from electronic charge-transfer and vibrational carbon- hydrogen stretch overtone absorptions, trans to cis isomerization, exposure to visible or ultraviolet (UV) light and changes in dye pendant group number density are investigated. A waveguide absorption spectrometer is described which can measured waveguide losses (alpha) ((lambda) ) from 600 - 1800 nm. Absorption losses are compared to the wavelength dependent electro-optic coefficient r33((lambda) ) and a figure-of-merit r33((lambda) )/(alpha) ((lambda) ) is determined for the material.
Polymeric materials that exhibit a controlled change in refractive index upon irradiation with UV light are promising candidates for the development of polymeric optical interconnects. We have demonstrated that polymers containing nitrone functional groups can be spatially patterned for single-mode waveguide devices using both laser direct writing and traditional photolithographic techniques.
Polymeric materials suitable for the formation of both passive and electro-optically active waveguide devices have been produced. We have developed methods for delineating channel waveguides in thin polymer films via a photopatteming technique. A description of the performance characteristics of devices incorporating these materials will be presented. An analysis of the advantages and drawbacks of polymeric systems will also be included.
The formation of both passive and active optical waveguide structures in thin films of organic polymers by a direct one-step photochemical process is reported. A photochemical transformation changes the chemical composition of a polymer of dye/polymer mixture. The reaction modifies the absorption spectrum of the material and thus alters its index of refraction. This technique is used to create waveguide structures both by spatially-selected laser direct writing and contact mask exposure. It is demonstrated that passive and active waveguide structures can be delineated in thin films of organic polymers by photochemically altering the index of refraction of the materials. The formation of single or multimode devices is possible using standard lithographic procedures which are suitable for mass production.
Nonlinear triplet-triplet absorption in organic molecules can be used to construct
all-optical switches and spatial light modulators. Experimental results using films
of eosin in polyvinylacohol are presented and compared with theoretical
calculations.
Organic polymeric materials offer great promise for the creation ofoptical guided-wave structures for use with silicon
or gallium arsenide semiconductor devices. We have developed a number of new polymeric materials for which the refractive
index may be photochemically controlled. These materials are ifiustrated by solid solutions of novel nitrone compounds in
polymer hosts such as PMMA. We have demonstrated the creation of planar guided-wave structures in these materials both
with direct laser writing and with traditional photolithographic techniques. We have also developed polymeric materials which
are electro-optically active and which provide for the photochemical delineation ofguided-wave structures. We have utilized
these materials to create electro-optic devices such as optical modulators.
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