Studies on Mathematical Modeling of Middle Ear Gas Exchange

Middle ear (ME) pressure regulation is a topic of fundamental interest to the pediatric otolaryngology community since a lack of proper regulation is a precursor to middle ear disease. Development of mathematical models of ME gas exchange can improve understanding of the underlying ME physiology. Previous models were limited in their description of gas exchange (based on inputted empirical exchange constants) and in their application (few models posses capacity for clinical relevance in diagnosis). Here, we present investigations which improve and expand on previous models. The first study presents a global description of ME pressure regulation and applies the model to flight-related barotrauma. While a well functioning Eustachian tube has long been known to protect from barotrauma, the simulation results show that a variety of buffering mechanisms can reduce the demand placed on the efficiency of that function. Using these results, subclasses of ears with little risk for barotrauma were identified and an algorithm was developed that makes these assignments based on measurable variables. The second study outlines and analyzes a morphometric approach to describing transmucosal gas exchange within the middle ear. Implementation of the morphometric model requires the measurement of diffusional length (tao) for the ME mucosa which contributes to the mucosal diffusing capacity, a measure of the resistance to gas flow between airspace and capillary. Two methods for measuring tao have been proposed: the linear distance between air-mucosal boundary and capillary as described by Ars and colleagues, and the harmonic mean of all contributing pathway lengths as described by Weibel and colleagues. Here, oxygen diffusing capacity was calculated for different ME mucosal geometries using the two tao measures, and the results were compared to those predicted by a 2-dimensional finite element analysis. Predictive accuracy was improved by incorporating the tao measure described by Weibel which captures important information regarding variations in capillary shape and distribution. However, when compared to the oxygen diffusing capacity derived from the finite element analysis, both measures yielded non-linear, positively biased estimates. The morphometric techniques underestimate diffusion length by failing to account for the curvilinear gas flow pathways predicted by the finite element model

Analysis and Modeling of Noninvasive measurement of Tissue Chromophores by the Optical Pharmacokinetic System

Efficient design of anti-cancer treatments involving radiation- and photo-sensitizing therapeutics requires knowledge of tissue-specific drug concentrations. This dissertation investigates the utility of the Optical Pharmacokinetic System (OPS), a fiber-optic based elastic-scattering spectroscopy device, to noninvasively quantitate concentrations of sensitizing compounds and hemoglobin within tissue in vivo. The OPS was used to quantitate concentrations of motexafin gadolinium (MGd), in mouse tissues in vivo and in situ. An algorithm was developed to quantify MGd absorbance by integration of the MGd peak absorbance area, thereby relaxing the requirement that the extinction coefficient be known a priori. Concentrations measured by OPS were well-correlated with measurements by high-performance liquid chromatography (HPLC). Compartmental pharmacokinetic models were developed from tissue-specific MGd concentrations measured by OPS and HPLC. Models predicted both rapid initial distribution and slow elimination of MGd in plasma, fast transport of MGd out of the skin, and MGd retention at long times in the tumor. In vivo tumor MGd concentrations measured by the OPS were estimated by a linear combination of the plasma, tumor, and skin PK profiles. A theoretical analysis of the OPS measurement of tissue was conducted using a Monte Carlo (MC) model of light transport through tissue that included discrete blood vessels. Simulation results motivated extensions to a previous analysis algorithm, including: (1) a novel analytic functionality between mean photon path length and total absorption coefficient; and (2) incorporation of a vessel correction factor to account for the pigment packaging effect of discrete vessels on the OPS-estimated absorption coefficient. These extensions improved OPS-estimates of both silicon phthalocyanine (Pc4) and hemoglobin concentration in a mouse xenograft in vivo following photodynamic therapy (PDT). Mathematical models were utilized to investigate in silico the sensitivity of the OPS to chronically and acutely hypoxic regions within tumor tissue. PDT-induced acute hypoxia occured via simulation of the photodynamic reaction. Subsequent simulation of the OPS measurement suggested that the OPS may be sensitive to the presence of chronically hypoxic vessels (an OPS-estimated hemoglobin saturation of &ge 57 indicated < 6 of vessels hypoxic), but may have limited application to detection of acute hypoxia following PDT

