ETD Search Results: instcode:case

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221 matches in the database. These are records: 1 - 30.

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1. Abbas, James Joseph. Neural network control of functional neuromuscular stimulation systems.

Degree: PhD, Biomedical Engineering, 1992, Case Western Reserve University

► A neural network control system has been designed for the purpose of… (more)

▼ A neural network control system has been designed for the purpose of controlling cyclic movements in Functional Neuromuscular Stimulation (FNS) systems. The design of the control system directly addresses three problems faced in the implementation of FNS control systems: customizing the control system parameters for a particular individual, adapting these parameters to account for changes in the musculoskeletal system, and resisting mechanical disturbances. The control system is implemented by a two-stage neural network that utilizes adaptive feedforward and feedback control techniques. The first stage of the neural network, the Pattern Generator, generates a cyclic pattern of activity. The design of this stage is based upon neural models of vertebrate motor control systems. The signals from the Pattern Generator are adaptively filtered by the second stage, the Pattern Shaper. A learning algorithm that accounts for system dynamics and input time delays was developed for use in adapting the Pattern Shaper filtering properties. Computer simulated models of electrically stimulated muscles acting on one- and two-segment skeletal systems were used to assess the potential utility of the neural network control system in FNS control. Results of the evaluation demonstrated that the control system can automatically c ustomize stimulation parameters, adapt them on-line, and resist mechanical disturbances. The control system was also demonstrated to be capable of controlling movements of multi-joint systems and of utilizing biarticular muscle effectively. The success of the control system in this evaluation indicates that it may provide significant improvements to existing FNS control system technology and suggests that the technique should be investigated further. These studies also indicate that this strategy may be appropriate for other applications in the control of dynamic, nonlinear systems with input time delays. The use of biologically motivated neural networks in the Pattern Generator provides this control system with unique features that are not readily available using existing control system techniques. The learning algorithm developed for use in the Pattern Shaper is particularly well-suited for use in engineering neural network control systems because it provides the ability to account for system dynamics and input time delays. Advisors/Committee Members: Chizeck, Howard Jay.

Subjects: Engineering, Biomedical

Keywords: Neural network control functional neuromuscular stimulation systems

2. Ackermann, Douglas Michael Jr. HIGH SPEED TRANSCUTANEOUS OPTICAL TELEMETRY LINK.

Degree: MS, Biomedical Engineering, 2008, Case Western Reserve University

► A transcutaneous optical telemetry link was constructed that is capable of transmitting… (more)

Subjects: Engineering, Biomedical

Keywords: telemetry, cortical interfacing, optical, skin optics

3. Ackermann, Douglas Michael Jr. REDUCTION OF THE ONSET RESPONSE IN HIGH FREQUENCY NERVE BLOCK.

Degree: PhD, Biomedical Engineering, 2010, Case Western Reserve University

► Many diseases are characterized by undesired or pathological neural activity. The local… (more)

▼ Many diseases are characterized by undesired or pathological neural activity. The local delivery of high frequency currents has been shown to be an effective method for blocking neural conduction in peripheral nerves and may provide a therapy for these conditions. However, this type of nerve block produces a finite burst of neuronal firing (several seconds) called the onset response when the high frequency currents are first delivered to the nerve. When the onset response is complete, the nerve is transitioned to a state of conduction block that can be maintained indefinitely with continued delivery of the high frequency alternating current. Reduction or elimination of the onset response is very important to moving this type of nerve block into clinical applications since the onset response is likely to result in undesired muscle contraction and pain. This dissertation presents studies that show that this onset response can be reduced to hundreds of milliseconds or less in many cases by choosing the proper combination of electrode geometry and high frequency waveform amplitude. The onset response can be completely eliminated with the delivery of a direct current block through a separate blocking electrode. However, this direct current block is not safe for the durations required for blockade of the onset response with the electrodes used in this study. Preliminary results suggest that it may be possible to safely block the entire onset response using direct currents delivered using a different electrode technology or with direct nerve cooling. This dissertation also presents studies showing that the minimal high frequency current amplitude required to achieve block (block threshold) is a function, in part, of the electrode geometry. A biophysical explanation for the relationship between block threshold and electrode geometry is proposed based upon computer simulation of single axon fibers. High frequency nerve block was also found to be possible using an intrafascicular electrode. This document provides guidance for selection of a high frequency block electrode based on application, optimization of block threshold and reduction of onset response. Advisors/Committee Members: Bhadra, Niloy.

Subjects: Biomedical research

Keywords: nerve block, neurostimulation, high frequency, peripheral nerve, cuff electrode, onset response, direct current, intrafascicular, monopolar, bipolar, nerve cooling, HFAC, alternating current

4. Ahuja, Punkaj N. Optode-bead-based Functional Chemical Imaging of 2D Substrates.

Degree: M. Eng., Biomedical Engineering, 2011, Case Western Reserve University

► We introduce a new technology for functional imaging of surfaces using microscopic… (more)

Subjects: Biomedical Engineering

Keywords: Imaging; electrochemical; electrochemistry; scanning electrochemical microscopy; secm; ion; pH; proton; multicellular tumor spheroids; MCTS; bulk optode

5. Allexandre, Didier. A Fast Numerical Method for Large-Scale Modeling of Cardiac Tissue and Linear Perturbation Theory for the Study and Control of Cardiac Spiral Wave Breakup.

Degree: PhD, Biomedical Engineering, 2004, Case Western Reserve University

► Ventricular fibrillation and tachycardia are the leading causes of sudden cardiac death… (more)

▼ Ventricular fibrillation and tachycardia are the leading causes of sudden cardiac death in the United States. Yet, despite extensive research, their nature as well as the electrophysiological mechanisms responsible for their initiation and sustenance are not fully understood. Researchers have suggested that the breakup of a spiral wave, a vortex-like electrical wave, may be one major mechanism by which tachycardia can evolve into fibrillation. We therefore apply linear perturbation theory, a mathematical technique, to gain new insights into the electrophysiological and dynamical mechanisms underlying this phenomenon. We found spiral wave perturbation dynamics to be composed of a multitude of characteristic and independent behaviors, called eigenmodes. Along with one meandering mode, not just one but several unstable alternans modes were found with differing growth rates, frequencies and spatial structures, suggesting different electrophysiological properties. We also explored a promising new approach, based on the theory, for the design of an energy efficient electrical stimulus protocol to control spiral wave breakup. We show a particular example in which the instability of an entire spiral wave can be controlled in the linear regime over several rotation periods using a single localized stimulus applied at one instant in time. Computer simulation of cardiac activity has been another popular approach used to study arrhythmia. However, due to various numerical constraints, these simulations are computationally costly when modeling large tissue size using realistic ionic cell models. We have therefore developed a new fast variable timestep method. The method is explicit, yet highly stable, permitting the use of adaptive timesteps much larger than the limit imposed by conventional explicit methods. We perform a thorough study of computational efficiency of the method, by examining how the grid spacing, tissue size and error tolerance affect runtimes obtained for the Hodgkin-Huxley (HH) and Luo-Rudy (LRd) ion channel models. We find the method to be 2-10 times faster for the HH model and typically an order of magnitude (30-40 times) faster for LRd when compared to the conventional fixed timestep forward Euler method. It is also about twice as fast as currently available methods when applied to the LRd model. Advisors/Committee Members: Otani, Niels F.

