UTSA Electronic Theses and Dissertations
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This collection contains electronic UTSA theses and dissertations (ETDs), primarily from 2005 to present. The collection is not comprehensive; search the UTSA Library Catalog for a complete list of UTSA theses and dissertations.
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Browsing UTSA Electronic Theses and Dissertations by Department "Biomedical Engineering"
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Item A Cellular Array of Three Dimensional Mono- and Polymicrobial Biofilms for High-throughput Drug Discovery and Diagnostics(2014) Srinivasan, AnandThe development of new antibiotics faces the long and arduous process of drug discovery, in which the search typically begins with High-Throughput Screening (HTS). In HTS, in vitro assays involving libraries of thousands or even hundreds of thousands small molecules are tested to identify "Hits" or effective biomolecules that affect a particular biological process. Unfortunately, the current methods of conventional drug discovery using classical microbiological culture techniques are not compatible with hunger for speed. Addressing these issues and quenching the thirst of HTS for a rapid screening platform we have developed a chip-based cellular array of single and polymicrobial, nano-scale biofilms of C. albicans, S. aureus and P. aeruginosa; as a model organisms for fungi, gram positive and gram negative bacteria respectively. Briefly, a robotic arrayer will be used to print single or co-culture of microorganisms, with a suitable media and synthetic hydrogel matrix onto a surface-modified glass slide which upon incubation leads to biofilm formation. An array of 1200 identical spots of nano-biofilms can be printed on a microscopic glass slide, making the chip-based platform a "truly" high-throughput screen. Compared to current industry standards (namely the 96-well microtiter plate model of biofilm formation), this biofilm chip has advantages in terms of miniaturization and automation, which combine to cut reagent use and analysis time, minimize or eliminate labor intensive steps, and dramatically reduce assay costs. Such a chip will speed up the drug discovery process by enabling rapid, convenient and inexpensive screening of hundreds-to-thousands of compounds simultaneously. On the diagnostic front, we have developed a lab-on-a-chip high-throughput platform for rapid detection of antimicrobials that are effective in treating skin and soft-tissue infections; caused by community-acquired Staphylococcus aureus. The High-Throughput-Antimicrobial Susceptibility Testing Chip (HT-ASTChip) is rapid, robust and culture-independent. We believe that the results obtained using this universal platform will ameliorate the prescription of empirical antibiotic therapy.Item A Comprehensive Quantitative Evaluation of Rotator Cuff Muscle Properties Using Novel Imaging Techniques and Muscle Regenerative Therapeutics(2023) Treviño, Jose Hernandez, IIIThe current course of treatment for rotator cuff tears depends on numerous factors, such as tear size, intramuscular fatty infiltration, metabolic diseases, muscular atrophy, age, and muscle stiffness. These multiple factors affecting muscles and tendons are evaluated in the clinical setting via various diagnostics imaging tools and physical manipulations of the shoulder. However, current clinical methods present several limitations that prevent a comprehensive, quantitative, and accurate estimation of muscle properties and rotator cuff tear prognosis. As a result, treatment for such defects that have failed conservative management depends solely on surgical techniques. Thus, novel non-invasive imaging approaches that quantify muscle properties should be developed to aid clinicians during surgical planning and implementation of rehabilitation protocols. Furthermore, novel therapeutics should be designed to improve muscle quality and reduce the high rates of repair failures. For this purpose, the goal of the current study was twofold: first, to develop imaging approaches to quantify the properties of the rotator cuff muscles to improve diagnosis and rehabilitation management; second, to investigate the feasibility of novel therapeutics that can be used for muscle regeneration. The objectives of the current study were to quantify the degenerative properties (i.e., volumetric intramuscular fatty infiltration, atrophy, and stiffness) using magnetic resonance imaging (MRI) and ultrasound shear wave elastography (SWE) imaging of the rotator cuff muscles and to determine the response of skeletal muscle precursor cells when exposed to therapeutics involved in age-associated cell dysfunction. We have developed the following aims to reach our goal and objective: Specific Aim 1: Quantify the volumetric distribution of degenerative properties in the supraspinatus muscle using novel magnetic resonance imaging techniques. Specific Aim 2: Determine the role and activity of the individual sub-regions of the infraspinatus muscle and teres minor muscle using ultrasound shear wave elastography during external shoulder rotation. Specific Aim 3: Evaluate the effect of novel therapeutic interventions on muscle regenerative properties. Successful outcomes from this study will allow for a more comprehensive and quantitative evaluation of skeletal muscles and pave the way for developing novel therapeutics that can restore muscle function, eventually reducing the high incidence of repair re-tears.Item A computational model of the porcine eye for investigation of primary blast(2014) Watson, Richard A.The purpose of this work was to create a