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Title: Bus Tracker (Spring 2003) ENPRO 371: BusTracker ENPRO371 Spring2003 Final Presentation
Date: 2003, 2003-05
Description: Goal is to develop a cost effective bus tracking system based on affordable radio-frequency technology that will increase customer...
Show moreGoal is to develop a cost effective bus tracking system based on affordable radio-frequency technology that will increase customer satisfaction, safety and mass transit utilization.
Sponsorship: Charles Industries
Project Plan for ENPRO371: Bus Tracker for the Spring 2003 semester
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Title: Ethanol Ultra-Light Aircraft (Fall 2001) IPRO 317: Ethanol_Ultralight_IPRO317_Fall2001_Final_Presentation
Creator: Bockenfeld, Dan, Guerra, Jorge, Kuczaj, Mariusz, Lim, Ryan, Mcdaniel, Loren, Muliere, Dave, Orebaugh, Jesse, Parsons, Abigail, Williams, Ben
Date: 2001, 2001-12
Description: Students will convert a Quicksilver MXII ultralight airplane to run on E85 fuel (85% ethanol, 15% gasoline). This is technically challenging...
Show moreStudents will convert a Quicksilver MXII ultralight airplane to run on E85 fuel (85% ethanol, 15% gasoline). This is technically challenging because the plane uses a 2-stroke Rotax 503 engine, where the oil must be mixed in with the fuel. After the conversion, the plane will be flight-tested. In addition to the technical aspects, the project involves maintaining relationships with sponsors, public relations, and a study of the impact of ethanol on the ultralight aircraft market
Sponsorship: NA
Project Plan for IPRO 317: Ethanol Ultralight Aircraft for the Fall 2001 semester
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Title: High-rise mix-use: Final MC Board
Creator: Mei, Chuan
Date: 2012-05-02, 2012-05

Title: High-rise mix-use: Mei Chuan Master Project booklet
Creator: Mei, Chuan
Date: 2012-05-02, 2012-05

Title: The Nomad
Creator: Waxali, Nadir
Date: 2012-05-02, 2012-05
Description: Inspired by a need for personal space in a fast paced, highly mobile world, the nomad project combines the mobility and strength of a pickup...
Show moreInspired by a need for personal space in a fast paced, highly mobile world, the nomad project combines the mobility and strength of a pickup truck with the convenience of a small living space. By combining a work space, kitchen, sleeping area and bathroom, this project allows this compact space to allow for the comforts of a home to be available wherever a person can travel. This exploration of the duality of interior space experiments with the folding of program space from a collapsible set of planes to a space which can be used in daily life.
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Title: The Nomad: FINAL BOARDS
Creator: Waxali, Nadir
Date: 2012-05-02, 2012-05
Description: Inspired by a need for personal space in a fast paced, highly mobile world, the nomad project combines the mobility and strength of a pickup...
Show moreInspired by a need for personal space in a fast paced, highly mobile world, the nomad project combines the mobility and strength of a pickup truck with the convenience of a small living space. By combining a work space, kitchen, sleeping area and bathroom, this project allows this compact space to allow for the comforts of a home to be available wherever a person can travel. This exploration of the duality of interior space experiments with the folding of program space from a collapsible set of planes to a space which can be used in daily life.
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Title: The Nomad: Nadir Waxali Final Masters Project 2012sm
Creator: Waxali, Nadir
Date: 2012-05-02, 2012-05
Description: Inspired by a need for personal space in a fast paced, highly mobile world, the nomad project combines the mobility and strength of a pickup...
Show moreInspired by a need for personal space in a fast paced, highly mobile world, the nomad project combines the mobility and strength of a pickup truck with the convenience of a small living space. By combining a work space, kitchen, sleeping area and bathroom, this project allows this compact space to allow for the comforts of a home to be available wherever a person can travel. This exploration of the duality of interior space experiments with the folding of program space from a collapsible set of planes to a space which can be used in daily life.
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Title: THE CORRELATION BETWEEN FATIGUE PROPERTY AND PORE MORPHOLOGY OF POWDER METALLURGY TI6AL4V
Creator: Yan, Yingjie
Date: 2012-12-12, 2012-12
Description: The microstructure and fatigue properties of sintered Ti-6Al-4V were investi- gated as a function of sintered density and pore morphology. A...