Keywords: Cardiac Arrhythmia; Spiral Wave; Reentry; Fibrillation; Modeling; Computer model; Control; Electrode; Action Potential; Algorithm; Numerical method; Simulation; Finite Difference; Eigenmode; Linear Perturbation; Hodgkin-Huxley; Heart

6. Amankwah, Kofi. THE IMPACT OF LOWER EXTREMITY PASSIVE JOINT PROPERTIES ON STANDING FUNCTION.

Degree: PhD, Biomedical Engineering, 2004, Case Western Reserve University

► The impact of passive elastic and viscous joint properties during functional electrical… (more)

Keywords: Passive Properties; Stiffness; Viscosity; Musculoskeletal modeling; Nonlinear modeling; Spinal cord injury; Biomechanics; Computer simulation

7. Aufrichtig, Richard. Perception and filtering of interventional x-ray fluoroscopy image sequences.

Degree: PhD, Biomedical Engineering, 1994, Case Western Reserve University

► Due to the proliferation of interventional radiology the use of x-ray fluoroscopy… (more)

▼ Due to the proliferation of interventional radiology the use of x-ray fluoroscopy is increasing. Examples of treatments include balloon angioplasty, atherectomy and neuroembolizations. X-ray fluoroscopic imaging at high frame rates and low x-ray dose is used to guide catheters, position interventional devices, and give feedback during intervention. We use image perception experiments, mathematical modeling and image processing to determine ways to reduce x-ray dose and optimize visualization. The human visual system (HVS) temporally filters image sequences, and effectively improves the signal-to-noise ratio (SNR) of an image sequence. It is important to include this phenomenon in the analysis of fluoroscopy. Paired-comparison, min-contrast, and forced-choice perception experiments are used to compare pulsed fluoroscopy at reduced frame rates with conventional continuous fluoroscopy. Experimentally we find average dose savings of 22%, 38%, and 49%, for pulsed at 15, 10 and 7.5 acq/sec, respectively. Dose savings depend on object size, with less savings for smaller objects. Theoretically we extend the framework on an ideal observer with three models of the spatio-temporal response of the HVS: (M1) separable, (M2) non-separable, and (M3) non-separable with internal noise. With no free parameters, M1 predicts the average dose savings within a 3% difference, but does not describe the effect of object size. M2 and M3 explain the influence of size, and M3, with a single free parameter, fits the measurements best. In similar experiments with single frames, we find that processing in the HVS effectively reduces noise variance by a factor of 3, corresponding to an effective averaging time of 100 msec. We suggest several variance reduction techniques to create a single last-image-hold frame having perception equal to the fluoroscopy sequence. Simply reducing the x-ray dose decreases the SNR to unacceptable low levels. We describe an image processing technique to enhance fluoroscopy sequences. The method consists of object detection, followed by spatial and recursive, temporal filtering. Based upon the object detection we adjust filter parameters, such as to reduce noise without blurring the objects. A receiver operating characteristic (ROC) curve analysis is used to optimize matched filters for the object detection. Dependent upon the noise level, the method improves SNR from 6-10 dB, with dose savings approaching 95%. Advisors/Committee Members: Wilson, David L.

Keywords: Perception filtering interventional x-ray fluoroscopy image sequences

8. Beamish, Jeffrey Alan. Engineering Poly(Ethylene Glycol) Hydrogel Scaffolds to Modulate Smooth Muscle Cell Phenotype.

Degree: PhD, Biomedical Engineering, 2009, Case Western Reserve University

► This work investigated the hypothesis that smooth muscle cell (SMC) phenotype can… (more)

▼ This work investigated the hypothesis that smooth muscle cell (SMC) phenotype can be modulated by a cell-instructive hydrogel scaffold. By modulating SMCs toward a quiescent contractile phenotype, such a scaffold may facilitate the regeneration of functional vascular tissue as part of a tissue engineered blood vessel (TEBV) and may mitigate SMC intimal hyperplasia, which is one of the common modes of vascular prosthesis failure. A photopolymerizable poly(ethylene glycol) diacrylate (PEGDA) hydrogel system was employed because this scaffold material can be engineered quantitatively to meet a broad range of physical and biological design specifications. PEGDA hydrogel networks were copolymerized with poly(ethylene glycol) monoacrylate (PEGMA), which could tether pendent cell-adhesive peptides to the network. The physical characteristics of a range of copolymer network compositions (5-20% w/w PEGDA, 0-20% PEGMA) were determined and analyzed for the scaffold design. Mass swelling ratio (7.5±0.1 to 27.1±0.7) and shear modulus (4.0±0.6 to 104±4 kPa) data indicated that hydrogel properties were controlled quantitatively and independently of PEGMA concentration. SMCs attached to PEGDA-co-GRGDSP-PEGMA (RGD-gels) in a ligand specific manner. RGD-gels also supported modulation toward a contractile SMC phenotype that was indistinguishable from fibronectin control substrates. In these experiments, low serum medium with heparin induced rapid up-regulation of contractile phenotype marker mRNA (2.7- to 25-fold) and proteins, as well as intracellular organization of these markers. Based on these results, RGD-bearing PEGDA hydrogel scaffolds were engineered to modulate SMC phenotype by providing controlled release of heparin. Using PEGDA molecular weight (1-6 kD) and concentration (10-30% w/w), a broad range of release profiles was achieved with durations from hours to weeks. These cell-instructive scaffolds stimulated up-regulation of contractile phenotype markers (~1.5-fold) that was driven by released heparin. These results suggest that the delivery of soluble signaling factors, such as heparin, from an RGD-gel scaffold is an effective approach to induce rapid changes in SMC phenotype. A cell-instructive scaffold system, such as described here, will facilitate the engineering of functional smooth muscle tissue for a variety of applications and may improve the long-term patency of TEBVs. Advisors/Committee Members: Marchant, Roger E.

Subjects: Biomedical research; Engineering

Keywords: smooth muscle cell; hydrogel; tissue engineering; poly(ethylene glycol)

9. Blana, Dimitra. Feedback Control of a High Level Upper Extremity Neuroprosthesis.

Degree: PhD, Biomedical Engineering, 2008, Case Western Reserve University

► The main focus of this study is controller design using a model-based… (more)

▼ The main focus of this study is controller design using a model-based approach, and implementation in a high level upper extremity neuroprosthesis. This is a system that aims to restore upper limb motor function to individuals who have suffered a spinal cord injury at the highest cervical level (C1-C4), and thus have lost voluntary control of most of the shoulder and arm muscles. To determine the optimal electrode set for this system, given the limited number of available stimulating channels, a musculoskeletal model of the upper extremity was used to run a large number of simulations and evaluate all the candidate electrode sets. The model was customized to represent a tetraplegic subject with an FES system, and the optimal electrode set was the one that allowed the model to successfully perform the largest number of movements. Subsequently, a combined feedforward-feedback controller approach was developed and tested first in a simplified arm model with six muscles and two degrees of freedom. In spite of its small scale, the model included an accurate muscle model, redundancy in the number of muscles, and kinematic coupling. It demonstrated the excellent trajectory tracking performance of the controller, even in the presence of considerable muscle fatigue and external forces. Next, the same design, augmented by a controller for shoulder stability was tested in a large-scale arm model with 22 muscles and five degrees of freedom, including a complete glenohumeral joint. In addition to its tracking ability, this controller was able to ensure shoulder stability in all cases of external disturbances. Finally, the controller was implemented in one subject with high level tetraplegia, and an adaptation method was developed to adjust the controller parameters according to the characteristics of the specific individual. In order to handle the redundancy of the upper limb, adaptation was performed using co-contraction of antagonistic muscles, and activation patterns among shoulder stabilizing and moving muscles. When tested in the shoulder and elbow of the subject, the controller achieved adaptation and allowed the execution of the desired movements. Advisors/Committee Members: Kirsch, Robert.

