Browsing by Author "McGilvray, Kirk, committee member"
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Item Embargo Computational methods for the analysis of cell migration and motility(Colorado State University. Libraries, 2024) Havenhill, Eric Colton, author; Ghosh, Soham, advisor; Heyliger, Paul, committee member; McGilvray, Kirk, committee member; Zhao, Jianguo, committee memberCollective cell migration (CCM) is necessary for many biological processes, such as in the formation or regeneration of tissue, fibroblast movement in wound healing, and the movement of macrophages and neutrophils in the body's immune response, to name a few. CCM is commonly modeled with PDEs, however these equations usually model the population density, rather than the displacement field describing the movement of any arbitrary cell. One unknown aspect of this movement is the various methods that cells use to facilitate communication to each other. Chemical communication plays a substantial role in directed cell movement, however, other mechanical methods, such as the propagation of stresses through a shared substrate to neighboring cells and cell behavior in a crowded environment, also play an important role which is less understood. The quantification of the kinematic and dynamic characteristics in CCM would present several novel advancements in understanding the collective cell behavior. First, the dynamic mode decomposition (DMD) framework is utilized. DMD allows for the recovery of a dynamic system, in the form of an ODE or PDE, by sampling the states of a system. In the context of the cell migration, the displacements of fibroblasts during a scratch-wound assay are obtained, which result in a governing PDE through the DMD process. This PDE is used in conjunction with modern optimal control theory to develop a 2D and 3D trajectory for the migration of controllable cells to a target. On an individual level, with the hybrid use of modern static structural optimization and simple non-linear control, a cell's cytoskeleton during migration can be studied, providing for the quantification of the traction force exerted on the substrate. The results of this analysis are compared with stress and structural optimization models in ANSYS and FEBio, which uses the finite element method, so that a reasonable range of these stresses during CCM can be provided. To further study the individual mechanics of cell migration, the proposed hybrid model is extended to a fully dynamic model which predicts the cytoskeletal stress fiber formations over time that require the minimal amount of material with the use of optimal control theory. The results of this research could provide useful applications in many real-world situations, from the generating of a trajectory for microrobots during drug delivery to the study of the collective migration of organisms including cells.Item Embargo Culture-expanded articular chondrocytes: a potential cellular therapeutic for osteoarthritis with MSC-like properties(Colorado State University. Libraries, 2022) Liebig, Bethany Ellen, author; Goodrich, Laurie, advisor; Kisiday, John, advisor; Regan, Daniel, committee member; Santangelo, Kelly, committee member; McGilvray, Kirk, committee member; Bahney, Chelsea, committee memberOsteoarthritis (OA) is a highly prevalent and debilitating joint disease in horses, dogs, and humans. OA affects more than 303 million people globally with an annual economic loss to Americans approaching $200 billion. It has a considerable impact on the patient, resulting in pain and disability and more than 1 million people undergo knee arthroscopy or joint replacement surgery each year due to end-stage OA in the United States. Therefore, OA therapies that produce lasting symptom- and disease-modifying effects are a medical priority. Mesenchymal stromal cells (MSCs) are considered 'medicinal signaling cells' that have been postulated to treat OA by reducing inflammation and restoring joint function. However, IA injection of MSCs into diseased human or companion animal joints has demonstrated only a modest benefit to date, as symptom-modifying effects are often temporary, and evidence of disease-modification has been minimal. It has been reported that culture-expanded chondrocytes (CECs) can assume many of the hallmark properties of MSCs, such as immunomodulation and immunophenotype. However, unlike MSCs, chondrocytes are known to thrive in suspension, which is important as IA injections release cells into synovial fluid. The goal of this research aims to characterize the growth, immunomodulatory properties, and gene expression of equine CECs as a function of expansion in vitro as well as CEC persistence in the joint after intra-articular injection using a validated model of OA in rats. Additional goals of this research are to 1) determine how CECs may (persistence) or may not (immunomodulation and molecular fingerprint) differ from bone marrow derived MSCs, and 2) compare cellular properties of CECs across age to determine an ideal donor for generating allogeneic therapies. The results shown in chapters 2 and 3 indicate that chondrocytes retain a strong propensity for immunomodulation, that increases with expansion and dedifferentiation does not coincide with other temporal changes in gene expression. Further, these data do not indicate a benefit of neonatal donors. Future in vitro studies should further characterize the immunomodulatory, redifferentiation (chondrogenic) and angiogenic potential of CECs. The preliminary results described in chapter 4 indicate that CECs may have greater persistence than MSCs in the first 3 days post IA injection. Future in vivo studies should focus on determining the symptom- and disease-modifying effects following IA injection of CECs in relevant preclinical models, such as the rodent, horse, and dog.Item Open Access Design, fabrication, and characterization of 3D printed ceramic scaffolds for bone regeneration(Colorado State University. Libraries, 2024) Baumer, Vail Olin, author; Prawel, David, advisor; McGilvray, Kirk, committee member; Heyliger, Paul, committee memberSynthetic bone tissue scaffolds are a promising alternative to current clinical techniques for treating critically large bone defects. Scaffolds provide a three-dimensional (3D) environment that mimics the properties of bone to accelerate bone regeneration. Optimal scaffolds should match the mechanical properties of the implantation site, feature a highly porous network of interconnected channels to facilitate mass transport, and exhibit surface properties for the attachment, proliferation, and differentiation of bone cell lineages. 