computational model for investigating the internal dynamics of the eye under the uniquely transient loading imposed by blasts. A model of the porcine eye was developed in conjunction with a large cohort of physical blast experiments to porcine eyes. The model was based on extensive review of previous computational models as well as data from physical experiments in the literature. The response of the model showed potentially injurious stress and strain values in the regions of the eye that sustained injury in the physical experiments. The model response suggests a mechanism of injury wherein the motion of the vitreous, induced by the compressive effects of the blast at the front of the eye, resulted in contrecoup loading in the posterior layers of the eye.Item A novel tissue engineering based endovascular aneurysm repair using electrospun scaffolds(2012) Kaufmann, Jennifer Jordan MasseyAbdominal Aortic Aneurysms (AAA) consist of a dilation of the sub-renal aorta such that it is at least 150% of the original diameter. These aneurysms occur predominately in males at least 65 years of age and are generally asymptomatic. As the vessel dilates, there is an increased incidence of rupture. If rupture occurs, most individuals die before reaching the hospital. Therefore, it is critical to detect and treat these aneurysms before they rupture. Endovascular Aneurysm Repair (EVAR) is one of the two techniques used to treat an AAA and consists of inserting a graft through the femoral artery and positioning it over the dilation. The graft is deployed so that it barricades the aneurysmal sac from the blood flow while providing a viable conduit for blood flow. While most current grafts consist of bioinert materials, the purpose of this study is to examine the feasibility of using a bioresorbable tissue engineering scaffold. A tissue engineering scaffold for aneurysm repair (TESAR) would promote cell attachment, infiltration and organization while acting as a typical EVAR graft. Hypothetically, a new aortic tissue wall could be formed and then the TESAR would bioresorb. The benefits of such a device may include better apposition to the native wall to reduce the incidence of endoleaks and the reduction of foreign materials implanted. A tissue engineering repair may also prove beneficial for diverse anatomical structures and allow appropriate remodeling. The results of this study include a novel scaffold graft which may be a viable option for use in AAA repair based on the mechanical properties, in vitro cell response and in vivo implantation of the device. Studies determined appropriate manufacturing parameters for viable physical characteristics. In vitro studies using human aortic endothelial cells and human aortic smooth muscle cells in both static and dynamic culture environments demonstrated appropriate cell attachment and infiltration. The TESAR which was developed demonstrated promising results in a surgical swine AAA model in which an endothelium was present at 28 days and smooth muscle cells had infiltrated and began to organize within the TESAR material. In addition, the TESAR material was well adhered to the aorta wall and no thrombotic events were apparent.Item A Physiochemical Investigation of the Role of Pili Forming Genes in Mediating Acinetobacter baumannii Multidrug Resistance to Model Antibiotics(2023) Salinas, Joel H.The impact of pili forming genes from the Type IV Pili system on the multidrug resistance and biofilm formation of Acinetobacter baumannii, a bacterium responsible for numerous hospital-acquired infections, was investigated. Utilizing the AB5075 wildtype strain and its pili mutants, the growth kinetics, electrophoretic mobilities, surface wettabilities, and biofilm formation were quantified. These properties were used to predict bacterial interactions with common hospital materials. Techniques such as disk diffusion assay, minimum inhibitory concentration (MIC) assays, checkerboard assays, contact angle measurements, electrophoresis, and Derjaguin-Landau-Verwey-Overbeek (DLVO) modeling were employed to quantify the effects of pili genes and antibiotic treatment on bacterial adhesion and biofilm formation. Our findings revealed that pili genes significantly influenced the physicochemical properties and antibiotic resistance of A. baumannii. Furthermore, the type of material and antibiotic used can influence bacterial adhesion to common hospital materials and biofilm inhibition. Our results can be used to inform the development of new strategies to combat A. baumannii infections and enhance infection control measures in clinical settings.Item A strategy to optimize mesenchymal stem cell function pertinent to bone tissue engineering(2011) Creecy, Courtney MichelleThe present research study is motivated by intriguing, but limited, information reported in the literature of phenomenological studies showing enhanced bone-fracture healing in animals under electric stimulation. However, the underlying mechanisms at the cellular- and molecular-levels are not fully understood. The present in vitro research aims to overcome such limitations by establishing the presently undefined conditions that expedite the process of adult human mesenchymal stem cell (MSC) differentiation into osteoblasts. For this purpose, a multidisciplinary approach, which encompassed aspects of cellular engineering, molecular biology, biochemistry, and tissue engineering, was implemented. Specifically, molecular and biochemical assays were used to determine the effects of alternating electric current on MSCs cultured in three-dimensional constructs; these effects were further validated through comparisons of the effects of