Subjects: Biomedical research; Rehabilitation

Keywords: biomechanics; functional electrical stimulation; musculoskeletal modeling; feedback control

10. Boada, Fernando E. Inverse ultrasonic scattering with model function constraints.

Degree: PhD, Biomedical Engineering, 1990, Case Western Reserve University

► This dissertation discusses the problem of optimally reconstructing a soft acoustic scattering… (more)

Keywords: Inverse ultrasonic scattering model function constraints

11. Boger, Adam Sprott. Application of High Frequency Electrical Block on the Efferent Nerves to the Lower Urinary Tract for Bladder Voiding.

Degree: PhD, Biomedical Engineering, 2009, Case Western Reserve University

► Individuals with neurologic disease or injury such as spinal cord injury often… (more)

▼ Individuals with neurologic disease or injury such as spinal cord injury often develop dyssynergic lower urinary tract reflexes, which can prevent bladder-voiding and compromise their health. Permanent and destructive neurotomies can allow bladder-voiding, but eliminate residual sacral sensation and disrupt reflexes governing defecation and sexual function, severely affecting quality of life. High frequency electrical (HF) stimulation can immediately and reversibly block nerve impulse conduction, effectively providing a reversible neurotomy. This dissertation demonstrated effective bladder voiding in an acute feline model using HF stimulation. Complete bladder voiding was achieved using sacral root stimulation to activate the bladder and either PN or sacral root HF block to prevent activation of the external urethral sphincter (EUS). Effective bilateral HF PN EUS block was achieved, allowing complete bladder-voiding equivalent to voiding following pudendal neurotomy and reducing maximum bladder pressure during voiding. PN HF block for voiding extended previous research demonstrating unilateral HF PN EUS block. Sacral HF EUS block allowed bladder voiding comparable to voiding in the absence of EUS activation. Complete bladder voiding could be achieved through successive HF block trials or by extending the HF block trial duration. Development of bladder-voiding neuroprostheses utilizing sacral HF block may require only modification of existing technology. Both sacral and PN HF block bladder-voiding neuroprostheses significantly improve upon existing approaches by preserving sacral reflexes and sensation. Thus HF based bladder-voiding neuroprostheses expand the population of patients willing to consider bladder-voiding neuroprostheses, potentially improving patient quality of life and decreasing the cost of patient care. HF block of small (1 -3 µm) myelinated parasympathetic bladder efferents at the sacral root level was also demonstrated. Small fiber block characteristics were dependent on stimulation frequency and amplitude and HF block was localized to the region near the blocking electrode. Complete, rapid nerve block and the minimization of HF evoked bladder responses could be achieved with the appropriate choice of stimulation parameters. The demonstration of small fiber HF block supports research into HF block neuroprostheses for chronic pain or autonomic disorders. Such neuroprostheses could benefit an extremely large patient population currently lacking many treatment options. Advisors/Committee Members: Gustafson, Dr. Kenneth.

Subjects: Biomedical research

Keywords: High Frequency Stimulation; Electrical Stimulation; Bladder; Chronic Pain; Nerve Block

12. Bonner, Matthew David. The pulse clamp method for analyzing neural stimulating electrodes.

Degree: PhD, Biomedical Engineering, 1991, Case Western Reserve University

► The Pulse-Clamp (P-C) method was developed and used to analyze the electrochemical… (more)

▼ The Pulse-Clamp (P-C) method was developed and used to analyze the electrochemical behavior of neural stimulating electrodes on the same time scale as typical neural stimulating pulses. The P-C method consists of applying a controlled current stimulating pulse, followed by a controlled potential pulse. The instrumentation, cell, and technique were shown to measure accurately electrochemical processes for times greater than 10μS. These experiments were performed with uniform current distribution at 1 Hz pulsing. The P-C method of analysis was applied to gold, platinum, and SS316 electrodes. The charge recovered during the controlled potential pulse was divided into three segments based on time. A 3 element model was compared with the observed electrode behavior. The model could imitate most of the observed electrode behaviors for changes in the pulse width, delay, and clamp potential. The difference between the three materials was in the relative amount of charge found in the three time segments. From these findings it was deduced that gold stored the majority of charge in double layer, while platinum stored most of the charge in the hydrogen adsorption reaction. Almost two thirds of the evolved hydrogen on platinum could be reoxidized during the reversal phase. SS316 primarily stored the charge in the oxi de reduction process. The response of the three electrode materials was similar in that the electrode potential during an electrochemically reversible pulse was substantially more negative than the H2 evolution potential as determined by slow cyclic voltammetry. An estimate of the safe charge injection limits was based on the measurement of unreversed electrochemical products. On gold unrecoverable charge was detected above -75 μC/cm2. On SS316 the safe limit is unknown, but it was in excess of -150 μC/cm2. The safe limit was also not reached on platinum, but it was in excess of -300 μC/cm2. The optical reversal waveform was found to be a large current spike containing the double layer charge followed by an exponentially decaying current timed to the rate of the reversal processes for the particular material. Advisors/Committee Members: Mortimer, J Thomas.

Subjects: Engineering, Biomedical

Keywords: pulse clamp method neural stimulating electrodes

13. Bookwalter, Candice Anne. CONTINUOUS SAMPLING IN MAGNETIC RESONANCE IMAGING.

Degree: PhD, Biomedical Engineering, 2008, Case Western Reserve University

► MRI pulse sequences are used to acquire spatial-frequency data (k-space) by using… (more)

▼ MRI pulse sequences are used to acquire spatial-frequency data (k-space) by using linear magnetic field gradients to encode a k-space trajectory. Common k-space trajectories including rectilinear typically limit sampling to periods of constant gradient amplitude resulting in uniformly-sampled data during the acquisition period. However, these trajectories often do not acquire data during gradient ramp times or during read gradient dephase/rephase lobes. In this work, data acquisition and image reconstruction techniques were developed to improve the effective utilization of these times to improve image quality. Continuous sampling (CS) is defined as data collected anytime after RF excitation. A Cartesian CS acquisition was developed by extending the acquisition window over the entire balanced and isolated read gradient. The gradients were designed to sample each k-space pixel at least twice to essentially accomplish two averages in a single acquisition. Cartesian CS resulted in over 40% improvement in SNR for a true-FISP sequence relative to the traditional Cartesian acquisition in phantom and asymptomatic volunteer imaging studies. Non-Cartesian CS sequences including the BOWTIE trajectory and unequal gradient amplitude CS were developed for faster CS sequences with similar SNR gains. For the unequal gradient amplitude case a range of SNR gain of 19 to 50% was seen. The BOWTIE trajectory was accomplished by overlapping PE and read gradients and resulted in a 35% increase in SNR compared to the traditional Cartesian. Both resulted in a reduction of imaging time at the cost of SNR compared to the original CS sequence. A Cartesian CS Dixon fat/water separation techniques was developed by applying the Dixon echo time variation between CS echoes. The redundant data collected during CS produced two Dixon images in one acquisition. The CS Dixon resulted in equivalent fat suppression in water images in approximately half the time compared to a 2PD acquisition. A novel 2D translational motion artifact correction method was developed that uses phase differences at trajectory intersections. Unlike conventional navigator methods, the described technique allows motion artifact correction with data collected along different trajectories, demonstrated here with the BOWTIE trajectory. Corrections based on simulations and experiments both result in image artifact reduction. Advisors/Committee Members: Duerk, Jeffrey L.