Show moreThe microstructure and fatigue properties of sintered Ti-6Al-4V were investi- gated as a function of sintered density and pore morphology. A quantitative analysis of microstructure was conducted to correlate with tensile and fatigue properties to understand the in uence of sintering density and pore morphology. Low cycle fatigue (LCF) using constant strain control was conducted at room temperature, R=-1 and sine waveform. High cycle fatigue (HCF) using constant stress control was conducted at room temperature, R=0.1 and sine waveform. It was found that there was no signi cant di erence in tensile strength but the fatigue endurance limit was increased by 20% when the sintering density was increased from 95% to 99%. Moreover, fatigue endurance limit was increased when the shape factor increased among three di er- ent sintering conditions(1010 -60min-690MPa, 1130 -90min-410MPa, 1250 -30min- 550MPa). Fracture surface analysis indicated that the fatigue crack initiated from the cluster of pore either at surface or at the sub-surface. The implication of pore morphology and porosity on mechanical behaviour and fatigue fracture of P/M Ti- 6Al-4V were discussed. It was estimated that the shape factor was 0.05 for A-50 and 0.07 for A-100, respectively. A polynomial relationship was found between the fatigue endurance limit and shape factor among three sintering con gurations. It was found that the PM parts with a higher shape factor had a higher fatigue endurance limit.
M.S. in Materials Science and Engineering, December 2012
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Title: TWO PROBLEMS ON CROSSING NUMBERS
Creator: Wang, Lujia
Date: 2013-05-01, 2013-05
Description: The crossing number of a graph G, cr(G) is the minimum number of intersections among edges over all possible drawings on a plane. The pairwise...
Show moreThe crossing number of a graph G, cr(G) is the minimum number of intersections among edges over all possible drawings on a plane. The pairwise crossing number pcr(G) is the the minimum number of pairs of edges that cross at least once over drawings. In the rst part of this survey, we deal with the conjecture that pcr(G) = cr(G), and prove that this is true for 4-edge weighted maps on the annulus. Moreover, we develop methods for solving analogous n-edge problems including the classi cation of permutations on a circle. In the second part, we de ne the generalized crossing number cri(G) as the crossing number of a graph on the orientable surface of genus i. The crossing sequence is de ned as (cri(G))g(G) i=0 , where g(G) is the genus of the graph. This part aims at the conjecture that for each sequence of four numbers decreasing to 0, there is some graph with such numbers as its crossing sequence. We come up with a particular family of graphs which have concave crossing sequences of length 4, but partially prove it.
M.S. in Applied Mathematics, May 2013
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Title: ISOLATION OF MONOSPECIFIC ANTIBODY AGAINST SPLICED VARIANT OF DYSTROPHIN PROTEIN USING YEAST SURFACE DISPLAY TECHNIQUE
Creator: Saraswathi, Raj Prabu Vijayakumar
Date: 2011-05-04, 2011-05
Description: Dystrophin gene is the largest in the human genome with 79 exons covering greater than 0.1% of the total genome, located on the Xp21 locus of...
Show moreDystrophin gene is the largest in the human genome with 79 exons covering greater than 0.1% of the total genome, located on the Xp21 locus of the “X” chromosome resulting in a 427kDa protein, “Dystrophin”. Dystrophin is an important cytoskeletal protein which belongs to the β-Spectrin/α-actinin family of proteins. It comprises of an amino terminal domain, alpha helical coiled structure COOH domain, central rod region with 24 STRs and four proline rich hinge regions. It plays a vital role in localizing the Dystrophin glycoprotein complex (DGC) in the Sarcollema and is associated with the DGC in controlling the signaling events of certain proteins associated with DGC. The large size of the gene makes it more vulnerable to mutations resulting in partially functional or non-functional Dystrophin. The absence of Dystrophin results in disruption of sub sarcolemma-extracellular matrix linkage, loss of nitric oxide, progressive muscle weakening and muscle wasting leading to the death of patients typically before the end of their teenage. In certain cases alternatively spliced isoforms produce Dystrophin with reduced length yet stable and completely functionality. The main focus of this project was to select monospecific antibody against the more stable alternatively spliced variant D14 (15”16”) 17, which is functional and more stable compared to unspliced parent D14:17. The yeast surface display technique was used to effectively screen and select the yeast scFv clones containing the monospecific antibody against our target spliced variant D14 (15”16”) 17 protein and D2:3. The yeast scFv sub population was enriched by repeated MACS and FACS selection. Test colonies picked from the enriched scFv pool were confirmed via PCR and restriction digestion analysis. The scFv for the respective antigens were then sub cloned into pPnnl-9 secretion vector using YVH10 yeast cells via LiTRAFCO method. It was clear that by repeated MACS and FACS selection the scFv pool can be enriched and the yeast scFv clone sub population can be reduced to a significant level. The scFv sub cloned into Pnnl-9 secretion vector can be purified using affinity chromatography and the further affinity and avidity studies can be conducted.
