Brian Kwon

Currently, hemodynamic management is one of the only treatment options to improve neurologic recovery in patients with acute spinal cord injury (SCI). Our team has developed a novel implantable sensor based on near-infrared spectroscopy (NIRS) that is able to monitor spinal cord hemodynamics and oxygenation in real-time following acute SCI. In order to collect data, the NIRS sensor should be in direct contact with the spinal cord and emit near-infrared light into the tissue. As a safety assessment measure, I aimed to study the potential heat generation and contact compression effects of a series of custom implantable NIRS sensors developed in our research laboratory on the spinal cord tissue, as it is important prior to its clinical translation. In Chapter 1, I describe acute SCI and clinical treatment options such as hemodynamic management, as well as using NIRS to monitor spinal cord hemodynamics and improve the management of acute SCI. I also provide a background of NIRS technology, its clinical transcutaneous and novel implantable applications, and its risk factors and safety aspects. In Chapter 2, I investigate the potential heating effect of our spinal cord NIRS sensor using an in vitro setup. In this chapter, I have compiled information for a review article titled "Thermal Threshold for Tissue Damage from Near-Infrared Spectroscopy Sensors," which I plan to submit to a peer-reviewed journal. In Chapter 3, I focus on the potential impact of NIRS sensor compression on the spinal cord tissue in a porcine model of acute SCI. In Chapter 4, I provide a summary, conclusions, and future directions. In the appendix, I provide a summary of the regulatory process for the application of the NIRS sensor (version 5) in the NIRS clinical trial. With these pre-clinical experiments, I have assessed the safety of the first series of the spinal cord NIRS sensors, which will ultimately lead to the design of the newest version of the sensor to be placed on the spinal cord of human SCI patients in a clinical trial. This study could help future studies in evaluating the safety of implantable NIRS sensors.

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Neurogenic lower urinary tract dysfunction after spinal cord injury results in severe morbidity and mortality. Consequences of neurogenic lower urinary tract dysfunction include urinary tract infections, incontinence, upper urinary tract deterioration, and reduced quality of life. Urodynamic studies are the current gold standard for characterizing neurogenic lower urinary tract dysfunction. Currently, there is a need for a large animal model of neurogenic lower urinary tract dysfunction for evaluation of the utility and safety of novel human-sized devices or treatments. In this thesis, the functional and morphologic changes of the bladder were characterized in a porcine model of spinal cord injury. In Chapter 1, I provide background on spinal cord injury and the pathophysiology of neurogenic lower urinary tract dysfunction. I also discuss about the use of animal models for evaluation of human lower urinary tract diseases.In Chapter 2, I pioneered a protocol to perform clinically relevant urodynamic studies in a porcine model of thoracic spinal cord injury. I identified that the pig’s lower urinary tract function is very similar to human bladder function before and after spinal cord injury. In Chapter 3, I describe a protocol to implant radio telemetric devices into a porcine model to characterize physiologic bladder function and to evaluate the practicality of the system. I identified comparable detrusor pressure and external urethral sphincter activity recordings between the urodynamics and telemetry systems before and after spinal cord injury. In Chapter 4, I evaluated the effects of chronic bladder drainage on the functional and histologic features of the bladder. I found high-risk urodynamic features in pigs that received chronic bladder drainage.I have established a protocol to perform urodynamic studies in a porcine model of spinal cord injury to characterize neurogenic lower urinary tract dysfunction. The potential to perform repeated urodynamic studies in a single animal allows for investigation into the efficacy of treatment of therapies and devices over time. This scientific contribution will help bridge the gap between animal experimentation and human application for neurogenic lower urinary tract dysfunction after spinal cord injury.  

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Spinal cord injuries (SCI) are one of the most physically and psychologically devastating injuries one can survive. Despite decades of intense research effort, robust therapeutic treatment for this catastrophic condition remains elusive. The nature of the sequelae of SCI is characterized by progressive cell death in the injury penumbra, resulting in further neurological impairments. The intricate relationship between the vascular and nervous systems has become increasingly evident in many aspects of both normal physiology, and various pathological conditions, including SCI. Vascular abnormalities play a central role in the propagation of secondary damage after SCI. The aim of this thesis is to further the understanding of the vascular changes that occur after acute SCI. The endogenous expression of three angiogenic proteins: Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2) and Angiogenin will be examined after acute traumatic SCI. In the first study, the concentration of these proteins will be measured in a temporal series of cerebrospinal fluid (CSF) samples after human SCI. In the second study, the relative protein expression of Ang1 and Ang2 will be characterized in rat spinal cord after SCI. In human, Ang1 in CSF is not significantly different from non-SCI values after the initial spike at 24 hours post-SCI. Ang2 in CSF shows a delayed but persistent increase through the first 5 days post-SCI. In contrast, Ang1 in rat spinal cord decreases as early as 2 hours post-SCI, while low molecular weight Ang2 increases dramatically after SCI, from 2 hours to 3 days post-injury, peaking with a 13-fold elevation at 24 hours post-injury. These findings represent the first description of these proteins in the acute SCI setting in human CSF and rat spinal cord. The sustained elevation of Ang2 illustrates a possible mechanism by which reported vascular dysfunction and increases in blood-spinal cord-barrier (BSCB) permeability occurs after SCI. The patterns of change reported between the two studies may allude to the feasibility of using CSF as a biological proxy to future investigations into the biochemical events which occur in the spinal cord after SCI, and guide the development of pharmacologic treatments for this devastating condition.

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Spinal cord injury (SCI) is a devastating condition that causes paralysis below the level of the injury. To date, there is no convincingly effective treatment. An enormous preclinical and clinical effort is underway to find a treatment, and one approach is to search for pharmacological agents that are already in clinical use (albeit for different indications), but that may also have neuroprotective properties. Examples of such drugs are magnesium, Riluzole (sodium channel blocker), minocycline and statins. While the majority of human SCI occur in the cervical spinal cord, the vast majority of laboratory SCI research employs animal models of thoracic SCI. An important step, therefore, in the preclinical evaluation of novel treatments is to assess their efficacy in a model of cervical SCI. First, I describe the development of a novel unilateral contusive model of cervical SCI with refined biomechanical, functional, and histological parameters using the Infinite Horizon spinal cord injury device. I conducted a series of experiments in which the spinal cord was injured using various impact forces, impact trajectories, and impact locations off the midline. Behavioral deficits were assessed using a variety of forelimb function tests, after which the cords were evaluated histologically. From these series of experiments, I established a new cervical unilateral spinal cord injury contusion model. Next, I evaluated the neuroprotective effects of minocycline and simvastatin in the clinically relevant unilateral cervical contusion model. Minocycline is a commonly prescribed tetracycline antibiotic that is prescribed for acne. Simvastatin is one of many hydroxymethylglutaryl-coenzyme-A reductase inhibitors that lower cholesterol. As both drugs have translational potential and have been reported to have neuroprotective properties in various neurological diseases, I assessed the neuroprotective effects of these drugs using a host of functional and histological assessments. In the end, there were no neurological improvements with minocycline or simvastatin treatment after a cervical contusion injury.

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