Subjects: Engineering, Biomedical

Keywords: magnetic resonance imaging; signal-to-noise ration (SNR); fat/water separation; motion correction

14. Bos, Cindy Renee. Characterization of membrane traffic from the cell surface to the Golgi complex.

Degree: PhD, Biomedical Engineering, 1991, Case Western Reserve University

► Studies from this and other laboratories have established that certain glycoproteins are… (more)

▼ Studies from this and other laboratories have established that certain glycoproteins are transported from the cell surface to the Golgi complex. However, very little is known about this pathway of membrane traffic. Several surface receptors including transferrin receptor, mannose 6-phosphate receptors, and asialoglycoprotein receptor have been shown to cycle slowly through the Golgi complex. These receptors are known to enter cells through clathrin-coated pits, raising the question of whether these structures are involved in the transport of surface proteins to the Golgi complex. To address this question, we studied the transport of two LDL receptors, a wild type receptor and an internalization-defective receptor which is unable to cluster in coated pits, from the cell surface to the Golgi complex. Since sialyltransferases are thought to reside in the trans Golgi and TGN, transport from the surface to the Golgi complex was measured by determining the extent of resialylation of surface asialo-LDL receptors. We found that the internalization-defective LDL receptor was resialylated at half the rate of resialytlation of wild type receptor even though it was internalized 20-fold less efficiently. These results suggest that internalization through clathrin-coated pits on the cell surface is either not a necessary step in the transport of surface receptors to the Golgi complex or does not represent the rate-limiting step in this transport pathway. To further characterize the surface to Golgi pathway we examined the effect of brefeldin A (BFA) on the resialylation of surface asialo-TfR in K562 cells. BFA has been shown to inhibit transport from the endoplasmic reticulum (ER) to the Golgi complex and to cause the collapse of cis and medial Golgi cisternae into the ER. We found that BFA inhibited resialylation. Further studies showed that newly synthesized TfR and LDL receptor were sialylated in BRA-treated cells despite BFA's inhibitory effect on transport from the ER to the Golgi complex. In addition, immunofluorescence studies showed that TCP-1, a marker of the TGN, was redistributed in the presence of BFA. In summary, our results suggest that BFA inhibited resialylation of asialo-TfR by inducing the redistribution of the trans Golgi and TGN where the enzymes are located to the ER Advisors/Committee Members: Snider, Martin D.

Subjects: Biology, Cell

Keywords: Biological transport; Cell Surface; Golgi complex

15. Breen, Michael Scott. TISSUE RESPONSE TO INTERVENTIONAL MRI-GUIDED THERMAL ABLATION THERAPY.

Degree: PhD, Biomedical Engineering, 2004, Case Western Reserve University

► This research project is part of a larger, long-term effort to develop… (more)

Subjects: Engineering, Biomedical

Keywords: interventional therapies, magnetic resonance imaging, thermal ablation therapy, image guided procedures

16. Bruder, Scott Philip. Characterization of the osteogenic cell lineage.

Degree: PhD, Biomedical Engineering, 1990, Case Western Reserve University

► Studies of the origin, commitment, and differentiation of osteogenic cells can be… (more)

▼ Studies of the origin, commitment, and differentiation of osteogenic cells can be facilitated by cell-specific markers. To this end, monoclonal antibodies against surface determinants on osteogenic cells were generated by immunizing naive mice with a heterogeneous population of chick embryonic bone cells. Four monoclonal cell lines, SB-1, SB-2, SB-3, and SB-5, which each secrete a different antibody against the surface of osteogenic cells, were immortalized and subsequently used to study the developmental progression of osteogenic cells in a variety of developmental systems. Detailed morphologic analyses during the process of bone formation in embryonic chick tibiae, organ culture of embryonic chick periosteum, and in vivo diffusion chamber culture of avian marrow stem cells reveal that a precise sequence of cell surface alterations occur during osteogenic differentiation. Of particular interest is the observation that this sequence of cellular events is conserved in all the developmental systems studied. Results of these analyses indicate the Pre-Osteoblastic cells, which are recognized by antibody SB-1, proceed through their lineage to become Transitory 1 Osteoblasts, which are immunostained by SB-1 and SB-3. These cells continue differentiating to become Transitory 2 Osteoblasts, which are reactive wit h antibodies SB-1, SB-3, and SB-2. These non-secretory cells then elaborate a type I collagen-rich osteoid matrix as SB-1, SB-3, and SB-2-positive Secretory Osteoblasts. Those Secretory Osteoblasts which are incorporated into the bone matrix then loose surface antigens SB-1 and SB-3, while they begin expressing the SB-5 antigen on their surface. The resulting Osteocytic Osteoblasts, which are reactive with both the SB-2 and SB-5 antibodies, finally undergo a terminal differentiation step to become Osteocytes. This final lineage step is characterized by the loss of the SB-2 antigen and the retention of SB-5 immunoreactivity. Additional studies have focused on characterizing the identity of the antigens recognized by these antibodies. Interestingly, SB-1 is shown to react with alkaline phosphatase isoenzymes present in bone, liver, kidney, cartilage and intestine. While the alkaline phosphatase isoform in embryonic bone has an apparent molecular weight of 155 kD, the intestinal isoenzyme is approximately 185 kD. In both isoforms, however, the immunoreactive epitope is stable to SDS denaturation, not associated with the active site of the enzyme, and dependent on disulfide bonds which impart secondary structure to the protein. Advisors/Committee Members: Caplan, Arnold I.

Keywords: osteogenic cell lineage

17. Bruns, Timothy Morris. Afferent Stimulation for Exciting Reflex Micturition Circuits.

Degree: PhD, Biomedical Engineering, 2009, Case Western Reserve University

► Individuals with bladder voiding dysfunction who do not respond to standard treatments… (more)