M.S. in Biology, May 2011
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Title: PHASE EQUILIBRIA AND THERMODYNAMIC MEASUREMENTS OF SOME HEUSLER COMPOUNDS
Creator: Chen, Song
Date: 2012-08-14, 2012-07
Description: Heusler alloys are compounds based on the original Heusler phase Cu2MnAl which are ternary intermetallics with a particular chemical...
Show moreHeusler alloys are compounds based on the original Heusler phase Cu2MnAl which are ternary intermetallics with a particular chemical stoichiometric formula X2YZ and face-centered cubic structure. Heusler alloys are of interest because of a range of physical phenomena which may occur in them that can be applied in mechanical or electronic devices, including shape memory property and disorder/order phenomenon. In this work, a high temperature drop calorimeters and Setaram calorimeters were used to obtain the enthalpy of formation and heat capacity of compounds in the Mn-based Heusler compounds (X2MnZ). Lattice parameters of these compounds were determined with XRD, and phase equilibria in these alloy system were studied in this work. Phase transformations were studied with DSC and dilatometry. The work is aimed at populating databases for computational thermodynamics, developing an understanding of alloying and clarifying phase equilibria.
M.S. in Material Science and Engineering, July 2012
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Title: QUALITY-OF-SERVICE AWARE SCHEDULING AND DEFECT TOLERANCE IN REAL-TIME EMBEDDED SYSTEMS
Creator: Li, Zheng
Date: 2015, 2015-05
Description: For real-time embedded systems, such as control systems used in medical, automotive and avionics industry, tasks deployed on such systems...
Show moreFor real-time embedded systems, such as control systems used in medical, automotive and avionics industry, tasks deployed on such systems often have stringent real-time, reliability and energy consumption constraints. How to schedule real-time tasks under various QoS constraints is a challenging issue that has drawn attention from the research community for decades. In this thesis, we study task execution strategies that not only minimize system energy consumption but also guarantee task deadlines and reliability satisfaction. We first consider the scenario when all tasks are of the same criticality. For this case, two task execution strategies, i.e. checkpointing based and task re-execution based strategies are developed. Second, considering the scenario when tasks are of different criticalities, a heuristic search based energy minimization strategy is also proposed. When tasks are of different criticalities, a commonly used approach to guaranteeing high-criticality task deadlines is to remove low-criticality tasks whenever the system is overloaded. With such an approach, the QoS provided to low-criticality tasks is rather poor, it can cause low-criticality tasks to have high deadline miss rate and less accumulated execution time. To overcome this shortcoming, we develop a time reservation based scheduling algorithm and a two-step optimization algorithm to meet high-criticality task deadlines, while minimizing low-criticality task deadline miss rate and maximizing their accumulated execution time, respectively. As many-core techniques mature, many real-time embedded systems are built upon many-core platforms. However, many-core platforms have high wear-out failure rate. Hence, the last issue to be addressed in the thesis is how to replace defective cores on many-core platforms so that deployed applications’ real-time properties can be maintained. We develop an offline and an online application-aware system reconfiguration strategy to minimize the impact of the physical layer changes on deployed real-time applications. All the developed approaches are evaluated through extensive simulations. The results indicate that the developed approaches are more effective in addressing the identified problems compared to the existing ones in the literature.
Ph.D. in Computer Science, May 2015
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Title: QUANTITATIVE ANALYSIS OF THE EFFECTS OF BIOFUNCTIONAL AND PHYSICAL GRADIENTS ON CELL BEHAVIOR IN POLY (ETHYLENE GLYCOL) DIACRYLATE HYDROGELS
Creator: Turturro, Michael
Date: 2012-10-29, 2012-12
Description: The continued enhancement of tissue engineered scaffolds relies on their ability to stimulate the formation of a stable microvascular network...
