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The master thesis is focused on how a local volatility surfaces can be extracted by optimization with respectto smoothness and price error. The pricing is based on utility based pricing, and developed to be set in arisk neutral pricing setting. The pricing is done in a discrete multinomial recombining tree, where the timeand price increments optionally can be equidistant. An interpolation algorithm is used if the option that shallbe priced is not matched in the tree discretization. Power utility functions are utilized, where the log-utilitypreference is especially studied, which coincides with the (Kelly) portfolio that systematically outperforms anyother portfolio. A fine resolution of the discretization is generally a property that is sought after, thus a seriesof derivations for the implementation are done to restrict the computational encumbrance and thus allow finer discretization. The thesis is mainly focused on the derivation of the method rather than finding optimal parameters thatgenerate the local volatility surfaces. The method has shown that smooth surfaces can be extracted, whichconsider market prices. However, due to lacking available interest and dividend data, the pricing error increasessymmetrically for longer option maturities. However, the method shows exponential convergence and robustnessto different initial (flat) volatilities for the optimization initiation. Given an optimal smooth local volatility surface, an arbitrary payoff function can then be used to price thecorresponding option, which could be path-dependent, such as barrier options. However, only vanilla optionswill be considered in this thesis. Finally, we find that the developed

<p>Asthma is a disease characterized by transient airway smooth muscle contraction leading to episodes of reversible airway narrowing. It affects over 300 million people worldwide and is implicated in over 250 000 deaths annually. The primary clinical features of asthma include airway inflammation, hyperresponsiveness, and remodeling. Generally, asthmatic patients experience exacerbations between periods of diminished symptoms. Interestingly, in addition to these above mentioned hallmarks, asthmatics have also been shown to react differently to ventilatory mechanical strain. This is most evident when assessing the effect of a deep inspiration (DI), clinically measured as a breath taken from functional residual capacity to total lung capacity, in healthy individuals <em>versus</em> asthmatics. These deep inspiratory efforts have been shown to produce a bronchodilatory response in healthy individuals, whereas in asthmatics, DIs are less effective in producing bronchodilation, can cause more rapid airway re-narrowing, and even bronchoconstriction in moderate to severe asthmatics. The mechanism by which a DI is able to cause bronchoconstriction remains ambiguous. Previous theories suggest that this phenomenon is intrinsic to airway smooth muscle (ASM) itself. However, the airway inflammation present in asthmatic airways may also add to the increased ASM contractility following stretch, by the release of mediators that can prime the contractile apparatus to react excessively in the presence of stretch.</p> <p>Thus, collectively, the studies contained in this thesis are linked to the general theme of greater characterization of the signalling mechanisms that regulate airway stretch-activated contractions using a pharmacological approach in intact bovine bronchial segments, with the hope of providing novel insights into the mechanisms that regulate the DI-induced bronchoconstriction seen in asthmatics.</p> / Doctor of Philosophy (Medical Science)

<p><strong>Introduction</strong></p> <p>Asthma is a chronic respiratory disease that is becoming more prevalent. Airway hyperresponsivness, a key feature of asthma, involves increased narrowing of the airways in response to bronchoconstricting agents. Airway smooth muscle (ASM) functioning is largely responsible for hyperresponsiveness yet the mechanisms behind excitation-contraction coupling are not fully understood. Src tyrosine kinase contributes to contraction in other smooth muscle types. Furthermore, STIM1, Orai1, IPLA₂b and RyRs play a role in ASM excitation-contraction coupling.</p> <p><strong>Aim</strong></p> <p>We sought to determine whether Src activity is involved in serotonin (5-HT)- and acetylcholine (ACh)-induced ASM contraction. We also examined whether the gene expression of molecules involved in sarcoplasmic reticulum emptying and refilling is altered during airway hyperresponsiveness.</p> <p><strong>Methods</strong></p> <p>Bovine tracheal ASM strips were pre-treated with the non-specific tyrosine kinase inhibitor genistein (10^-4M), src kinase family inhibitors PP1 (10^-5M) and PP2 (10^-5M) or vehicle and challenged with either 5-HT or ACh to determine the involvment of Src in contraction. Western blotting was used to examine Src activity following 5-HT or ACh treatment. Female BALB/c mice were exposed to an intranasal injection of [1.7mg/ml] HDM extract or saline. Real time, reverse-transcriptase polymerase chain reaction was used to examine gene expression.