▼ Individuals with bladder voiding dysfunction who do not respond to standard treatments have limited options. Activation of reflex micturition through sensory pudendal nerve stimulation provides a means to empty the bladder. Little is known about the mechanisms behind this pathway, and afferent-mediated voiding is less than results obtained by direct sacral root drive. This project investigated the neurophysiology of reflex bladder activation and evaluated new stimulus patterns and locations to improve afferent excitation of spinal circuits that produce bladder excitation and voiding.The use of novel physiologically based burst-patterned pudendal nerve stimuli significantly increased bladder contractions over currently used continuous stimulation (52.0 ± 44.5%, p < 0.004). Bladder excitation was effective at lower frequencies (1–10 pulses at 100–200 Hz repeated at 0.5–1 Hz) and higher frequencies (1–2 pulses at 200 Hz repeated at 20–33 Hz). Stimulating with lower and higher frequencies at different urethral locations before and after spinalization suggested two neural pathways for exciting reflex bladder contractions: a supra-sacral circuit initiated in the proximal urethra that responds to both frequency ranges and a sacral circuit initiated in the distal urethra that only responds to higher frequency stimuli. Subject pathology will dictate which circuit is the neuroprosthetic target. Stimulation with fine wire electrodes in the urethral wall excited the proximal urethra initiated circuit with minimal sphincter recruitment and evoked greater voiding efficiencies for the use of lower frequency burst-patterned stimuli (72.7 ± 27.6%) than other stimulus patterns on the same electrodes (p > 0.08) or any stimulus patterns on electrodes with urethral closure (p < 0.01). This pre-clinical translational study extended the functional proxy of bladder excitation to an effective functional voiding output. This work increases the knowledge-base of lower urinary tract neurophysiology, indicating more effective stimulation strategies and locations. This research will advance peripheral nerve-based neuroprostheses for bladder excitation, improving functional outputs and matching interventions to the patient population. Advisors/Committee Members: Gustafson, Kenneth J.

Subjects: Biomedical research; Engineering

Keywords: Functional Electrical Stimulation; FES; neuroprosthesis; stimulation pattern; pudendal nerve; urethra; voiding dysfunction; spinal cord injury

18. Bulea, Thomas Campbell. A Variable Impedance Hybrid Neuroprosthesis for Enhanced Locomotion after Spinal Cord Injury.

Degree: PhD, Biomedical Engineering, 2012, Case Western Reserve University

► A hybrid neuroprosthesis combines functional neuromuscular stimulation with controllable bracing to restore… (more)

▼ A hybrid neuroprosthesis combines functional neuromuscular stimulation with controllable bracing to restore walking function after paralysis from spinal cord injury. This approach confines stimulation to driving the limbs forward while utilizing bracing to lock joints for postural support during stance. However, a stiff leg during stance is inefficient and can limit the range of achievable walking tasks. We hypothesize that a hybrid neuroprosthesis which regulates joint motion under loading will augment stimulation driven gait to create better walking performance. A novel variable impedance mechanism was developed to control the knee joint during stance phase of locomotion. This mechanism was optimized to provide adequate torque for regulation of knee motion under load at all joint angles, creating an orthosis capable of achieving power absorption which is not possible through stimulation of muscles or lockable orthotics. A finite state, closed loop control system based on sensor feedback was developed to coordinate activation of the variable impedance knee mechanism with electrical stimulation to create a new hybrid neuroprosthesis for walking (VIKM-HNP). The goal of the VIKM-HNP was to allow knee extensor muscles to rest while providing power absorption for stance phase knee flexion and enabling unencumbered swing phase motion. The new VIKM-HNP was evaluated during level walking in two individuals with thoracic level spinal cord injury. The results showed a significant increase in stance knee flexion and power absorption while reducing knee extensor stimulation duty cycle by up to 40%. The altered knee behavior created more steady forward progression, increased minimum instantaneous gait speed, and reduced impulsive ground reaction forces compared to stimulation alone. A second finite state machine was developed to enable step-by-step forward stair descent using the VIKM-HNP. Knee extensor stimulation of the trailing limb was deactivated while the orthosis was activated to regulate lowering speed. The system was evaluated in one participant. Regulation of lowering speed during descent was possible with minimal upper extremity effort during the initial parts of lowering and a maximum upper extremity force of approximately 45% body weight, constituting a significant improvement over previously published values for stimulation only systems. Advisors/Committee Members: Knothe Tate, Melissa.

Subjects: Biomechanics; Biomedical Engineering; Robotics

Keywords: Hybrid Neuroprosthesis; Functional Neuromuscular Stimulation; Spinal Cord Injury; Controllable Orthosis; Exoskeleton

19. Buxton, Amanda Nicole. DESIGN AND CHARACTERIZATION OF PHOTOPOLYMERIZABLE SEMI-INTERPENETRATING NETWORKS FOR IN VITRO CHONDROGENESIS OF HUMAN MESENCHYMAL STEM CELLS.

Degree: PhD, Biomedical Engineering, 2007, Case Western Reserve University

► Cartilage is formed through the process of chondrogenesis, in which mesenchymal stem… (more)

▼ Cartilage is formed through the process of chondrogenesis, in which mesenchymal stem cells (MSCs) differentiate to become chondrocytes. Chondrocytes then synthesize all of the components of the intricate extracellular matrix (ECM) of which cartilage is comprised. Articular cartilage has a very poor reparative ability and extracellular matrix degradation leads to the eventual destruction of the tissue. Tissue engineering presents a possible avenue for its repair and regeneration. Because hydrogels are mimetic of the native, 3-dimensional, water-swollen environment in which chondrocytes exist, they have been the focus of much research in terms of cartilage tissue engineering, but success has been limited. This thesis describes the design and characterization of poly(ethylene diacrylate) (PEGDA) and poly(ethylene) (PEG)-based semi-interpenetrating networks that facilitated the formation of cartilage by human MSCs. Alterations in the molecular weight of the PEGDA crosslinker and the ratio of PEGDA:PEG, resulted in substantial changes in extracellular matrix elaboration. Proteoglycan content was significantly increased through lowering the PEGDA:PEG ratio at the lowest PEGDA molecular weight used (6 kDa). Furthermore, the profile of proteoglycan deposition within the scaffold was substantially altered with lower PEGDA:PEG ratio and with higher PEGDA molecular weight. With higher PEGDA molecular weight, toluidine blue staining revealed intercellular/interterritorial deposition of proteoglycan, as compared with pericellular deposition exhibited by constructs fabricated at PEGDA:PEG of 2:1 with PEGDA (6 kDa). Collagen content, however, was lower in constructs fabricated with higher PEGDA molecular weight at a PEGDA:PEG ratio of 1:2. The effects of culture conditions on subsequent matrix development in the optimized polymer hydrogel were also examined. Initial experiments defined the optimal cell seeding density that produced maximum matrix deposition throughout the construct at 25 x106 cells/ml. Pretreatment of monolayer cells with defined chondrogenic medium retarded matrix elaboration, while withdrawal of either TGF-β1, or dexamethasone (DEX) lowered collagen content per cell at all timepoints. These findings are informative for in vitro tissue engineering of cartilage, but may also aid in vivo implantation strategies for hydrogels that contain MSCs rather than preformed cartilage. Advisors/Committee Members: Johnstone, Brian.

Subjects: Engineering, Biomedical

Keywords: PEGDA; Cartilage; collagen; Hydrogels; Proteoglycan; chondrocytes; PEG

20. Cabrera, Marco Eugenio. Identification, modeling, and analysis of the dynamics of lactate and oxygen uptake during exercise in man.

