Biosimulation of Vocal Fold Inflammation and Healing

Personalized, pre-emptive and predictive medicine is the capstone of contemporary medical care. The central aim of this dissertation is to address clinical challenges in prescribing personalized therapy to patients with acute phonotrauma. Inflammation and healing, which are innate tissue responses to mechanical stress/ trauma, are regulated by a complex dynamic system. A systems biology approach, which combines empirical, mathematical and computational tools, was taken to study the biological complexity of this dynamic system in vocal fold injury.Computational agent-based models (ABMs) were developed to quantitatively characterize multiple cellular and molecular interactions around inflammation and healing. The models allowed for tests of various hypothetical effects of motion-based treatments in individuals with acute phonotrauma. A phonotrauma ABM was calibrated and verified with empirical data of a panel of inflammatory mediators, obtained from laryngeal secretions in individuals following experimentally induced phonotrauma and a randomly assigned motion-based treatment. A supplementary ABM of surgically induced vocal fold trauma was developed and subsequently calibrated and verified with empirical data of inflammatory mediators and extracellular matrix substances from rat studies, for the purpose of gaining insight into the &ldquo net effect &rdquo of cellular and molecular responses at the tissue level.ABM simulations reproduced and predicted trajectories of inflammatory mediators and extracellular matrix as seen in empirical data of phonotrauma and surgical vocal fold trauma. The simulation results illustrated a spectrum of inflammatory responses to phonotrauma, surgical trauma and motion-based treatments. The results suggested that resonant voice exercise may optimize the combination of para- and anti-inflammatory responses to accelerate healing. Moreover, the ABMs suggested that hyaluronan fragments might be an early molecular index of tissue damage that is sensitive to varying stress levels - from relatively low phonatory stress to high surgical stress.We propose that this translational application of biosimulation can be used to quantitatively chart individual healing trajectories, test the effects of different treatment options and most importantly provide new understanding of laryngeal health and healing. By placing biology on a firm mathematical foundation, this line of research has potential to influence the contour of scientific thinking and clinical care of vocal fold injury

Dynamic characterization of vocal fold virbrations

An emerging trend among voice specialists is the use of quantitative protocols for the diagnosis and treatment of voice disorders. Vocal fold vibrations are directly related to voice quality. This research is devoted to providing an objective means of characterizing these vibrations. Our goal is to develop a dynamic model of vocal fold vibration, and map the parameter space of the model to a class of voice disorders; thus, furthering the assessment and diagnosis of voice disorder in clinical settings. To this end, this dissertation introduces a new seven-mass biomechanical model for the vibration of vocal folds. The model is based on the body-cover layer concept of the vocal fold biomechanics, and segments the cover layer into three masses along the longitudinal direction of the vocal fold. This segmentation facilitates the model comparison with the motion of the vocal glottis contour derived from modern high-speed digital imaging systems. The model simulation is compared to 14 sets of experimental data from human subjects with healthy vocal folds and pathological vocal folds including nodule, polyp, and unilateral paralysis. We also propose a semi-empirical two-stage procedure for tuning the parameters so that the model response matches as closely as possible the experimental data in the time and frequency domains. The first stage involves the manual coarse tuning of parameters based on limited data to expedite the process. The second stage is an automatic (or manual) fine tuning process on a subset of the parameters tuned in the first stage based on a larger amount of data. Once an ‘optimal’ set of model parameters has been identified, two model-based factors, quantifying the asymmetry between left and right vocal folds and anterior and posterior segments of the vocal folds, are introduced and calculated for each of the 14 cases. The two factors form an asymmetry plane. Based on the value of the asymmetry factors for the 14 cases, the plane is subdivided into four regions corresponding to healthy vocal folds, nodule, polyp, and unilateral paralysis. This yields a clear visual aid for clinicians, correlating the model parameters to voice quality