alternating electric current on MSC differentiation to those of a well-established biochemical stimulus, bone morphogenetic proteins. The present research study is the first to provide evidence that alternating electric current accelerated and enhanced the differentiation of adult human mesenchymal stem cells toward the osteoblastic pathway. Specifically, exposure of mesenchymal stem cells to either 10 or 40 µA alternating electric current for six hours per day, for various periods of time up to 14 days, enhanced gene expression of select proteins pertinent to the osteogenic differentiation pathway. Most importantly, gene expression of proteins pertinent to either the adipogenic or chondrogenic pathways was not detected when MSCs were exposed to the aforementioned alternating electric current conditions tested in the present study. These in vitro results elucidated aspects of the molecular-level mechanisms through which this stem cell differentiation may occur in vivo under alternating electric current. In addition to providing fundamental information pertinent to bone physiology, the results of the present study provided evidence that alternating current, a biophysical stimulus, alone has the yet untapped potential to achieve successful tissue engineering alternatives to traditional bone grafts; such novel methodologies are needed to meet the projected clinical demands for bone tissue repair and healing applications. In this respect, the present study could have major impact on the bioengineering, biotechnology, and clinical milieu.Item A Tissue Engineered Treatment for Chronic Diabetic Skin Wounds: An Advanced Collagen Wound Matrix Combined with Adipose Derived Stem Cells(2018) Edwards, Nicole J.Chronic, non-healing skin wounds are a significant clinical challenge in diabetic patients, and few effective treatments are currently available. Often, after many failed treatments, physicians are forced to resort to amputation of the affected extremity due to the high risk of infection and eventual sepsis. An effective treatment to heal chronic diabetic skin wounds is urgently needed to reduce the risk of infection, eliminate the need for limb amputation, and improve the quality of life of people with diabetes. To address this need, we have developed a tissue-engineered treatment that combines a novel electrochemically deposited type I collagen scaffold, termed the advanced collagen wound matrix (CWM), and human adipose derived stem cells. The CWM is fabricated by an electrochemical deposition method, as opposed to a traditional collagen gelation method, which creates a densely packed, robust collagen matrix that possesses excellent material properties for skin tissue engineering. The CWM possesses high porosity, an appropriate degradation profile, and significantly higher tensile strength than a standard gelated collagen scaffold. The CWM is highly biocompatible and supports cellular growth and proliferation well. To increase the wound healing capabilities of this treatment, the CWM is seeded with human adipose derived stem cells. Adipose derived stem cells (ADSCs) are abundant, easily harvested, and well suited for tissue culture. They also possess inherent wound healing properties, making them ideal for treatment of chronic diabetic skin wounds. To fully investigate this treatment, the CWM with and without the addition of ADSCs is used to treat full thickness excisional skin wounds in a murine model of type 2 diabetes and wound healing is monitored to 21 days. In this model, untreated diabetic skin wounds regenerated low volumes of granulation tissue during the first 7 days of healing, then had no increase in granulation tissue formation past the initial 7 days, highlighting the impaired wound healing capabilities associated with diabetes. Treatment with the CWM alone and the CWM combined with ADSCs, however, consistently stimulated significantly increased volumes of regenerated granulation tissue and formed higher quality tissue than the untreated wounds. We prove that the CWM stimulates healthy tissue regeneration in diabetic skin wounds when used both alone and in combination with adipose derived stem cells. We have developed an excellent treatment option for patients with chronic, non-healing diabetic wounds who may otherwise be forced to consider limb amputation.Item A whole eye finite element analysis of accommodation(2014) Wilkes, Robert PeytonThe young human eye has the ability to change focus from far to near distance by changing the shape of the lens in a process called accommodation. Contraction of the ciliary muscle drives accommodation. Hypothetically it also plays a mechanical role in the etiology of glaucoma and presbyopia. Biomechanical assessment of the associated tissues has been done primarily with tissue samples in isolation after dissection, or through optometric measurements. The ciliary muscle has been inaccessible without dissection, except with various imaging modalities, including UBM OCT and MRI. However, it has not been well characterized in terms of its contraction kinetics. To address this gap in knowledge a biomechanical finite element analysis (FEA) model was built of the entire globe of the eye that includes the tissue components in the loading pathway of accommodative forces, and with an active ciliary muscle. This time-based model, consisting of discrete 3D geometric regions for each tissue, was populated with tissue material models from literature, and calibrated based on reported measurements of tissue movement from the clinical literature. It is hoped that the knowledge and modeling tools from this work will provide a platform for future study of pathologies associated