Degree: PhD, Biomedical Engineering, 1995, Case Western Reserve University

► In this study, the human bioenergetic system is identified and then modeled… (more)

▼ In this study, the human bioenergetic system is identified and then modeled to relate cellular metabolism to whole-body responses during hypoxia and exercise. First, the dynamic characteristics of the physiological system are investigated using system identification methods. A time series model of the lactate concentration (LA) and oxygen uptake (VO2) response to incremental changes in work rate was fitted to simulated and experimental data. Time-varying system response parameters were determined and then examined. Two major transitions in the parameters were found to occur, at intensity levels equivalent to 53 ± 8% VO2max and 77 ± 9% VO2max. These changes in the parameters indicate that the best linear dynamic model that fits the observed system behavior has changed. The identified parameter changes over time suggest that the exercise intensity range (from rest to VO2max) is divided into three main intensity domains, each with distinct dynamics. Secondly, we developed a mathematical model of human bioenergetics that links cellular metabolism to whole-body responses. Our aim is to examine and quantify the mechanisms that control LA accumulation when O2 avail ability to the muscle is lowered. The model equations, which are based on dynamic mass balances for glycogen, glucose, pyruvate, LA, O2, and CO2, were solved numerically to simulate the system responses to hypoxia. The simulations predict (a) the substrate concentration changes in muscle, splanchnic bed, and other tissues, and (b) changes in other metabolites whose reactions are coupled to the main reactions processes. System responses to simulated respiratory and circulatory hypoxia were examined and compared to experimental data. Model simulations closely predicted the pattern of change in substrates and control metabolites to that from experimental data. A large decrease can occur in muscle O2 concentration without affecting muscle respiration. Only one-third of the increase in LA production can be attributed to changes in redox state (NADH/NAD).Thirdly, we extended the mathematical model to incorporate changes in metabolic rate. Our aim was to examine and quantify the mechanisms that control LA accumulation when the muscle O2 concentration is lowered with moderate exercise. Model simulations of system responses to exercise predict (a) the substrate concentration changes in muscle, splanchnic bed, and other tissues, and (b) changes in other metabolites whose reactions are coupled to the main reactions processes. System responses to a step change in metabolic rate were simulated, examined, and compared to experimental data. Model simulations closely predicted the pattern of change in substrates and control metabolites to that from experimental data. A large decrease can occur in muscle O2 concentration without affecting muscle respiration. Redox state decreased to 50% its initial value during exercise. With exercise initiation, LA increased abruptly, most likely as a result of a concurrent increase in pyruvate due to the sudden stimulation of glycolysis induced by the sharp rise in phosphorylation state. Therefore, during moderate exercise, (a) there are appropriate levels of oxyge nation at the tissue level even during the transient state, and (b) the observed increase in LA concentrations in the muscle and arterial blood are mainly due to the sudden increase in the glycolytic rate. (Abstract shortened by UMI) Advisors/Committee Members: Saidel, Gerald M.

Subjects: Engineering, Biomedical

Keywords: Exercise, lactate and oxygen uptake

21. Caralla, Tonya. Selection of Connective Tissue Progenitors Based on Cell-associated Hyaluronan for Enhanced Bone Regeneration.

Degree: PhD, Biomedical Engineering, 2012, Case Western Reserve University

► The frequency of CTPs in bone marrow is quite low and this… (more)

▼ The frequency of CTPs in bone marrow is quite low and this rarity highlights the need for clinically relevant selection strategies to optimize the impact of these cells in a graft site. This project represents the first exploration of the potential utility of using the extracellular matrix niche around a cell as a potential marker for positive or negative selection. We hypothesized that hyaluronan represents a distinguishing feature of the in vivo niche of one or more subsets of the heterogeneous population of CTPs in bone marrow, and would therefore provide a means for enrichment of CTPs from a fresh bone marrow aspirate. HA-based magnetic separation resulted in the isolation of a cell fraction enriched in highly proliferative CTPs. We also hypothesized that positive selection of CTPs based on hyaluronan (HA) will increase the efficacy of a bone graft in vivo due to increased concentration and prevalence of CTPs in a graft site. In order to test this hypothesis in vivo in a biologically relevant large animal model, we designed a new magnetic separation system to process larger volumes of marrow and defined a preferred method (drip soaking) for loading of HA-positive cells onto scaffolds. The canine femoral defect model provides a method for comparison of bone grafting materials using four cylindrical bone defects in the canine femur. Defects were grafted using either HA-positive cells or heparinized bone marrow aspirate (hBMA). Both defects grafted with MS-processed HA-positive cells and hBMA showed robust bone formation at 4 weeks, but the amount of total bone mineral in the defect was not different between the two groups as assessed by microCT. Using histomorphometric analysis, both the area of new bone formation and vascular sinusoids was significantly greater when MS processing was used. In aggregate, these data support the initial hypotheses of these projects. They provide the first proof-of-concept that HA can be used as a marker for selection of CTPs and that rapid intraoperative processing of bone marrow using HA can improve the outcome of local bone regeneration in vivo. Advisors/Committee Members: Eppell, Steven.

Subjects: Biomedical Engineering

Keywords: connective tissue progenitors, hyaluronan, magnetic separation, bone regeneration, canine femoral multidefect model

22. Carter, Randy Ray. Reflex regulation of antagonist muscles in the normal human hand.

Degree: PhD, Biomedical Engineering, 1990, Case Western Reserve University

► This study evaluated reflex regulation of an antagonist muscle pair to lengthening… (more)

▼ This study evaluated reflex regulation of an antagonist muscle pair to lengthening and shortening during single muscle activation and to reciprocal lengthening and shortening during cocontraction. The total neuromuscular response of the flexor and extensor pollicis longus muscles (FPL and EPL, respectively) to an externally imposed displacement was recorded in normal human subjects. The operating point was varied by changes in the initial torque levels of the two muscles. Results indicated that the total stiffness varied with changing background torque during both lengthening of the FPL and shortening of the EPL. The relationship between total stiffness and initial torque was well fit by a linear regression model. Thus, stiffness was not regulated to a constant value across operating points, arguing against application of the stiffness regulation hypothesis to these conditions. The stiffness regulation hypothesis has suggested that the role of reflex action may be to compensate for the dependence of total stiffness on operating point. To investigate this, the total response was decomposed into three stiffness components (passive, intrinsic and reflex) during single muscle contraction and during cocontraction. The passive, intrinsic and reflex stiffness components were found to each con tribute significantly to the total response measured during muscle lengthening, shortening or during reciprocal lengthening and shortening. Furthermore, comparison of the stiffness with and without reflex action demonstrated that reflex action did not strongly reduce the dependence on the operating point. Investigation of stiffness regulation about an operating point has produced three important results. First, the stiffness measured during cocontraction is not equal to the sum of the contributions from each of the two muscles acting alone. Thus, stiffness varied about a value set by the operating point of each active muscle. Second, stiffness varied across different cocontraction levels even though the net joint torque was held constant. Third, at low concentration levels the measured stiffness was less than expected based on summation of the action of the two muscles, while at high cocontraction levels the measured stiffness was greater than expected. This indicated that during cocontraction the shape of the torque angle curves of the muscles changed significantly. Advisors/Committee Members: Crago, Patrick E.