</p> <p><strong> </strong></p> <p><strong>Results</strong></p> <p>Genistein, PP1 and PP2 significantly reduced 5-HT-induced ASM contractions and Src activity was significantly increased in response to 5-HT. ACh-induced contractions were significantly reduced by genistein, but not PP1 and PP2. However, Src activity was significantly increased by ACh. RyR3 mRNA expression was significantly increased, Orai1 was significantly decreased, and STIM1, IPLA₂b, RyR1 and RyR2 were unchanged by the house dust mite treatment.</p> <p><strong>Conclusion</strong></p> <p>These data suggets 5-HT-induced ASM contraction involves Src activity. However, ACh-induced ASM contractions might not require Src. The changes in RyR3 and Orai1 expression might alter Ca²⁺-handling in such a way as to potentiate airway hyperresponsiveness but further investigation is required.</p> / Master of Science (MSc)

<p>Atherosclerosis is a disease affecting the blood vessels that is inflammatory in nature, and plays an important role in cardiovascular disease (CVD), one of the leading causes of morbidity and mortality worldwide. Oncostatin M (OSM), a member of the IL-6/gp130 cytokine family, has been implicated in atherosclerosis both in mouse models and in humans. OSM synergizes with other stimuli in various systems to regulate cells. Infectious pathogens as well as danger associated host molecules stimulate members of the innate immune system, including Toll-like Receptors (TLRs), to respond in a pro-inflammatory manner to cause cell activation and cytokine release. Experiments were performed to determine whether OSM and LPS (a TLR-4 ligand) synergize in regulation of vascular wall cells <em>in vitro</em>.</p> <p>Upon stimulation of Aortic Adventitial Fibroblasts from mice (MAAFs) and humans (HAoAFs) as well as Human Aortic Smooth Muscle Cells (HAoSMCs) with LPS in combination with OSM, it was determined that there was a synergistic increase in IL-6 and VEGF levels in the cell supernatants as measured by ELISA compared to either treatment alone. MAAFs were also able to synergistically express KC upon stimulation with LPS and OSM, while in HAoAFs and HAoSMCs, LPS induced IL-8 levels were supressed by OSM. These effects were unique to OSM among gp130 cytokine members, as treatment of these cells with LPS in combination with LIF, IL-6, IL-31, or IL-11 had no marked effects compared to LPS alone. Furthermore, MCP-1 steady state mRNA levels were elevated 6 hours post stimulation with LPS and OSM compared to either treatment alone in HAoAFs and HAoSMCs.</p> <p>While OSM did not appear to modulate TLR-4 expression, OSM treatment resulted in an increased phosphorylation signal in STAT-1,-3, and -5, as well as Akt in MAAFs and HAoAFs. In addition, combined LPS and OSM stimulation resulted in an increased phosphorylation signal of the MAPK p38 compared to either treatment alone. Furthermore, a neutralizing antibody to the OSMr-β was able to inhibit HAoAF IL-6 responses to PBMC conditioned medium. Together, these findings indicate that OSM and LPS can synergize <em>in vitro </em>to induce the expression of inflammatory factors in vascular wall cells, emphasizing the potential role of OSM, TLR-4 ligands, and adventitial fibroblasts in vascular inflammation.</p> / Master of Science (MSc)

<p><h1>Abstract</h1></p> <p>As a compact, robust, and reliable power distribution method, hydraulic systems have been used for flight surface control for decades. Electro-hydrostatic Actuator (EHA) is increasingly replacing the conventional valve-controlled system for better performance, lighter weight and higher energy efficiency. The EHA is increasingly being used for flight control. As such its reliability is thereby critical important for flight safety. This research focuses on fault detection and diagnosis (FDD) for the EHA to enable predictive unscheduled maintenance when fault detected at its inception.</p> <p>An EHA prototype previously built at McMaster University is studied in this research and modified to physically simulate two faults conditions pertaining to leakage and friction. Nine different working conditions including normal running and eight fault conditions are simulated. Physical model has been derived mathematically capable of numerically simulating the fault conditions. Furthermore, for comparison, parametric model was obtained through system identification for each fault condition. This comparison revealed that parametric models are not suitable for fault detection and diagnosis due to the computation complexity.