Show moreThe continued enhancement of tissue engineered scaffolds relies on their ability to stimulate the formation of a stable microvascular network within the biomaterial. In vivo, the spatial presentation of immobilized extracellular matrix cues and matrix mechanical properties play an important role in directed and guided cell behavior and neovascularization. The overall goals of this thesis are to develop a technique for the generation of gradients of physical properties and incorporated biofunctionality within poly(ethylene glycol) diacrylate (PEGDA) scaffolds and to investigate the effects of these gradients on 3D cell invasion and neovascularization. To this end, a novel photopolymerization technique for generating spatial variations in matrix properties and incorporated biofunctionality within synthetic PEGDA hydrogels, perfusion-based frontal polymerization (PBFP), was developed. This technique relies on the controlled perfusion of a photoinitiator to a reaction chamber containing a precursor solution and results in the propagation of a polymer reaction front that travels through the monomer solution creating a gradient in hydrogel crosslinking. Manipulation of the magnitude of the gradient can be achieved through alterations in the polymerization conditions. Scaffolds with embedded gradients were designed and optimized based on a range of properties shown to support 2D cell adhesion, proliferation, and 3D vascular cell invasion in bulk photopolymerized hydrogels with homogeneous properties. An in vitro model of neovascularization was used to evaluate the effect of these gradients on vascular sprout formation. Sprout invasion in gradient hydrogels occurred bi-directionally with sprout alignment observed in the direction parallel to the gradient while control hydrogels with homogeneous properties resulted in uniform invasion. In PBFP gradient hydrogels, sprout xvi length was found to be twice as long in the direction parallel to the gradient as compared to the perpendicular direction after three weeks in culture. This directionality was found to be more prominent in gradient regions of increased stiffness, crosslinked matrix metalloproteinase (MMP)-sensitive peptide presentation, and immobilized YRGDS concentration. In vivo tissue invasion was shown to be directly related to gradient properties and orientation. Alterations in the magnitude of the gradient in elastic modulus enhanced the directionality of invading vascular sprouts while restricting in vivo tissue invasion.
PH.D in Biomedical Engineering, December 2012
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Title: SOCIAL FUNCTIONING AND CORE SYMPTOMATOLOGY AS PREDICTORS OF RESPONSE TO A SUMMER TREATMENT PROGRAM FOR YOUTH WITH COMBINED TYPE ATTENTION DEFICIT HYPERACTIVITY DISORDER
Creator: Uribe, Roberto Alejandro
Date: 2015, 2015-12
Description: The study was a retrospective repeated measures analysis of 108 youth (age 6-12) who took part in the 2008-2012 Camp STAR (Summer Treatment...
Show moreThe study was a retrospective repeated measures analysis of 108 youth (age 6-12) who took part in the 2008-2012 Camp STAR (Summer Treatment Program for ADHD and Related Disorders) Summer Treatment Program. Developed by William E. Pelham in 1980, the Summer Treatment Program (STP) is an intensive psychosocial intervention delivered to children ages 6-12 in natural settings through the medium of summer camp. A recognized evidence base for the STP has steadily developed and evolved leading to improved stabilization of ADHD associated issues and treatment satisfaction. The following investigation sought to address questions about the efficacy of the STP with respect to predicting treatment responses for a subgroup of ADHD youth presenting with complex clinical presentations of combined type ADHD. The study built on prior evaluations of predictor importance by utilizing socio-emotional measures from the daily behavioral data of the STP, as well as more typically used ADHD dimensional symptom severity measures to inform treatment fit. As anticipated, because the heterogeneity of the disorder suggests that response to treatment is multifaceted, no combination of predictor variables produced a regression equation model that significantly explained variance across all of the treatment outcome variables. After controlling for concurrent pharmacotherapy and age, the combined effects of pretreatment core ADHD symptom severity and social functioning measures were found to significantly explain variance in a criterion variable corresponding with camp objectives (e.g., developing social competencies and coping skills, decreased functioning; Overall STP Improvement Index), as well as positive and negative socio-emotional behaviors measured directly by the STP Point System at the end of the camp. Change in R2 statistics confirmed the study hypothesis in which, the pretreatment socio-emotional factor sets significantly improved the prediction of multiple treatment outcomes over and above DSM-IV ADHD symptom dimensions and control variables. Ten percent of unique variance when predicting informant ratings of improvement made while at camp, 4% unique variance when predicting positive social behavior at the conclusion of Camp STAR, and 2% unique variance when predicting negative social behavior at the conclusion of Camp STAR were among the results. Observed negative behaviors at baseline demonstrated predictive utility whereas results pertaining to hyperactivity/impulsivity and inattention symptom dimensions did not significantly influence behavior, and subsequently, revealed little about the observed variation in outcomes in this particular dataset. While each of the core DSM-IV symptom dimensions are known to be differently associated with a variety of domain specific impairments in the general population (Lahey, & Willcutt, 2010), the results from this study suggest that with ADHD subgroups featuring severe symptom and impairment profiles, the core symptom dimensions did not appear to be as differentially associated with functional impairment. In cases of severe combined type ADHD, decisions about treatment fit should be based more on the socio-emotional impact of symptoms rather than their mere presence. The findings underscore the value in identifying socio-emotional impairments for individuals diagnosed with severe and complicated ADHD as early as possible and to intervene with intensive modalities specifically aimed at developing skills and cognitive faculties that enhance abilities to maintain healthy relationships.