Keywords: antagonist muscles human hand

23. Cassidy, James Joseph. Hierarchical structure and mechanical properties of collagen in the intervertebral disc.

Degree: PhD, Biomedical Engineering, 1990, Case Western Reserve University

► The hierarchical organization of collagen fibrils in the intervertebral disc is characterized… (more)

▼ The hierarchical organization of collagen fibrils in the intervertebral disc is characterized by structural gradients. In the annulus fibrosus, the thickness of lamellae increases abruptly 2 mm inward from the edge of the disc, dividing the annulus into peripheral and transitional regions. Lamellae in the lateral and posterior annulus have a broad distribution of lamellae thicknesses. In alternate lamellae, fibrils are inclined with respect to the vertical axis of the spine in a layup structure. From the edge of the disc inward to the nucleus, this interlamellar angle decreases from 62 to 45 degrees. Within lamellae, collagen fibrils exhibit a planar crimped morphology. The plane of the waveform is inclined with respect to the spinal axis by the interlamellar angle. From the edge of the disc inward, the crimp angle increases from 20 to 45 degrees and the crimp period decreases from 26 to 20 um. A hierarchical model of the disc is presented that incorporates these morphological gradients. Mechanical testing in load-deflection, stress relaxation, and creep modes reveals the response at each level of the hierarchy to compression. The stress-strain curve of the disc in compression contains toe, linear elastic, and yield regions similar to other collagenous tissues in tension. This demonstrat es that while the disc is loaded in compression, the fibrils of the annulus are loaded in tension. The role water transport plays in determining the mechanical properties of the disc is also established. During constant compressive strain stress relaxation experiments, the volume of the disc decreases with time by an amount equal to the macroscopic strain. A model is developed which hypothesizes that the relaxation and creep responses are due to transport of water out of the disc as the result of the pressure gradient across the cartilage endplates caused by an externally applied stress. The model considers cases analogous to the 3- and 4-parameter viscoelastic models, but contains elements which have a physical significance. Advisors/Committee Members: Fouke, Janie.

Keywords: Hierarchical structure mechanical properties collagen intervertebral disc.

24. Chang, Chung-Che Jeff. The effect of Staphylococcus epidermidis adherence to biomaterials: On antibiotic susceptibility, antibiotic release, and infection risk.

Degree: PhD, Biomedical Engineering, 1991, Case Western Reserve University

► The adherence of slime producing S. epidermidis and the consequent biofilm formation… (more)

▼ The adherence of slime producing S. epidermidis and the consequent biofilm formation onto biomaterials are critical in the pathogenesis of biomaterial-associated infection. From the results of the present studies, it becomes evident that the bacteria adhered to biomaterials are most resistant to antibiotics. Organisms adhered to polystyrene (POS) were most resistant while those adhered to poly(methyl methacrylate) (PMMA) and agar substrates had limited susceptibilities to antibiotics. Planktonic, vegetative organisms were susceptible to the antibiotics. Thus by applying the susceptibility testing method developed here, the susceptibility of the bacteria in biofilm to antibiotics can be better determined than by the routine susceptibility tests now in clinical use. This will be helpful in providing accurate information for physicians to choose effective antibiotics to treat biomaterial-associated infection cases and in developing new antibiotics targeted to act on bacteria in the biofilm. These results led to the hypothesis that the biofilm acts as a barrier to antibiotic penetration and thus increases the resistance to antibiotics. However studies showed that the gentamicin release from the PMMA sp ecimens containing gentamicin was not significantly altered by the presence of biofilm and thus resistance is more than a barrier phenomenon. The results of in vitro adhesion assays and the simultaneous in vivo studies, have indicated that the biomaterial which causes more biofilm formation (greater bacterial adherence) in vitro will lead to a higher amount of viable S. epidermidis recovered from the implant sites with the biomaterial. This is true when bacteria are preadhered to biomaterials in vitro and also when bacteria are injected into the sites of sterile biomaterials. In addition, the polymicrobial adhesion assay presented here indicated that the S. epidermidis biofilm formation, dead or alive, on the PMMA and PMMA containing gentamicin specimens promotes the adherence of P. mirabilis and P. aeruginosa. This is further confirmed by the in vivo study which has shown that the infection rates, caused by injecting P. mirabilis into the implantation sites, were higher at the sites of specimens coated with dead or live biofilm than at the sites with specimens not coated. Thus it is illustrated by these studies that the biofilm can contribute to the pathogenic mechanisms by the promotion of adherence of other more pathogenic bacteria and by decreasing the susceptibility of the adherent bacteria to antibiotics. Advisors/Committee Members: Merritt, Katharine.

Keywords: Staphylococcus epidermidis antibiotic

25. Chang, David T. LYMPHOCYTE AND MACROPHAGE INTERACTIONS IN THE RESPONSE TO BIOMATERIAL SURFACES.

Degree: PhD, Biomedical Engineering, 2008, Case Western Reserve University

► Synthetic polymers provide a wide array of physical properties and chemical compositions… (more)

▼ Synthetic polymers provide a wide array of physical properties and chemical compositions that can be exploited as components in prosthetics, devices, and tissue-engineered constructs. This requires elucidating the biological response to biomaterials and the relationship between surface characteristics and cellular behavior. Lymphocytes transiently appear at implant sites and have been observed clinically to be reactive. However, the role of lymphocytes in the tissue response and the mechanisms involved are still unclear. This research aimed to gain insight into the interactions between lymphocytes and macrophages at biomaterial surfaces and explore the relationship between surface properties and lymphocyte/macrophage interactions. The studies addressed the hypothesis that biomaterial surface chemistries modulate the direct and indirect lymphocyte interactions with macrophages and foreign body giant cells. PET-based photograft copolymerized surfaces with hydrophobic, hydrophilic/neutral, hydrophilic/anionic, and hydrophilic/cationic characteristics were utilized as model surfaces. Quantification of select inflammatory mediators showed that hydrophilic/neutral and hydrophilic/anionic surfaces promoted pro-inflammatory responses and a reduced potential for ECM degradation relative to other surfaces. Proteomic cytokine arrays provided a useful tool for assessing the role of soluble mediators in the response to biomaterials and identified potential fusion factors. We subsequently showed the capability of lymphocytes, through direct and indirect mechanisms, to enhance macrophage activation and production of pro-inflammatory mediators. Hydrophilic/neutral and hydrophilic/anionic surfaces were shown to be highly but distinctly activating. These surfaces also promoted distinct lymphocyte subset adhesion to macrophages and FBGCs compared to hydrophobic PET suggesting induction of differential macrophage and FBGC phenotypes on varying biomaterial surfaces. IFN-γ production in direct and indirect co-cultures rather than individual cultures suggested nonspecific mechanisms of lymphocyte activation. Direct cell-cell interactions enhanced IFN-γ production more so on the hydrophilic/anionic surfaces than on any other surface, indicating this surface as highly lymphocyte activating. These findings provide insight into lymphocyte and macrophage interactions in response to biomaterial surfaces along with evidence consistent with the hypothesis that distinct surface chemistries modulate lymphocyte and macrophage interactions. Finally, we present a mechanistic model which provides a tool for further analysis of lymphocyte and macrophage interactions in response to biomaterial surfaces and a step toward quantitative predictability of biomaterial-dependent processes. Advisors/Committee Members: Marchant, Roger E.