3D printing has enabled the manufacture of complex scaffold topologies that meet these requirements in a variety of biomaterials which has led to rapidly expanding research. Structural innovations such as triply periodic minimal surfaces (TPMS) are enabling the production of scaffolds that are stiffer and stronger than traditional rectilinear topologies. TPMS are proving to be ideal candidates for bone tissue engineering (BTE) due to their relatively high mechanical energy absorption and robustness, interconnected internal porous structure, scalable unit cell topology, and smooth internal surfaces with relatively high surface area per volume. Among the material options, calcium phosphate-based ceramics, such as hydroxyapatite and tricalcium phosphate, are popular for BTE due to their high levels of bioactivity (osteoconductivity, osteoinductivity and osteointegration), compositional similarities to human bone mineral, non-immunogenicity, tunable degradation rates, and promising drug delivery capabilities. Despite the potential for TPMS ceramic scaffolds in BTE, few studies have explored beyond the popular Gyroid topology. Of the many TPMS options, the Fischer Koch S (FKS) has been simulated to be stronger, be more isotropic, have higher surface area, and absorb more energy than Gyroid at high porosities. In this report, we present a method for photocasting any TPMS in hydroxyapatite which is used to 3D print the first FKS ceramic scaffold. Results indicated that the resolution and accuracy of the process is suitable for BTE, and the custom software for producing the scaffolds was made available to the open-source community. Then, FKS and Gyroid scaffolds were designed to match the properties of trabecular bone using this method for use in critical bone defect repair. The scaffolds were printed and characterized using compressive and flow-based testing to reveal that, while both designs could mimic the low end of natural bone performance, the FKS were 32% stronger and only 11% less permeable than Gyroid. These findings emphasized the need for further characterization of these scaffolds beyond mechanical analysis and into studies of cell growth. To accomplish this, a custom multi-channel perfusion bioreactor was designed to culture cells on these scaffolds to investigate differences in cell behavior with higher efficiency than current designs. The design, capable of culturing many samples simultaneously, was validated using computational fluid dynamics and cell growth assays to demonstrate osteogenic effects and repeatability. In this work, novel TPMS scaffolds were fabricated from hydroxyapatite with sufficient accuracy and quality for large defects, testing of these scaffolds matched trabecular bone performance and suggested that FKS may be superior to Gyroid, and lastly, a four-channel bioreactor system was designed and validated to enable researchers to further characterize scaffolds for BTE.Item Embargo Development of an artificial temporomandibular joint disc replacement(Colorado State University. Libraries, 2023) Kuiper, Jason Paul, author; Puttlitz, Christian M., advisor; Prawel, David, committee member; McGilvray, Kirk, committee member; Henry, Charles, committee memberThe temporomandibular joint (TMJ) is a complex bilateral ginglymoarthroidal joint containing a fibrocartilaginous disc and is essential for chewing, speaking, and swallowing. Due to the high loading frequency, small imbalances in joint homeostasis can overcome the natural capacity for adaptation and lead to a cascade of degenerative changes. For progressive TMJ disorders, resection of the TMJ disc is the leading treatment, but disc resection inherently increases stress and friction on the articular cartilage surfaces, leading to a progression to total joint replacement in 11.7% of patients. The current methods of treatment for disorders of the TMJ musculoskeletal complex are predominantly palliative and do not reliably address disorders of arthrogenous origin. Unfortunately, no synthetic TMJ disc replacements currently exist due to profound implant failures in earlier attempts. Introduction of a robust artificial TMJ disc replacement after resection will prevent further joint degradation and improve patient outcomes. Rigorous preclinical evaluation of artificial TMJ disc replacement strategies must be conducted to support future translation to humans. Therefore, the following aims are proposed: (1) Characterize the biomechanical behavior of the ovine temporomandibular joint soft tissues, (2) identify and evaluate a material candidate for a temporomandibular joint disc replacement, (3) develop in silico and in vitro methods for evaluating design candidates for artificial TMJ disc replacement, and (4) implement a temporomandibular joint disc replacement strategy in an ovine model.Item Open Access Effects of explosive pressure on cadaveric ovine auditory tissue(Colorado State University. Libraries, 2018) McCann, Amanda, author; Heyliger, Paul, advisor; Mahmoud, Hussam, committee member; McGilvray, Kirk, committee memberThe focus of this research centered around two main goals: 1) determine the allowable pressures that people can be exposed to in non-life-threatening situations and 2) determine the pressure required to rupture a sheep eardrum as a representative sample for human ears. For the first goal, blast pressure tests were conducted at a local football stadium using