with accommodation.Item Age effects on the material and mechanical properties of bone at the osteocyte lacuna(2009) Potter, Ryan ShawnThis is an exploratory study aimed at characterizing the microenvironment of bone tissue around osteocyte lacunae, referred to as peri-lacunar tissue, as a function of age. Comprising nearly 90% of all bone cells, osteocytes are ideally situated to sense mechanical strain and translate mechanical signals into biochemical signals to regulate bone modeling and remodeling. Previous work has shown that there is an amplification of globally applied macroscopic bone strains at the microstructural level of the osteocyte due to a strain concentrating effect around the osteocyte lacuna and surrounding extracellular matrix. This peri-lacunar region is believed to have different material and mechanical properties than bone tissue not associated with an osteocyte lacuna. These alterations in bone tissue at the osteocyte lacuna are believed to have a significant impact on the tissue strains sensed by the osteocyte. The global hypotheses are two-fold. First, peri-lacunar tissue is significantly different from non peri-lacunar bone tissue. Second, the mechanotransduction signal---the translation of mechanical stimuli to cellular signal---acting on the osteocyte is altered as the peri-lacunar tissue's mechanical and material properties change with aging. These hypotheses are tested using Raman spectroscopy, two dimensional displacement/strain mapping, and nanoindentation. Using these three techniques the mechanical and material properties of the peri-lacunar tissue were found to be significantly different from the surrounding non peri-lacunar tissue in its young crystalline structure, but not in its old crystalline structure, mineralization, carbonate substitution, collagen cross-linking, effective strains, and elastic modulus. Age effects on the bone tissue irrespective of location with respect to the lacuna were significant as carbonate substitution, crystallinity, collagen cross-linking, and effective strains near the loaded crack tip showed significant differences. These differences imply bone changes both with age and with proximity to an osteocyte lacuna. These findings further the understanding of how age effects and the osteocyte microenvironment affect the osteocyte mechanotransduction process.Item Age-related influence of bone remodeling on local tissue properties of human cortical bone(2010) Reyes, Michael JohnWith aging, cortical bone experiences deterioration in its mechanical competence, thus resulting in increased bone fragility. Studies have shown that the mechanical properties of cortical bone are significantly dependent on the quality and spatial arrangement of its constituents. Age-related changes have been observed in the mineral and collagen as well as the local microstructural properties of bone. Further, age-related changes in the material components and tissue architecture correlate significantly with decreases in bulk bone post-yield properties. Evidence indicates that these changes may be due in part to the bone remodeling process, which may alter material composition and spatial arrangement in a manner detrimental to the mechanical properties of the tissue. This study was performed to determine if the bone remodeling process has an age-related effect on the micromechanical and compositional properties of cortical bone, and whether or not such changes are correlated with decreased post-yield properties in newly remodeled tissue. To investigate this issue, the micromechanical properties of secondary osteons (newly remodeled tissue) and interstitial tissue (biologically older tissue) were assessed using a microcompression test protocol. The compositional properties of the mineral and collagen components of osteonal and interstitial tissues were assessed using High Performance Liquid Chromatography, X-ray Diffraction analysis, and Fourier Transform Infrared Microscopy. Additionally, morphometric analysis was performed to assess age-related changes in the proportion of newly remodeled tissue comprising cortical bone. The results of the micromechanical tests revealed secondary osteons to have significantly higher post-yield properties compared to interstitial tissues, with no age-related changes observed in the mechanical properties of either tissue. Additionally, compositional analyses showed that the bone remodeling process did not result in changes to the composition of the mineral and collagen that were correlated with reduced post-yield properties. However, differences were observed in the composition of the mineral and collagen that reflect tissue aging processes as secondary osteons age into interstitial tissues. Additionally, age-related decreases in the proportion of newly remodeled tissue comprising cortical bone were observed. The bone remodeling process does not appear to result in age-related changes in the composition and post-yield properties of newly remodeled tissue. Rather, it appears that processes associated with tissue aging contribute to the decline in post-yield properties of bone as secondary osteons age to eventually become interstitial tissues.Item Antibacterial self-assembled monolayers for hydroxyapatite implants(2010) Torres, Nelson SigfridoOpen fractures are common in battlefields, motor vehicle accidents, gunshot wounds, sports injuries, and high-energy falls. Such fractures are often treated using hydroxyapatite (HA)-based bone graft substitutes. However, open fracture wounds are highly susceptible to bacterial infections. Hence, this study was focused on incorporating anti-bacterial properties to HA using silver (Ag) carrying