Subjects: Biomedical research; Engineering

Keywords: biomaterials; foreign body reaction; foreign body giant cells; macrophages; lymphocytes; activation; cytokines

26. Chang, Hana. Anisotropic Adaptation of Stem Cells to Changing Mechanical Environments.

Degree: MS, Biomedical Engineering, 2012, Case Western Reserve University

► Shape and fate are intrinsic manifestations of form and function at the… (more)

Subjects: Biomedical Engineering; Biomedical Research

Keywords: Stem cells, cytoskeletal remodeling, actin, tubulin, shear stress, mechanoadaptation

27. Chaturvedi, Ashutosh. Development of Accurate Computational Models for Patient-Specific Deep Brain Stimulation.

Degree: PhD, Biomedical Engineering, 2012, Case Western Reserve University

► Deep brain stimulation (DBS) is a surgical treatment that involves implanting electrodes… (more)

▼ Deep brain stimulation (DBS) is a surgical treatment that involves implanting electrodes within the brain to alleviate the symptoms of various neurological disorders. One such disorder, Parkinson’s disease (PD), is a neurodegenerative disease whose primary symptoms are tremor, rigidity, bradykinesia, and gait instability. DBS uses an implanted pulse generator (IPG) to stimulate deep cortical structures using high frequency stimulation (HFS). This therapeutic stimulation helps manage some of the patient’s symptoms and subsequently improves their quality of life. We implemented and compared five different patient-specific electric field models to assess the degree of model complexity that was needed to make accurate predictions of neural response to DBS. We observed that the more simplistic models, ones that did not account for a tissue encapsulation layer around the electrode or a non-homogeneous tissue medium, generated excessive, non-realistic predictions of axonal activation. In this study, we also determined if current-controlled devices with independent current sources provided a more targeted stimulation. We investigated the impact of using current steering between multiple electrode contacts to selectively activate different target neural populations typically associated with therapeutic benefit, while avoiding populations associated with side effects. We found that current steering allowed for increased selectivity in activating different neural populations of interest, but at a price of a much larger stimulation parameter search space. Finally, we developed a novel predictor function that performed better than an AF-based approach in quantifying the spread of neural activation. This new artificial neural network (ANN)-based predictor function could also estimate volumes of tissue activated (VTAs) for multiple electrode geometries and multi-contact stimulation configurations without needing explicit computer simulations. Collectively, the analysis of these different components gave us the methodology and the tools to accurately predict neural activation by DBS on a patient-specific basis. In turn, an application of these tools can be used to develop novel electrode designs and optimize clinical therapeutic stimulation. Advisors/Committee Members: Durand, Dominique M.

Subjects: Biomedical Engineering; Neurology; Neurosciences

Keywords: neural engineering; deep brain stimulation; Parkinson's disease; computational modeling; artificial neural networks

28. Chen, Xin. MRI MONITORING AND MODEL PREDICTION OF THERMAL ABLATION DYNAMICS IN TISSUE.

Degree: PhD, Biomedical Engineering, 2007, Case Western Reserve University

► This research is motivated by the need for more effective and efficient… (more)

▼ This research is motivated by the need for more effective and efficient clinical application of minimally invasive thermal ablation of solid tumors. During the ablation procedure, it is important to determine the region of tissue in which the cells have been killed and to predict input changes needed to kill tumor cells with minimal damage to normal tissue. To achieve this goal, we proposed an approach that combines fast magnetic resonance image (MRI) with mathematical modeling and simulation to monitor and predict the dynamics of temperature distribution and lesion boundary. The interactive use of MRI monitoring and model prediction provides a foundation for a real-time, clinical technique. The development of this approach has been described in the following chapters. Chapter 1: Background is presented about solid cancerous tumors and methods of thermal therapy and image techniques for monitoring. Chapter 2: The combination of MRI and model simulation to monitor and predict thermal ablation dynamics is developed and validated by in vivo experiments using radio-frequency (RF) ablation in normal paraspinal muscle of rabbits. Simulations of tissue temperature distribution and cell damage dynamics are compared with data obtained from MR phase and magnitude images. Chapter 3: The validity of this approach is tested by its application to RF ablation in VX2 tumors implanted in paraspinal muscle of rabbits. Chapter 4: A model of thermal ablation with laser light as a heat source is developed. Model simulation of tissue temperature distribution dynamics is compared with MR images from in vivo experiments with laser ablation of brain tissue of rabbits. Chapter 5: The thermal model is extended to describe the effects of an internal cooled RF probe that may also allow saline leakage into tissue. Model simulations quantify the lesion-enlarging effect of this type of RF probe. Chapter 6: Cooling by a large blood vessel in tissue near the heat source is simulated to determine how it would effect thermal ablation of tissue. Chapter 7: A summary is presented of major achievements of this research, its limitations, and possible future work. Advisors/Committee Members: Saidel, Gerald M.

Keywords: Thermal Ablation; Magnetic resonance imaging; Thermal mmodels; Image-guided therapy

29. Chin, LiKang. Tyramine Substituted-Hyaluronan Enriched Fascia for Rotator Cuff Tendon Repair.

Degree: PhD, Biomedical Engineering, 2011, Case Western Reserve University

► Rotator cuff tendon injury is a debilitating health concern that affects more… (more)

▼ Rotator cuff tendon injury is a debilitating health concern that affects more than 40% of the aging population. Despite advances in surgical treatment, the failure rate of rotator cuff repairs ranges 20-90%. Naturally-occurring extracellular matrices (ECMs) have been recently investigated as augmentation scaffolds, but none has yet demonstrated both the appropriate biological and mechanical properties. This dissertation proposes to enrich fascia ECM with high molecular weight tyramine substituted-hyaluronan (TS-HA) for rotator cuff repair. The central hypothesis is that TS-HA treatment will decrease chronic inflammation without decreasing the time-zero or post-implantation mechanical properties of fascia. The specific aims are to develop a TS-HA treatment method and to evaluate the host response and concomitant mechanical properties of treated fascia in a rat abdominal wall model. TS-HA treatment increased the HA content of fascia by an order of magnitude to ~1% tissue weight. The incorporated HA was distributed throughout the ECM and, upon cross-linking, was retained as a hydrogel network. Cross-linked TS-HA treated fascia exhibited an increased macrophage and giant cell response and a lower density of fibroblast-like cells than water treated controls. Treated fascia, with or without cross-linking, exhibited a predominantly M2 pro-remodeling macrophage profile similar to water controls, which is suggestive of constructive tissue remodeling. All grafts exhibited a chronic lymphocytic response that is suggestive of an immune response to the fascia xenograft. Fascia samples in all groups demonstrated time-dependent decreases in mechanical properties. Cross-linked TS-HA treated fascia exhibited a lower toe-region elastic modulus and trended towards a higher transition strain than water treated controls not only after implantation, but also at time zero. These findings demonstrate that HA augmentation can alter both the host response and the mechanical properties of fascia ECM. Contrary to the hypothesis, the particular TS-HA treatment (at the concentration, molecular weight, and tyramine substitution rate) employed in this dissertation elicited a heightened macrophage and giant cell response and a decrease in low-load elastic mechanical properties compared to water treated fascia. This work provides a starting point and guidance for the ongoing development of TS-HA enriched fascia ECM as an augmentation scaffold for rotator cuff repair. Advisors/Committee Members: Derwin, Kathleen.

Subjects: Biomedical Engineering

Keywords: ECM (extracellular matrix); hyaluronan; biocompatibility; macrophage; tendon

30. Conway, Brian D. The Effect of Tortuosity, Vascular Motion, and Stent Selection on Renal Artery Stent Fractures.

Degree: MS, Biomedical Engineering, 2011, Case Western Reserve University

► Fractured stent grafts in the renal arteries can result in a variety… (more)

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