Spectroscopic Separation of Čerenkov Radiation in High-Resolution Radiation Fiber Dosimeters

We have investigated Čerenkov radiation generated in phosphor-based optical fiber dosimeters irradiated with clinical electron beams. We fabricated two high-spatial resolution fiber-optic probes, with 200 and 400  μm core diameters, composed of terbium-based phosphor tips. A generalizable spectroscopic method was used to separate Čerenkov radiation from the transmitted signal by the fiber based on the assumption that the recorded signal is a linear superposition of two basis spectra: characteristic luminescence of the phosphor medium and Čerenkov radiation. We performed Monte Carlo simulations of the Čerenkov radiation generated in the fiber and found a strong dependence of the recorded Čerenkov radiation on the numerical aperture of the fiber at shallow phantom depths; however, beyond the depth of maximum dose that dependency is minimal. The simulation results agree with the experimental results for Čerenkov radiation generated in fibers. The spectroscopic technique used in this work can be used for development of high-spatial resolution fiber micro dosimeters and for optical characterization of various scintillating materials, such as phosphor nanoparticles, in ionizing radiation fields of high energy

A GAMOS Plug-In for GEANT4 Based Monte Carlo Simulation of Radiation-Induced Light Transport in Biological Media

We describe a tissue optics plug-in that interfaces with the GEANT4/GAMOS Monte Carlo (MC) architecture, providing a means of simulating radiation-induced light transport in biological media for the first time. Specifically, we focus on the simulation of light transport due to the Čerenkov effect (light emission from charged particle\u27s traveling faster than the local speed of light in a given medium), a phenomenon which requires accurate modeling of both the high energy particle and subsequent optical photon transport, a dynamic coupled process that is not well-described by any current MC framework. The results of validation simulations show excellent agreement with currently employed biomedical optics MC codes, [i.e., Monte Carlo for Multi-Layered media (MCML), Mesh-based Monte Carlo (MMC), and diffusion theory], and examples relevant to recent studies into detection of Čerenkov light from an external radiation beam or radionuclide are presented. While the work presented within this paper focuses on radiation-induced light transport, the core features and robust flexibility of the plug-in modified package make it also extensible to more conventional biomedical optics simulations. The plug-in, user guide, example files, as well as the necessary files to reproduce the validation simulations described within this paper are available online at http://www.dartmouth.edu/optmed/research-projects/monte-carlo-software

White Light-Informed Optical Properties Improve Ultrasound-Guided Fluorescence Tomography of Photoactive Protoporphyrin IX

Subsurface fluorescence imaging is desirable for medical applications, including protoporphyrin-IX (PpIX)-based skin tumor diagnosis, surgical guidance, and dosimetry in photodynamic therapy. While tissue optical properties and heterogeneities make true subsurface fluorescence mapping an ill-posed problem, ultrasound-guided fluorescence-tomography (USFT) provides regional fluorescence mapping. Here USFT is implemented with spectroscopic decoupling of fluorescence signals (auto-fluorescence, PpIX, photoproducts), and white light spectroscopy-determined bulk optical properties. Segmented US images provide a priori spatial information for fluorescence reconstruction using region-based, diffuse FT. The method was tested in simulations, tissue homogeneous and inclusion phantoms, and an injected-inclusion animal model. Reconstructed fluorescence yield was linear with PpIX concentration, including the lowest concentration used, 0.025  μg/ml . White light spectroscopy informed optical properties, which improved fluorescence reconstruction accuracy compared to the use of fixed, literature-based optical properties, reduced reconstruction error and reconstructed fluorescence standard deviation by factors of 8.9 and 2.0, respectively. Recovered contrast-to-background error was 25% and 74% for inclusion phantoms without and with a 2-mm skin-like layer, respectively. Preliminary mouse-model imaging demonstrated system feasibility for subsurface fluorescence measurement in vivo. These data suggest that this implementation of USFT is capable of regional PpIX mapping in human skin tumors during photodynamic therapy, to be used in dosimetric evaluations

Hyperspectral Data Processing Improves PpIX Contrast During Fluorescence Guided Surgery of Human Brain Tumors.