self-assembled monolayers (SAMs). Self-assembled monolayers (SAMs) are molecular coatings composed of a single layer (1-3 nm thick, 10-18 carbon atoms in length) of hydrocarbon chains with reactive head groups that have high affinity toward the substrate material. Furthermore, a monolayer can have reactive terminal groups such as carboxylic acid or amine groups that may serve as a starting point for further modification. Initially, the --COOH terminated phosphonic acid SAMs of two different chain lengths (11 carbon atoms -- short chain and 16 carbon atoms -- long chain) were deposited on HA. Anti-bacterial SAMs (ASAMs) were prepared by chemically attaching Ag to short and long chain SAMs coated HA. X-ray photoelectron spectroscopy, atomic force microscopy, and contact angle goniometry collectively confirmed the attachment of Ag onto SAMs coated HA. The bacterial adhesion study showed that the adherence of Staphylococcus aureus was significantly reduced on ASAMs coated HA when compared to control HA. The stability of Ag carrying SAMs on HA was investigated under different sterilization conditions, including autoclave, dry heat, ethylene oxide gas, oxygen gas plasma, and ultraviolet irradiation, and under physiological conditions by immersion in TBS at 37°C and pH 7.4. The stability studies showed that gas plasma, dry heat and autoclave based sterilization techniques degraded most of the ASAMs on HA. UV irradiation did not damage the short chain ASAMs as vigorously as other treatments, while it degraded the long chain ASAMs completely. Ethylene oxide treatment did not degrade the long chain ASAMs unlike all other treatments but it severely damaged the short chain ASAMs. Both short and long chain ASAMs significantly desorbed from the HA surfaces under simulated physiological conditions although long chain ASAM exhibited better stability than short chain ASAM. Thus, this thesis has demonstrated the potential for using ASAMs to provide anti-bacterial properties to HA, their relative stability after sterilization and under physiological conditions, and the need for developing techniques to further improve stability of SAMs.Item Artery wall remodeling under buckling in organ culture(2011) Zhao, YangArterial tortuosity is associated with cardiovascular diseases such as hypertension, atherosclerosis, and aneurysms. However, the process of tortuous development is poorly understood. Previous studies suggested that mechanical buckling of arteries under mechanical stress may relate to vessel tortuosity(Han 2011). One possibility is that arterial tortuosity develops due to artery remodeling initiated by buckling. However, the effect of buckling on arterial wall remodeling remains unclear. The objective of this study was to investigate the possible link between buckling and arterial tortuosity by evaluating cell proliferation and extracellular matrix remodeling in buckled arteries. We used an ex vivo organ culture model that allowed us to compare straight and buckled arteries while maintaining the same pressure and flow. Arteries were cultured for 3 days and 7 days, under a pressure of 200±20 mmHg and stretch ratio of 1.5. To examine arterial remodeling, endothelial cell and smooth muscle cell proliferation, collagen I content, elastin content, MMP9, fibronectin, arterial structure, local stress in the arterial wall were examined using BrdU staining, western blot, histological staining and mechanical analysis. Our results showed that after 3 days cell proliferation on the inner curve of buckled arteries and MMP9 levels on the outer curve of buckled arteries were significantly higher compared to the control group. No significant difference was observed for cell proliferation or MMP9 after 7 days in organ culture. Collagen I protein level, measured by western blot, did not change in both 3 day and 7 day organ culture; however, the trichrome stain showed that total collagen ratio significantly increased in the inner curve of the buckled artery after 7 days in organ culture. At the same time, stress analysis indicated that shear stress, circumferential stress, axial stress and radial stress were lower in the inner curve of buckled arteries compared to the control arteries, while the outer curve affords the highest shear stress and wall stress. Multiple linear regression analysis indicated that circumferential stress was significantly related with smooth muscle cell proliferation in the inner media. Fibronectin level, elastin content, wall thickness, deflection and curvature did not significantly change after 3-day and 7-day organ culture although deflection did increase gradually with days in organ culture. In conclusion, our results demonstrated, artery buckling stimulates cell proliferation as well as extracellular matrix remodeling, which could be factors contributing to the development of tortuosity. Shear stress is one possible stimulus of endothelial cell proliferation and MMP9 secretion, while circumferential stress correlates with smooth muscle cell proliferation. Our results improve our understanding of the mechanics of tortuosity formation, though further studies are needed to investigate longer term effect.Item Assessment of acute ocular trauma in rabbits following sublethal primary blast exposure(2014) Jones, Kirstin R.The purpose of this study is to determine whether clinically significant ocular trauma can be induced by a survivable isolated primary blast using a live animal model. Both eyes of eighteen blast-exposed and five control Dutch Belted rabbits were exposed to various overpressure levels in a large-scale shock tube, and subjected to pre- and post-blast assessments by slit lamp, fundus