Toward A Simulation-Based Tool for the Treatment of Vocal Fold Paralysis

Advances in high-performance computing are enabling a new generation of software tools that employ computational modeling for surgical planning. Surgical management of laryngeal paralysis is one area where such computational tools could have a significant impact. The current paper describes a comprehensive effort to develop a software tool for planning medialization laryngoplasty where a prosthetic implant is inserted into the larynx in order to medialize the paralyzed vocal fold (VF). While this is one of the most common procedures used to restore voice in patients with VF paralysis, it has a relatively high revision rate, and the tool being developed is expected to improve surgical outcomes. This software tool models the biomechanics of airflow-induced vibration in the human larynx and incorporates sophisticated approaches for modeling the turbulent laryngeal flow, the complex dynamics of the VFs, as well as the production of voiced sound. The current paper describes the key elements of the modeling approach, presents computational results that demonstrate the utility of the approach and also describes some of the limitations and challenges

Differentiation of voice disorders using objective parameters from harmonic waveform modeling in high-speed digital imaging

High-speed digital imaging (HSDI) has recently become clinically available for the direct observation of vocal fold movement in the last 20 years. However, before it can become routinely used in the clinical setting, a universal means of objectively analyzing and interpreting the HSDI data must be established. In this study, preliminary data was gathered for five parameters used to objectively analyze vocal fold vibratory patterns observed with HSDI. The parameters investigated were established by Ikuma, Kunduk, and McWhorter (2012a) and were previously studied with a small sample (N=8) comparing pre and post-phonosurgical removal of benign lesions. The five parameters included fundamental frequency standard deviation (F0SD), harmonics-to-noise ratio (HNR) mean, open quotient (OQ) mean, speed index (SI) mean, and relative glottal gap (RGG) mean. The current study aimed to statistically and visually analyze measurements of the five objective parameters for differences between pathology groups with different etiologies. High-speed videos (N=50) were divided into five groups based on one of the following medical diagnoses: normal voice, vocal fold nodules, polyps, true vocal fold motion impairment (TVFMI), and adductor spasmodic dysphonia (ADSD). Statistical analysis showed that HNR mean differentiated normal voices from ADSD voices and that F0 mean differentiated ADSD voices from all groups except vocal fold nodules (p \u3c 0.005). Visual analysis revealed a strong trend for RGG mean to differentiate vocal fold nodules from all other groups. Less prominent visual trends for OQ mean and SI mean were also noted

A Patient-Specific in silico Model of Inflammation and Healing Tested in Acute Vocal Fold Injury

The development of personalized medicine is a primary objective of the medical community and increasingly also of funding and registration agencies. Modeling is generally perceived as a key enabling tool to target this goal. Agent-Based Models (ABMs) have previously been used to simulate inflammation at various scales up to the whole-organism level. We extended this approach to the case of a novel, patient-specific ABM that we generated for vocal fold inflammation, with the ultimate goal of identifying individually optimized treatments. ABM simulations reproduced trajectories of inflammatory mediators in laryngeal secretions of individuals subjected to experimental phonotrauma up to 4 hrs post-injury, and predicted the levels of inflammatory mediators 24 hrs post-injury. Subject-specific simulations also predicted different outcomes from behavioral treatment regimens to which subjects had not been exposed. We propose that this translational application of computational modeling could be used to design patient-specific therapies for the larynx, and will serve as a paradigm for future extension to other clinical domains

Direct measurement and modeling of intraglottal, subglottal, and vocal fold collision pressures during phonation in an individual with a hemilaryngectomy