Ph.D. in Psychology, December 2015
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Title: DETECTING GNSS SPOOFING ATTACKS USING INS COUPLING
Creator: Tanil, Cagatay
Date: 2016, 2016-12
Description: Vulnerability of Global Navigation Satellite Systems (GNSS) users to signal spoofing is a critical threat to positioning integrity, especially...
Show moreVulnerability of Global Navigation Satellite Systems (GNSS) users to signal spoofing is a critical threat to positioning integrity, especially in aviation applications, where the consequences are potentially catastrophic. In response, this research describes and evaluates a new approach to directly detect spoofing using integrated Inertial Navigation Systems (INS) and fault detection concepts based on integrity monitoring. The monitors developed here can be implemented into positioning systems using INS/GNSS integration via 1) tightly-coupled, 2) loosely-coupled, and 3) uncoupled schemes. New evaluation methods enable the statistical computation of integrity risk resulting from a worst-case spoofing attack – without needing to simulate an unmanageably large number of individual aircraft approaches. Integrity risk is an absolute measure of safety and a well-established metric in aircraft navigation. A novel closed-form solution to the worst-case time sequence of GNSS signals is derived to maximize the integrity risk for each monitor and used in the covariance analyses. This methodology tests the performance of the monitors against the most sophisticated spoofers, capable of tracking the aircraft position – for example, by means of remote tracking or onboard sensing. Another contribution is a comprehensive closed-loop model that encapsulates the vehicle and compensator (estimator and controller) dynamics. A sensitivity analysis uses this model to quantify the leveraging impact of the vehicle’s dynamic responses (e.g., to wind gusts, or to autopilot’s acceleration commands) on the monitor’s detection capability. The performance of the monitors is evaluated for two safety-critical terminal area navigation applications: 1) autonomous shipboard landing and 2) Boeing 747 (B747) landing assisted with Ground Based Augmentation Systems (GBAS). It is demonstrated that for both systems, the monitors are capable of meeting the most stringent precision approach and landing integrity requirements of the International Civil Aviation Organization (ICAO). The statistical evaluation methods developed here can be used as a baseline procedure in the Federal Aviation Administration’s (FAA) certification of spoof-free navigation systems. The final contribution is an investigation of INS sensor quality on detection performance. This determines the minimum sensor requirements to perform standalone GNSS positioning in general en route applications with guaranteed spoofing detection integrity.
Ph.D. in Mechanical and Aerospace Engineering, December 2016
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Title: NON-LINEAR CREEP-RELAXATION CONSTITUTIVE MODEL FOR PLAIN CONCRETE WITH ANISOTROPIC DAMAGE
Creator: Teran Torres, Bernardo
Date: 2016, 2016-05
Description: A thermodynamic constitutive model for plain concrete, and other quasi-brittle materials, is developed. The model accounts for the anisotropic...
Show moreA thermodynamic constitutive model for plain concrete, and other quasi-brittle materials, is developed. The model accounts for the anisotropic damage-induced and the aging viscoelasticity of the material. The model is based on the theory of solidi cation proposed by Baºant and the continuum damage mechanics theory. The material is considered to be a viscoelastic-damageable material. The Helmholtz free energy utilized in the formulation is treated by means of the representation theorem of coupled damage-strain tensors. The model is capable of analyzing time-dependent damage (tertiary creep) under constant loading and damage due to cyclic creep. Two simple but practical examples are presented in order to illustrate the applicability of the model. The determination of the functions and constants representing the material behavior as well as any experimental companion is proposed for the continuation of the research.