imaging, ultrasound biomicroscopy, B-scan ultrasound, corneal confocal (immediate and 48-hours post), and retinal ocular coherence (immediate only) tomography. Linear regressions were applied to detect whether changes in the eye were significantly correlated with blast overpressure specific impulse. Normalized thicknesses of the cornea and inner retinal layers increased significantly with specific impulse immediately and 48 hours after blast exposure, providing new in vivo evidence of tissue damage due to primary blast (cornea pre- versus immediate post-blast: p=0.0011 and 48-hours post-blast: p=0.0014; retina p=0.00017). Survivable primary blast overpressure caused significant ocular damage in actively perfused living eyes. Clinically significant changes in corneal thickness arose immediately and were sustained through 48 hours, suggesting possible disruption of endothelial function.Item Augmenting Airway Management with Novel Tracheal Detection Mechanisms and Mechanical Securement Approaches(2019) Nawn, CorinneAirway management is an integral procedure across a wide variety of medical environments, from prehospital to operating room environments. Delayed or poorly performed airway management procedures can lead to major adverse events such as cardiac arrest or death. Despite the dramatic advances in modern biosensors and material science, airway management methods have changed very little over the past 30 years. Consequently, this dissertation seeks to transcend the traditional approaches of harsh airway manipulation by applying novel sensing mechanisms and material solutions to innovate the field of airway management. This dissertation characterized the existence and utility of unique biosignal properties of the airway, for the purpose of airway detection, alongside developing an alternative mechanical securement method designed for the purpose of reducing airway trauma. Through these aims, the central hypothesis evaluated whether an augmented airway management procedure would increase the rate of airway detection while decreasing the magnitude in force and movement of the head/neck axis when compared to that of direct laryngoscopy in various mannequin, cadaver, or in vivo models. The present studies characterized unique spectral reflectance properties in the trachea for multiple tissue models and developed several discrete tracheal detection devices based on the characteristic. Development of an alternative Digital Extenders mechanical platform demonstrated feasibility for intubation and showed reduced applied force as compared with current clinical standards in an instrumented mannequin model. These findings jointly represent promising advancements to the field of airway management in tracheal detection and reduction of upper airway trauma.Item Biochemical and biophysical aspects of Chlamydia pneumoniae -exacerbated atherosclerosis(2015) Evani, Shankar JaikishanMechanical forces and tissue mechanical properties are critical components of living systems to maintain homeostasis and controlled physiological functions. These forces play a critical role in vascular pathologies including atherosclerosis. Various bacterial and viral organisms have been implicated in chronic or acute vascular inflammatory diseases. Of interest, is Chlamydia pneumoniae, an intracellular pathogen which causes bronchitis is highly implicated in the development of atherosclerosis. In this work, we have examined the interplay of infection and mechanical forces/properties of the tissue in disease development and progression using physiologically relevant in vitro models of infection. This work combines biomechanical and biochemical components during infection to gain insights into the pathophysiology of Chlamydia pneumoniae -exacerbated atherosclerosis, and is divided into three parts. In the first part of the study, we analyzed the effects of physiological levels of shear stress on the inflammatory response of monocytes infected with Chlamydia pneumoniae . We found that shear-induced excessive inflammatory response by C. pneuomoniae -infected monocytes as measured the release of cytokines and chemokines, which contribute to localized 'hot spots' and exacerbated transendothelial infiltration of monocytes. In the second part, we show that C. pneumoniae infection of monocytes cause significant increase in the infected monocyte recruitment to the endothelium/E-selectin under physiological flow conditions due to altered membrane mechanics and the distribution of adhesion receptors, particularly CD44. Lastly, we elucidated the effect of C. pneumoniae-infected monocytes lodged in the subendothelial matrix on endothelial dysfunction and the changes in the biomechanical properties of the encapsulating collagen matrices due to extensive remodeling. Overall in this study, we have examined the effect of shear forces due to blood flow on the infected monocyte inflammatory response in vasculature, their recruitment to the site of pathology and eventual aberrations in mechanical properties of the vasculature caused by the lodged infected cells. As a whole this study highlights the important role of chlamydial infection, mechanical forces and tissue mechanics in atherosclerotic progression and provides insights into mechanical cues regulating the progression of atherosclerosis. Broadly, this study could possibly shed light on the physiology of chronic vascular inflammatory disease progression mediated by pathogens.Item Biomaterial Graft to Enhance Bone Ligament Enthesis Regeneration(2019) Pearson, Joseph J.Bone-ligament interface (enthesis) tissue engineering requires uniquely designed constructs in order to regenerate the multiple types of tissue