Fluorescence guided surgery (FGS) using aminolevulinic-acid (ALA) induced protoporphyrin IX (PpIX) provides intraoperative visual contrast between normal and malignant tissue during resection of high grade gliomas. However, maps of the PpIX biodistribution within the surgical field based on either visual perception or the raw fluorescence emissions can be masked by background signals or distorted by variations in tissue optical properties. This study evaluates the impact of algorithmic processing of hyperspectral imaging acquisitions on the sensitivity and contrast of PpIX maps. Measurements in tissue-simulating phantoms showed that (I) spectral fitting enhanced PpIX sensitivity compared with visible or integrated fluorescence, (II) confidence-filtering automatically determined the lower limit of detection based on the strength of the PpIX spectral signature in the collected emission spectrum (0.014–0.041 μg/ml in phantoms), and (III) optical-property corrected PpIX estimates were more highly correlated with independent probe measurements (r = 0.98) than with spectral fitting alone (r = 0.91) or integrated fluorescence (r = 0.82). Application to in vivo case examples from clinical neurosurgeries revealed changes to the localization and contrast of PpIX maps, making concentrations accessible that were not visually apparent. Adoption of these methods has the potential to maintain sensitive and accurate visualization of PpIX contrast over the course of surgery

Light Scattering Measured with Spatial Frequency Domain Imaging can Predict Stromal Versus Epithelial Proportions in Surgically Resected Breast Tissue

This study aims to determine if light scatter parameters measured with spatial frequency domain imaging (SFDI) can accurately predict stromal, epithelial, and adipose fractions in freshly resected, unstained human breast specimens. An explicit model was developed to predict stromal, epithelial, and adipose fractions as a function of light scattering parameters, which was validated against a quantitative analysis of digitized histology slides for N  =  31 specimens using leave-one-out cross-fold validation. Specimen mean stromal, epithelial, and adipose volume fractions predicted from light scattering parameters strongly correlated with those calculated from digitized histology slides (r  =  0.90, 0.77, and 0.91, respectively, p-value×  10  -  6). Additionally, the ratio of predicted epithelium to stroma classified malignant specimens with a sensitivity and specificity of 90% and 81%, respectively, and also classified all pixels in malignant lesions with 63% and 79%, at a threshold of 1. All specimens and pixels were classified as malignant, benign, or fat with 84% and 75% accuracy, respectively. These findings demonstrate how light scattering parameters acquired with SFDI can be used to accurately predict and spatially map stromal, epithelial, and adipose proportions in fresh unstained, human breast tissue, and suggest that these estimations could provide diagnostic value

Macroscopic Optical Imaging Technique for Wide-Field Estimation of Fluorescence Depth in Optically Turbid Media for Application in Brain Tumor Surgical Guidance

A diffuse imaging method is presented that enables wide-field estimation of the depth of fluorescent molecular markers in turbid media by quantifying the deformation of the detected fluorescence spectra due to the wavelength-dependent light attenuation by overlying tissue. This is achieved by measuring the ratio of the fluorescence at two wavelengths in combination with normalization techniques based on diffuse reflectance measurements to evaluate tissue attenuation variations for different depths. It is demonstrated that fluorescence topography can be achieved up to a 5 mm depth using a near-infrared dye with millimeter depth accuracy in turbid media having optical properties representative of normal brain tissue. Wide-field depth estimates are made using optical technology integrated onto a commercial surgical microscope, making this approach feasible for real-world applications