Ph.D. in Civil Engineering, May 2016
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Title: SEISMIC STRUCTURAL ANALYSIS USING INTERVAL GROUND MOTION
Creator: Venezia, Adam
Date: 2011-12-05, 2011-12
Description: Seismic analysis is a crucial procedure for the design of a structure subjected to ground motion. In conventional seismic analysis procedures,...
Show moreSeismic analysis is a crucial procedure for the design of a structure subjected to ground motion. In conventional seismic analysis procedures, a structure is subjected to a limited number of earthquake excitations. Moreover, these procedures do not consider the presence of variations and uncertainties in those excitations. Interval analysis is one method capable of accounting for both of these limitations. In this work, a new method for seismic structural analysis, with interval uncertainty in the response spectrum, is developed, which is capable of obtaining the bounds of the dynamic response of a structure. This method is hereinafter referred to as Interval Ground Motion Analysis (IGMA). In this method, first, various response spectra are combined as an interval function, referred to as an interval response spectrum. Then, the response spectrum analysis is performed using the developed interval response spectrum, and the bounds of the dynamic response of the structure are obtained. It is shown that obtaining these bounds is computationally feasible and does not require iterative procedures such as Monte Carlo simulation. Numerical example problems, which illustrate the developed algorithm, are presented, along with a comparison of solutions obtained by another solution method.
M.S. in Civil Engineering, December 2011
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Title: DETERMINATION OF REDUNDANCY IN STRUCTURES USING INTERVAL UNCERTAINTY ANALYSIS
Creator: Amirshaghaghi, Sayeh
Date: 2014, 2014-05
Description: Existence of redundancy in structures plays an important role in increasing their safety and reliability. However, using state-of-the-art...
Show moreExistence of redundancy in structures plays an important role in increasing their safety and reliability. However, using state-of-the-art deterministic and probabilistic approaches, all possibilities for estimation of redundancy (e.g. due to occurrence of different damage scenarios) have not been considered. One of the methods to quantify the presence of uncertainties in a system is to use interval variables. In this work, a new method for estimating the redundancy using interval structural analysis is developed. This method, hereafter referred to as Interval Redundancy Analysis (IRA), is robust and considers possibilities of strength reduction for each element leading to failure. Independent intervals for reduction of the strength for five damage scenarios of intact, slightly damage, moderately damaged, severely damaged, and completely damaged as well as strength of each element are considered. A numerical example to show the behavior of the developed method with comparison to Monte-Carlo simulation results is presented.
M.S. in Civil Engineering, May 2014
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Title: NATURAL AGING EFFECT ON DOUBLE AGED ALUMINUM ALLOY AA7075
Creator: Kara, Baris
Date: 2012-04-27, 2012-05
Description: The effect of natural aging (NA) on mechanical properties in double aged aluminum alloys, AA7075, was studied by means of hardness tests,...
Show moreThe effect of natural aging (NA) on mechanical properties in double aged aluminum alloys, AA7075, was studied by means of hardness tests, tensile tests and stress corrosion cracking (SCC) tests. Natural aging can strengthen AA7075 alloys after solution heat treatment, and reaching the stable condition can take years for the alloy. Double aging (DA) is very beneficial method in terms of energy savings and productivity because this method provides the peak hardness in a much shorter time compared to single aging, and DA treatment produces hardness, yield stress and tensile stress which are comparable with those produced by SA. In this study, the alloys were naturally aged for different times before double aging treatment, and the relationship between double aging treatment and natural aging treatment was observed. The results show that different natural aging times do not significantly affect the final mechanical properties of double aged alloys. Consequently, the loading time to aging furnace after solution heat treatment does not play an important role in the double aging treatment of AA7075 alloys.
M.S. in Materials Science and Engineering, May 2012
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Title: ENHANCED DEGRADATION AND PEPTIDE SPECIFICITY OF MMP-SENSITIVE SCAFFOLDS FOR NEOVASCULARIZATION OF ENGINEERED TISSUES
Creator: Sokic, Sonja
Date: 2013, 2013-07
Description: Biomaterial strategies for engineering tissues of clinically relevant size require the formation of rapid and stable neovascularization. The...