within a miniscule region. These transitions include either bone, mineralized fibrocartilage, fibrocartilage, and bone (direct enthesis) or ligament and bone (indirect enthesis) connected by embedded tissue fibers. Tissue engineering approaches seek to mimic these physiological cues through biomaterials, growth factors, and cells. The objective of this study was to develop an enthesis scaffold and environment that could produce cell responses similar to the tissues found within the transition zones of the enthesis. The first step in this process was determining the appropriate material. Silk was chosen as a base material for the entire scaffold as its structure allows for tunable mechanical properties. The silk bone portion of the scaffold was mineralized to mimic native bone. This mineralized scaffold combined with calcitriol produced enhanced osteogenic responses. These findings suggested that the bone scaffold and calcitriol could be effective for enthesis formation and that local high doses of calcitriol could be effective for tissue regeneration. The ligament portion of the scaffold was composed of silk combined with collagen in a unique aligned structure to mimic native ligament matrix. The silk/collagen scaffold produced an enhanced ligamentogenic response on stem cells when combined with ascorbic acid and tensile dynamic stimulation. This combination also significantly improved the mechanical strength of the scaffold. The mineralized silk bone scaffold and silk/collagen ligament scaffolds were combined to form a stable enthesis graft. A uniquely designed dynamic stimulation system was created to stimulate the ligament portion in tension, but not the bone portion. This system also separated the culture media of the two portions. The static, control scaffold without stimulation or vitamins produced stem cell responses that are indicative of a direct enthesis with distinct zones that were spatially controlled. The enthesis scaffold with tensile stimulation without vitamins had a similar response, but it was not as controlled spatially. The enthesis scaffold with tensile stimulation and vitamins produced a response more indicative of an indirect enthesis with the addition of chondrogenesis. This research provides insights into how vitamins and mechanical stimulation can change the regenerative response of cells and can be tailored to which type of enthesis is required. This information can also aid in the development of preconditioning metrics and new tissue regenerative strategies.Item Biomaterial Strategies and Therapeutic Delivery Systems to Model, Prevent, and Treat Laryngotracheal Stenosis(2020) Miar, SolalehLaryngotracheal stenosis is a fibrotic disorder known to be a late-stage complication following prolonged intubation or tracheostomy. Prevention of scar tissue formation during intubation and controlling restenosis are currently open challenges in the field of otolaryngology. The present research focuses on addressing the multiple clinical needs arising from laryngotracheal stenosis and fibroplasia. In Aim I, we focus on controlling focal tissue damage and achieve local delivery of anti-inflammatory agents by using modified endotracheal tubes (ETTs). ETTs modified with Polycaprolactone-4–arm-Poly(EthyleneGlycol)Acrylate (PCL-4APEGA) composite were developed to decrease the possible damage using a self-lubricating system which is also capable of simultaneously releasing dexamethasone in a sustained manner and small interfering RNA (siRNA) targeting smad3 in a burst release fashion to suppress possible inflammation and fibroplasia during prolonged intubation. In Aim II, a minimally invasive therapeutic epithelial wound-coverage alternative was developed to facilitate local drug delivery to the defect site. A gecko-inspired tracheal mucosa-adhesive patch was designed based on PCL-4APEGA capable of controlled multimodal dexamethasone delivery to ameliorate local inflammation and promote tissue healing. In Aim III, we investigate the underlying physiology and model the microenvironment of the epithelial-mucosal lining of the trachea by establishing an in vitro three-dimensional microphysiological model. In this model, electrospun PCL fibers were used as a substrate for epithelial-fibroblast coculture in order to mimic the mucosal layer and the basement membrane of the trachea and establish the biophysical milieu of the native tissue. This research demonstrated the novel approaches to control possible damage to the trachea during prolonged intubation. Alternative approaches have been developed to deliver medications locally. And finally, an in vitro model has been established to mimic the mucosal lining of the upper airway.Item Biomechanical evaluation of mixed architecture hydroxyapatite scaffolds for bone tissue engineering(2008) Guda, TejaBone tissue engineering aims at attempting to restore function and regenerate tissue by using synthetic materials to fabricate graft substitutes. It is targeted as an alternative to answer the increasingly unmet demand for autologous bone grafts. The objectives of this research were to optimize the design of 3 dimensional (3-D) hydroxyapatite (HA) scaffolds to increase both mechanical strength as well as fluid permeability and to understand the changes in the biomechanical properties of the scaffolds during the course of in vitro culture and in vivo implantation. Micro computed tomography (micro-CT) was used to compute scaffold architectural indices as a non-destructive predictor of scaffold biomechanical properties and to evaluate in vitro and in vivo changes. The effect of variations in pore size and porosity on scaffold mechanical properties was