</p> <p>The FDD approach in this research uses model-based state estimation using filters. The filter based combined with the Interacting Multiple Model fault detection and diagnosis algorithm is introduced. Based on this algorithm, three FDD strategies are developed using a combination of the Extended Kalman Filter and IMM (IMM-EKF), the Smooth Variable Structure Filter with Varying Boundary and IMM (IMM-SVSF (VBL)), and the Smooth Variable Structure Filter with Fixed Boundary and IMM (IMM-SVSF (FBL)). All the three FDD strategies were implemented on the EHA prototype. Based on the results, the IMM-SVSF (VBL) provided the best performance. It detected and diagnosed faults correctly at high mode probabilities with excellent robustness to modeling uncertainties. It also was able to detect slow growing leakage fault, and predicted the changing trend of fault conditions.</p> / Master of Applied Science (MASc)

Cardiovascular disease is the leading cause of mortality in the western world. The pro-inflammatory and pro-proliferative etiology of vascular proliferative diseases is well characterized, while much less is known about the mechanisms of anti-inflammatory and anti-proliferative processes. Interleukin-19 (IL-19) is a newly described member of the IL-10 family of anti-inflammatory interleukins, and our group was the first to discover IL-19 expression in activated, synthetic, but not quiescent, contractile human vascular smooth muscle cells (hVSMC). We also found that IL-19 is anti-inflammatory and anti-proliferative for hVSMC. IL-19 is able to reduce the abundance of COX-2, IL-1&beta;, IL-8, and Cyclin D1 transcripts which contain AU-rich elements (ARE) in their 3'-untranslated regions (3'-UTR). IL-19 is able to reduce the abundance of HuR, a stabilizing RNA-binding protein, which we feel provides a mechanism for these effects. The overall goal of this study is to elucidate IL-19's anti-inflammatory and anti-proliferative mechanism(s) in hVSMC in the context of vascular proliferative diseases. This goal has directed our overall hypothesis: IL-19's anti-proliferative and anti-inflammatory effects in hVSMC are mediated, at least in part, by modulation of HuR abundance and translocation, resulting in decreased stability of mRNA transcripts. HuR functions through a translocation mechanism, and IL-19 is able to reduce HuR cytoplasmic abundance. IL-19 also reduces HuR phosphorylation, which is a pre-requisite for HuR translocation, possibly through a PKC&alpha;-dependent mechanism. The stability of ARE-containing transcripts is reduced with IL-19 treatment, and reducing HuR expression by siRNA has the same inhibitory effect. VSMC are important mediators in the initiation of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) is able to induce IL-19 expression in these cells. VSMC are known to express scavenger receptors that take up ox-LDL. IL-19 is able to reduce the uptake of ox-LDL and the abundance of ox-LDL induced LOX-1 and CX-CL16 scavenger receptors. Interestingly, these scavenger receptors also have ARE in their 3'-UTR. IL-19 is able to reduce ox-LDL induced HuR cytoplasmic abundance. HuR knockdown by siRNA reduces the uptake of ox-LDL by hVSMC. These data suggest that IL-19 reduced scavenger receptor abundance may be due to decreased total and cytoplasmic HuR abundance. IL-19 reduces the abundance of ox-LDL induced COX-2 expression. Taken together, these results demonstrate that IL-19 down-regulates vital steps in vascular proliferative disease processes through an HuR-dependent mechanism. / Molecular and Cellular Physiology

A number of non-invasive fault detection and diagnosis (FDD) techniques have been researched and have proven to have worked well in classifying faults in internal combustion engines (ICE) and other mechanical and electrical systems. These techniques are an integral step to creating more robust and accurate methods of determining where or how a fault has or will occur in such systems. These FDD techniques have the potential to not only save time avoiding a tear-down of a costly machine, but could potentially add another layer of safety in detecting and diagnosing a fault much earlier than was possible before. Looking at the previous research methods and the systems they used to acquire this data, it is a natural progression to try and make a system which is able to encapsulate all of these ideologies into one inexpensive module capable of integrating itself into the advanced set of FDD. This thesis follows along with the development of a new wireless sensor that is developed specifically for the use in FDD for ICE and other mechanical systems. A new set of software and firmware is created for the system to be able to be incorporated into previously designed algorithms. After creating and manufacturing the sensor it is put to the test by incorporating it into several Artificial Neural Networks (ANN) and comparing the results to previous experiments done with previous research equipment. Using vibration data acquired from a running engine to train a neural network, the wireless sensor was able to perform equally as well as its expensive counter parts. It proved to have the ability to achieve 100% accuracy in classifying specific engine faults. The performance of three ANN training algorithms, Levenberg-Marquardt (LM), extended Kalman Filter (EKF), and Smooth Variable Structure filter (SVSF), were tested and compared. Adding to the feasibility of a standalone system the wireless sensor was tested in a live environment as a method of instant ICE fault detection. / Thesis / Master of Applied Science (MASc)