Show moreBiomaterial strategies for engineering tissues of clinically relevant size require the formation of rapid and stable neovascularization. The ability of an engineered scaffold to induce vascularization is highly dependent on its rate of degradation. During the process of material degradation, the scaffold should degrade in a manner allowing for cellular infiltration, lumen formation, and extracellular matrix (ECM) synthesis. Matrix metalloproteinases (MMPs) play a key role in mediating cell-induced proteolytic matrix degradation, remodeling, and controlled neovascularization. Poly (ethylene glycol) PEG hydrogels have been extensively investigated as scaffolds for tissue engineering applications due to their ease of chemical modification allowing for the recapitulation of key aspects of the neovascularization process. The goal of the work described in this thesis was to develop strategies to enhance and control the degradation of MMP-sensitive PEG diacrylate (PEGDA) hydrogels without inducing changes to the bulk physical and mechanical properties of the material and to further study the effect of the cleavage site concentration and MMP-sensitive peptide substrate specificity on the rate of neovascularization and tissue remodeling in vitro and in vivo. In the first part of this study, a detailed investigation was completed to investigate the effects of the mechanical and physical properties of the scaffolds as well as the role of proteolytically mediated hydrogel degradation on 3D fibroblast invasion within MMPsensitive PEGDA hydrogels. Initial studies focused on the use of a modified version of a previously published multistep conjugation method to generate degradable PEGDA macromer conjugates containing variations in the number of MMP-sensitive domains. Theoretical and experimental characterization of this multistep conjugation demonstrated xi that this method leads to the formation of multiple species that directly affect the compressive modulus and degradation rate of the scaffold making it difficult to control degradation independent of alterations in the bulk physical and mechanical hydrogel properties. After manipulation of multiple polymerization conditions, hydrogels with similar compressive moduli but different hydrogel degradation rates were synthesized. These initial studies showed that an increase in the incorporation of proteolytically sensitive domains in PEGDA hydrogels of similar modulus lead to enhanced degradation and 3D fibroblast invasion. In this study, the role of soluble FGF-1 on fibroblast invasion within these scaffolds was investigated and it was demonstrated that the inclusion of FGF-1 in the scaffolds results in further enhancement of fibroblast invasion in a dosedependent fashion. Further studies were necessary to develop a more controllable and robust approach in tuning scaffold degradation independent of alterations in the bulk physical and mechanical properties. In order to address this, a novel approach was developed to engineer protease-sensitive peptides with multiple proteolytic cleavage sites that could be covalently crosslinked into hydrogels without compromising the physical and mechanical biomaterial properties. This approach avoided the need for utilizing a multistep conjugation process as peptides could be incorporated into the backbone of PEG using a single step conjugation. Using this approach, hydrogels formed with the engineered peptides led to significantly enhanced degradation and neovascularization in vitro as compared to scaffolds with a single protease sensitive peptide between crosslinks. In addition, hydrogels with enhanced susceptibility to degradation promoted vascularization over a wider range of matrix properties. This approach allowed for controlled xii concentration of the proteolytic cleavage sites within the matrix and thus tuning of hydrogel degradation for tissue engineering applications. In the final study, MMP-sensitive peptide substrates specific to degradation by MMPs known to be expressed during neovascularization were screened for degradation and their role in neovascularization. MMP-sensitive PEGDA hydrogels (SSite and TriSite) were synthesized with peptide substrates sensitive to cleavage by MMP-2, MMP- 9, MMP-14, a mixed sequence of MMP-2, 9 and 14, and compared to the peptide substrate used in the previous studies, which is degraded by collagenase enzymes. The hydrogels were evaluated for their sensitivity and specificity to degradation by MMPs, in terms of cleavage site concentration, and for their role in neovascularization and tissue remodeling in vitro and in vivo. The presented approach allows for the incorporation of varying cleavage site concentration and MMP-sensitive peptide substrates into PEG hydrogels without alterations in the mechanical and physical properties of the hydrogels. Results showed that without the incorporation of growth factors in this scaffold, vascularization and tissue invasion was supported in all MMP-sensitive hydrogel groups regardless of the MMP-sensitive peptide substrate embedded in the matrix. In addition, the cleavage site concentration had a profound impact in enhancing vascularization in vitro and tissue invasion in vivo. These techniques can be used to tune the properties of polymer scaffolds for neovascularization and tissue remodeling. In addition, these studies provide insight into the effect of the physical, mechanical, and degradative properties of these systems and on the role of cleavage site concentration, and MMP substrate specificity on xiii neovascularization and tissue invasion within proteolytically degradable PEG hydrogel constructs.
PH.D in Biomedical Engineering, July 2013
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