evaluated by preparing 3-D trabecular like scaffolds of HA of four different pore sizes. Taking a cue from the cancellous---cortical organization of human bone, bilayer scaffolds were then prepared with outer cortical-like shells having a smaller pore size and inner trabecular-like cores having a larger pore size while maintaining a fully interconnected structure. A significant increase in mechanical compressive strength was observed between the bilayer architectures and the pure trabecular-like scaffolds. Permeability was measured for both the trabecular scaffolds and the bilayer scaffolds with a fixed volume ratio of outer cortical-like shell and inner trabecular-like core. It was observed that the permeability was highly dependent on the choice of the inner trabecular-like core. The micro-CT based architectural indices were used to predict both compressive strength as well as fluid permeability with high correlation. Changes in compressive strength and permeability were then measured after static in vitro cell culture on the trabecular-like porous scaffolds. It was observed that the deposition of extensive amounts of extra cellular matrix in the scaffolds during in vitro cell culture led to a significant multiple fold increase in compressive toughness. However, no significant change in permeability was observed for all the pore sizes evaluated. Finally, bilayer scaffolds were characterized for in vivo mechanical integrity using a rabbit radius segmental defect model. After 8 weeks implantation, no difference in mechanical strength, modulus or toughness of the scaffold was observed when compared to intact contralateral controls. Micro-CT evaluations indicated changes in cell attachment in vitro as well as tissue infiltration in vivo.. This research demonstrated the biomechanical optimization of scaffolds to both improve strength and retain permeability via a novel bilayer scaffold design. Micro-CT was demonstrated as a robust technology for evaluating architectural indices to predict scaffold mechanical properties and permeability with high correlation. It was also observed that micro-CT evaluations were sensitive to both in vitro and in vivo changes, and thus can be used as a design optimization tool in developing scaffold technology from laboratory benchtops to clinically relevant product development.Item Bmp-2 - tethered polyelectrolyte coated scaffolds for bone tissue regeneration(2011) Shiels, Stefanie M.The combination of therapeutic growth factor and tissue platform is a highly researched topic for replace of autogenic and allogenic bone grafts. Hydroxyapatite scaffolds combined with rhBMP-2 have to potential to regenerate functional bone tissue while reducing the therapeutic dose. The goal of this research project was to develop a rhBMP-2 coated implant for bone tissue regeneration. To investigate this objective, the coating chemistry, in vitro biological signaling propagation, and in vivo performance were evaluated. From these studies it was concluded that a polyelectrolyte coating on HAp can retain the rhBMP-2 to the surface of the HAp and encourage osteoblast attachment. The in vitro evaluation revealed that the rhBMP-2 bound to a polyelectrolyte coating on HAp caused a delayed osteogenic initiation, but increased the BMP cell receptor number and osteopontin production. This revealed that the signal propagation was activated by a signaling complex associated with Smad-dependent signaling pathway. Finally, after 8 weeks implanted into a rabbit femoral condyle, it was concluded that the rhBMP-2 coating didn't increase the bone volume, but did increase vascular recruitment around the implant. From these findings, it was concluded that a rhBMP-2 coated implant is a viable step toward the regeneration of functional bone tissue using synthetic means.Item Characterization of refrigerated platelets to improve storage time and function for transfusion(2015) Reddoch, KristinPlatelets are vital for regulating thrombosis and hemostasis. Current blood bank practice dictates platelets are stored at room temperature (RT, 22°C) for no more than 5 days owing to a high risk of bacterial contamination. Refrigeration (4°C) of platelets can mitigate issues of contamination and may even extend shelf life since metabolism is slowed at the lower temperature. However, cold storage of platelets was abolished due to poor recovery and survival upon transfusion. This dissertation demonstrates the feasibility of using cold-stored platelets to improve transfusion efficiency and prolong storage time for the treatment of acute bleeding. Apheresis platelets from healthy donors (n=4-10) were utilized. Platelets were stored at either RT (RT-PLT) or 4°C (4C-PLT) from 5-15 days and characterized in terms of hemostatic function, activation markers, metabolism, safety in response to physiologic inhibitors, and apoptosis status. 4C-PLT showed superior preservation of hemostatic potential, reduced metabolic activity, compared to RT-PLT at Day 5 of storage, but 4C-PLT also exhibited higher levels of activation creating cause of concern for unwanted thrombosis upon transfusion. When treated with endothelial inhibitors 4C-PLT showed similar aggregation, activation, and adhesion profiles as fresh platelets, suggesting 4C-PLT respond to physiologic controls and may truly be safe upon transfusion. Mitochondrial depolarization was increased in 4C-PLT, but caspase activity remained low compared to RT-PLT, suggesting full-fledged apoptosis in RT and only partial initiation of apoptosis in 4°C. Altogether, the data presented in this dissertation strengthens the case to re-evaluate the use of cold-stored platelets for therapeutic transfusion.