Goosegrass [Eleusine indica (L.) Gaertn.] and smooth crabgrass [Digitaria ischaemum (Schreb.) Schreb. ex Muhl.] are problematic weeds in bermudagrass and creeping bentgrass turf. Increased incidences of herbicide resistant weed populations and severe use restrictions on formerly available herbicides have increased need for selective, postemergence control options for these weeds in creeping bentgrass and bermudagrass turf. This weed management exigency has led turf managers to utilize less effective, more expensive, and more injurious options to manage goosegrass and smooth crabgrass. Although potentially injurious, topramezone can control these weeds, especially goosegrass, at low doses. Low-dose topramezone may also improve bermudagrass and creeping bentgrass response. An initial investigation of three 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibiting herbicides in different turf types showed that Kentucky bluegrass, perennial ryegrass, and tall fescue were highly tolerant to topramezone, while creeping bentgrass and bermudagrass could tolerate topramezone doses that may control grassy weeds. Further investigation suggested that frequent, low-dose topramezone applications or metribuzin admixtures could enhance weed control and may conserve turfgrass quality. A novel mixture of topramezone at 3.7 g ae ha-1 and metribuzin at 210 g ai ha-1 controlled goosegrass effectively and reduced bermudagrass foliar bleaching associated with topramezone 10-fold compared to higher doses of topramezone alone in 19 field and 2 greenhouse trials. In an attempt to further enhance bermudagrass tolerance to topramezone, post-treatment irrigation was applied at various timings. When bermudagrass turf was irrigated with 0.25-cm water at 15 or 30 minutes after herbicide treatment, bermudagrass injury was reduced to acceptable levels when following low-dose topramezone plus metribuzin but not when following high-dose topramezone alone. Goosegrass control was reduced significantly by post-treatment irrigation in all cases, while irrigation reduced goosegrass control by low-dose topramezone plus metribuzin to below-commercially-acceptable levels. Novel, low-dose, frequent application programs containing topramezone or siduron were developed for season-long crabgrass or goosegrass control on creeping bentgrass greens. Greens-height creeping bentgrass quality was preserved following five biweekly treatments of siduron at rates between 3,400 to 13,500 g ai ha-1 and topramezone at 3.1 g ha-1. Siduron programs controlled smooth crabgrass and suppressed goosegrass while topramezone programs controlled goosegrass and suppressed smooth crabgrass. In laboratory and controlled-environment experiments, goosegrass absorbed three times more 14C than bermudagrass within 48 hours of 14C-topramezone treatment. Bermudagrass also metabolized topramezone twice as fast as goosegrass. Metribuzin admixture reduced absorption by 25% in both species. When herbicides were placed exclusively on soil, foliage, or soil plus foliage, topramezone controlled goosegrass only when applied to foliage and phytotoxicity of both bermudagrass and goosegrass was greater from topramezone than from metribuzin. Metribuzin was shown to reduce 21-d cumulative clipping weight and tiller production of both species while topramezone caused foliar discoloration to newly emerging leaves and shoots with only marginal clipping weight reduction. These data suggest that selectivity between bermudagrass and goosegrass is largely due to differential absorption and metabolism that reduces bermudagrass exposure to topramezone. Post-treatment irrigation likely reduces topramezone rate load with a concomitant effect on plant phytotoxicity of both species. Metribuzin admixture decreases white discoloration of bermudagrass by decreased topramezone absorption rate and eliminating new foliar growth that is more susceptible to discoloration by topramezone. / Doctor of Philosophy / Goosegrass and smooth crabgrass are problematic weeds in bermudagrass and creeping bentgrass turf. Increased incidences of herbicide resistant weed populations and severe use restrictions on formerly available herbicides have increased need for selective, postemergence control options for these weeds in creeping bentgrass and bermudagrass turf. Although potentially injurious, topramezone (Pylex™) can control these weeds, especially goosegrass, at low doses. Low-dose Pylex™ may also improve bermudagrass and creeping bentgrass response. An initial investigation evaluating tembotrione (Laudis®), Pylex™, and mesotrione (Tenacity®) in different turfgrass species showed that Kentucky bluegrass, perennial ryegrass, and tall fescue were highly tolerant to Pylex™ at rates ranging from 0.75 to 2.25 fl. oz./A, while creeping bentgrass and bermudagrass were low to moderately tolerant to Pylex™. Further investigation suggested that frequent, low-dose (less than 0.25 fl. oz./A) Pylex™ applications or metribuzin (Sencor®) admixtures could enhance weed control and may conserve turfgrass quality. A novel mixture of Pylex™ at 0.15 fl. oz./A and Sencor® at 4 oz. wt./A controlled goosegrass effectively and reduced bermudagrass injury to near acceptable levels and significantly less than Pylex™ applied alone at 0.25 fl. oz/A. In an attempt to further enhance bermudagrass tolerance to Pylex™, post-treatment irrigation was applied at different timings. When bermudagrass turf was irrigated at 15 or 30 minutes after herbicide treatment, bermudagrass injury was reduced to acceptable levels when following Pylex™ at 0.25 fl. oz./A plus Sencor® at 4 oz but not when following Pylex™ applied alone at 0.5 fl. oz./A. Goosegrass control was reduced significantly by post-treatment irrigation in all cases, while irrigation reduced goosegrass control by low-dose Pylex™ plus Sencor® to below-commercially-acceptable levels. Novel, low-dose, frequent application programs containing Pylex™ or siduron (Tupersan®) were developed for season-long crabgrass or goosegrass control in creeping bentgrass greens. Greens-height creeping bentgrass quality was preserved following five biweekly treatments of Tupersan® at rates between 6 and 24 lb./A and Pylex™ at 0.125 fl. oz./A. Tupersan® programs controlled smooth crabgrass and suppressed goosegrass while Pylex™ programs controlled goosegrass and suppressed smooth crabgrass. The data from these studies indicate that utilizing low-dose Pylex™ in combination with Sencor® can impart acceptable bermudagrass safety while also controlling goosegrass effectively. For creeping bentgrass greens, the low-dose, frequent application of Tupersan® is the safest legal option for golf course superintendents to control smooth crabgrass effectively, while having some ability to suppress goosegrass.

Cardiovascular disease is the leading cause of death in the United States, and coronary artery disease (CAD) kills over 370,000 people annually. There are available therapies that offer a temporary solution; however, only a heart transplant can fully resolve heart failure, and donor organ shortages severely limit this therapy. C-kit+ human cardiac stem cells (hCSCs) offers a viable alternative therapy to treat cardiovascular disease by replacing damaged cardiac tissue; however, low cell viability, low retention/engraftment, and uncontrollable in vivo differentiation after transplantation has limited the efficacy of stem cell therapy. Tissue engineering solutions offer potential tools to overcome current limitations of stem cell therapy. Materials derived from natural sources such as keratin from human hair offers innate cellular compatibility, bioactivity, and low immunogenicity. Keratin proteins extracted using oxidative chemistry known as keratose (KOS) have shown therapeutic potential in a wide range of applications including cardiac regeneration. My studies utilize KOS hydrogels to modulate c-kit+ hCSC differentiation, and explore the capability of differentiated cells to regenerate vascular tissue. In the first Chapter, we reviewed literature relevant to keratin-based biomaterials and their biomedical applications, the use of stem cells in cardiovascular research, and the differentiation of vascular smooth muscle cells (VSMCs). The section on biomedical applications of keratin biomaterials focuses on the oxidized form of keratin known as keratose (KOS), because this was the material used for our research. Since we planned to use this material in conjunction with c-kit+ hCSCs, we also briefly explored the use of stem cells in cardiovascular research. Additionally, we examined some key signaling pathways, developmental origins, and the cell phenotype of VSMCs for reasons that will become clear after observing results from chapters 2 and 3. Based upon our review of the literature, KOS biomaterials and c-kit+ hCSCs were determined to be promising as a combined therapeutic for the regeneration of cardiac tissue. Research in Chapter 2 focused on characterizing the effects of KOS hydrogel on c-kit+ hCSC cell viability, proliferation, morphology, and differentiation. Results demonstrated that KOS hydrogels could maintain hCSC viability without any observable toxic effects, but it modulated cell size, proliferation, and differentiation compared to standard tissue culture