The purpose of this paper is to report on the first in vivo application of a recently developed transoral, dual-sensor pressure probe that directly measures intraglottal, subglottal, and vocal fold collision pressures during phonation. Synchronous measurement of intraglottal and subglottal pressures was accomplished using two miniature pressure sensors mounted on the end of the probe and inserted transorally in a 78-year-old male who had previously undergone surgical removal of his right vocal fold for treatment of laryngeal cancer. The endoscopist used one hand to position the custom probe against the surgically medialized scar band that replaced the right vocal fold and used the other hand to position a transoral endoscope to record laryngeal high-speed videoendoscopy of the vibrating left vocal fold contacting the pressure probe. Visualization of the larynx during sustained phonation allowed the endoscopist to place the dual-sensor pressure probe such that the proximal sensor was positioned intraglottally and the distal sensor subglottally. The proximal pressure sensor was verified to be in the strike zone of vocal fold collision during phonation when the intraglottal pressure signal exhibited three characteristics: an impulsive peak at the start of the closed phase, a rounded peak during the open phase, and a minimum value around zero immediately preceding the impulsive peak of the subsequent phonatory cycle. Numerical voice production modeling was applied to validate model-based predictions of vocal fold collision pressure using kinematic vocal fold measures. The results successfully demonstrated feasibility of in vivo measurement of vocal fold collision pressure in an individual with a hemilaryngectomy, motivating ongoing data collection that is designed to aid in the development of vocal dose measures that incorporate vocal fold impact collision and stresses.Fil: Mehta, Daryush D.. Massachusetts General Hospital; Estados UnidosFil: Kobler, James B.. Massachusetts General Hospital; Estados UnidosFil: Zeitels, Steven M.. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Zañartu, Matías. Universidad Técnica Federico Santa María; ChileFil: Ibarra, Emiro J.. Universidad Técnica Federico Santa María; ChileFil: Alzamendi, Gabriel Alejandro. Universidad Nacional de Entre Ríos. Instituto de Investigación y Desarrollo en Bioingeniería y Bioinformática - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigación y Desarrollo en Bioingeniería y Bioinformática; ArgentinaFil: Manriquez, Rodrigo. Universidad Técnica Federico Santa María; ChileFil: Erath, Byron D.. Clarkson University; Estados UnidosFil: Peterson, Sean D.. University of Waterloo; CanadáFil: Petrillo, Robert H.. Center For Laryngeal Surgery and Voice Rehabilitation; Estados UnidosFil: Hillman, Robert E.. Center For Laryngeal Surgery and Voice Rehabilitation; Estados Unidos. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados Unido

A systematic review of resonant voice therapy

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High Fidelity Computational Modeling and Analysis of Voice Production

This research aims to improve the fundamental understanding of the multiphysics nature of voice production, particularly, the dynamic couplings among glottal flow, vocal fold vibration and airway acoustics through high-fidelity computational modeling and simulations. Built upon in-house numerical solvers, including an immersed-boundary-method based incompressible flow solver, a finite element method based solid mechanics solver and a hydrodynamic/aerodynamic splitting method based acoustics solver, a fully coupled, continuum mechanics based fluid-structure-acoustics interaction model was developed to simulate the flow-induced vocal fold vibrations and sound production in birds and mammals. Extensive validations of the model were conducted by comparing to excised syringeal and laryngeal experiments. The results showed that, driven by realistic representations of physiology and experimental conditions, including the geometries, material properties and boundary conditions, the model had an excellent agreement with the experiments on the vocal fold vibration patterns, acoustics and intraglottal flow dynamics, demonstrating that the model is able to reproduce realistic phonatory dynamics during voice production. The model was then utilized to investigate the effect of vocal fold inner structures on voice production. Assuming the human vocal fold to be a three-layer structure, this research focused on the effect of longitudinal variation of layer thickness as well as the cover-body thickness ratio on vocal fold vibrations. The results showed that the longitudinal variation of the cover and ligament layers thicknesses had little effect on the flow rate, vocal fold vibration amplitude and pattern but affected the glottal angle in different coronal planes, which also influenced the energy transfer between glottal flow and the vocal fold. The cover-body thickness ratio had a complex nonlinear effect on the vocal fold vibration and voice production. Increasing the cover-body thickness ratio promoted the excitation of the wave-type modes of the vocal fold, which were also higher-eigenfrequency modes, driving the vibrations to higher frequencies. This has created complex nonlinear bifurcations. The results from the research has important clinical implications on voice disorder diagnosis and treatment as voice disorders are often associated with mechanical status changes of the vocal fold tissues and their treatment often focus on restoring the mechanical status of the vocal folds