polystyrene cell culture (TCPS). KOS hydrogel produced gene and protein expression consistent with a VSMC phenotype. Further, we also observed novel "endothelial cell tube-like" microstructures formed by differentiated VSMCs only on KOS hydrogel, suggesting a potential capability of the hCSC-derived VSMCs for in vitro angiogenesis. Results from this study lead us to question what signaling pathways might be responsible for the apparent VSMC differentiation pattern we observed on KOS hydrogels. Research in Chapter 3 explored the time course of VSMC differentiation, cell contractility, inhibition of VSMC differentiation, and measured protein expression of transforming growth factor beta 1 (TGF-β1) and its associated peptides for hCSCs cultured on KOS hydrogels, tissue culture polystyrene, and collagen hydrogels. A review of VSMC differentiation signaling pathways informed our decision to investigate the role of TGF-β1 in VSMC differentiation. Results demonstrated that KOS hydrogel differentiated hCSCs significantly increased expression for all three vascular smooth muscle (VSM) markers compared to TCPS differentiated cells. Additionally, KOS differentiated hCSCs were significantly more contractile than cells differentiated on TCPS. Recombinant human (rh) TGF-β1 was able to induce VSM differentiation on TCPS. VSM differentiation was successfully inhibited using TGF-β NABs and A83-01. Enzyme-Linked Immunosorbent Assay (ELISA) analysis revealed that both TCPS and KOS hydrogel differentiated cells produced TGF-β1, with higher levels being measured at early time points on TCPS and later time points on KOS hydrogels. Results from supplementing rhTGF-β1 to TCPS and KOS hydrogels revealed that KOS seems to interact with TGF-β to a greater extent than TCPS. Western blot results revealed that latency TGFβ binding protein (LTBP-1) and latency associated peptide (LAP) had elevated levels early during differentiation. Further, the levels of LTBP-1 and LAP were higher on KOS differentiated hCSCs than TCPS hCSCs. This study reaffirms previous results of a VSM phenotype observed on KOS hydrogels, and provides convincing evidence for TGF-β1 inducing VSM differentiation on KOS hydrogels. Additionally, results from ELISA and western blot provide evidence that KOS plays a direct role in this pathway via interactions with TGF-β]1 and its associated proteins LTBP-1 and LAP. Results from chapter 2 and 3 offered significant evidence that our cells exhibited a VSMC phenotype, and that TGF-β1 signaling was a key contributor for the observed phenotype, but we still needed an animal model to explore the therapeutic potential of our putative VSMCs. Research in Chapter 4 investigated a disease model to test the ability of KOS hydrogel differentiated cells to regenerate vascular tissue. To measure vascular regenerative capability, we selected a murine model of critical limb ischemia (CLI). CLI was induced in 3 groups (n=15/group) of adult mixed gender NSG mice by excising the femoral artery and vein, and then treated the mice with either PBS (termed as PBS-treated), Cells differentiated on TCPS (termed as Cells from TCPS), or KOS hydrogel-derived VSMCs (termed as Cells from KOS). Blood perfusion of the hind limbs was measured immediately before and after surgery, then 14, and 28 days after surgery using Laser Doppler analysis. Tissue vascularization, cell engraftment, and skeletal muscle regeneration were measured using immunohistochemistry, 1,1'-Dioctadecyl3,3,3',3'-Tetramethylindocarbocyanine Perchlorate (DiL) vessel painting, and hematoxylin and eosin (HandE) pathohistological staining. During the 4-week period, both cell treatment groups showed significant increases in blood perfusion compared to the PBS-treated control, and at day 28 the Cells from KOS group had significantly better blood flow than the Cells from TCPS group. Additionally, the Cells from KOS group demonstrated a significant increase in the ratio of DiL positive vessels, capillary density, and a greater density of small diameter arterioles compared to the PBS-treated group. Further, both cell-treated groups had similar levels of engraftment into the host tissue. We conclude that Cells from KOS therapy increases blood perfusion in an NSG model of CLI, but does not lead to increased cell engraftment compared to other cell based therapies. Overall, the results from this dissertation demonstrated that KOS hydrogels produce VSMC differentiation from c-kit+ hCSCs mediated by TGF-β1 signaling, and that the differentiated cells are able to increase blood perfusion in a CLI model by increasing capillary density, suggesting enhanced angiogenesis. Future studies should explore potential protein-protein interactions between KOS, TGF-β1 and its associated proteins. Additionally, we should plan animal studies that examine the efficacy of our cells to regenerate cardiac tissue following an acute myocardial infarction (AMI). / PHD