Composition 1 (C1) plastic explosive, 50-grain detonation cord, and the game cannon firing 75% strength shells. The results for each explosive were put into units of TNT equivalency to provide a common unit between explosive types. Based on the recorded pressures, spectators and staff in the vicinity of the game cannon are not at risk of severe ear damage, but should still take precautions and wear hearing protection when in the vicinity. The second goal, which forms the bulk of this thesis, was investigated through conducting two series of explosive tests on dissected sheep heads and sheep ears as a representative sample for human ears. Through these experiments, the author developed a refined process for preparing and analyzing the eardrum samples under blast conditions. From these two blast tests, eight eardrums were ruptured when exposed to varying explosive pressures and this damage was used to estimate the threshold pressure at which severe damage initially occurs. The threshold pressure for these experiments is within the range of 34 kPa (4.9psi) to 42 kPa (6.1psi), which is substantially refined compared to the range of 8 kPa (1.2psi) to 104 kPa (15.1 psi) listed in other published literature. At this time, this result is only accurate for deceased sheep eardrum ruptures, but further testing could verify that this is applicable to humans.Item Open Access Establishment of biaxial testing system for characterization of small animal ventricle viscoelasticity under physiological loadings(Colorado State University. Libraries, 2022) Roth, Kellan, author; Wang, Zhijie, advisor; Garrity, Deborah, committee member; McGilvray, Kirk, committee memberVentricular dysfunction is a leading cause of heart failure. It is known that the mechanical behavior of both the left and right ventricles contribute to the function and changes during heart failure development. The ventricle tissue is viscoelastic meaning it is a stretch rate dependent material that exhibits both elastic and viscous behavior. The elasticity of the passive ventricular wall has been extensively investigated in cardiac research, but the viscous behavior is poorly understood. Moreover, as viscoelastic behavior is dependent on strain rate, characterizing the ventricle viscoelasticity under physiological loadings will invoke clinically relevant information. The objective of this thesis is to establish a biaxial testing system that can characterize rodent ventricle viscoelasticity under physiological loadings. The new tester was validated using polydimethylsiloxane (PDMS) sheets. The results from the biaxial tester's viscoelastic measurement of PDMS confirm that the tester is functioning properly for the measurement of viscoelastic soft tissue properties in small animal species under sinusoidal deformation at physiological stretch rates. Finally, rat right ventricular (RV) free walls in healthy and diseased specimens were characterized under physiological loadings. Significant alterations in viscoelastic properties and tissue anisotropy between the healthy and diseased tissues were observed. The rat RV study provides novel insight into the frequency-dependent and anisotropic viscoelasticity of the rat RV during heart failure development.Item Embargo Failure analysis and durability enhancement of polymeric heart valve leaflets(Colorado State University. Libraries, 2024) Khair, Nipa, author; James, Susan P., advisor; Bailey, Travis S., advisor; Li, Vivian, committee member; McGilvray, Kirk, committee memberRheumatic and calcified aortic heart valve disease is prevalent globally among all aged people, and the number is rapidly increasing. Clinically accepted, minimally invasive xenograft-based transcatheter aortic heart valve replacement (TAVR) shows limited durability (<10 years). Hyaluronic acid (HA) enhanced polyethylene polymeric TAVR shows excellent in vitro and in vivo anti-calcific, anti-thrombotic, and hydrodynamic performance, making it a suitable candidate for heart valve leaflets. The main problem, however, is during durability testing, cyclic impact loading causes premature failure in a consistent fashion related to TAVR assembly. This dissertation investigates leaflet premature failure mechanisms and provides two plausible solutions to upgrade heart valve durability without sacrificing performance. With regard to the failure mechanism, representative areas of retrieved failed leaflets are examined under electron microscopy and small angle x-ray scattering. The investigation finds abrasive wear, wear polishing, fine scratching, and imprints of the metal stent of the leaflet surface, indicating surface wearing from soft plastic rubbing against hard metal. A strong permanganate oxidizer etches away low-energy amorphous domain to unveil stable spherulitic structures of approximately 3 µm, bridging and tie molecular domains of pristine LLDPE. The oxidizer partially etches away polymeric buildups of failed leaflets only to reveal thinned-out and fractured spherulites beneath them, identifying the buildups as stress precursors. SAXS study reports local lamellar disruption further confirming the SEM results. Most. Notably, this is the first study that, to our knowledge, to directly image stable craze cross-tie microstructure that formed due to chain disentanglement from high amplitude cyclic stress. The SEM images validate previous theoretical and computational molecular dynamics models of cross-tie structure architecture. Therefore, leaflet premature failures are the compound effect of cyclic fatigue-initiated crazing and surface wear. Heart valve leaflet durability can be upgraded by controlling crazing and surface wearing. Both the crazing and surface wearing can be controlled by crosslinking of randomly folded amorphous chains. Because they are direct impacts of chain disentanglement under high amplitude cyclic stress. Crosslinked covalent bonds of polymer limit chain movements. LLDPE thin sheets are crosslinked at 50, 70, 100, and 150 kGy doses using 200 KeV (low energy) and 4 MeV (low energy) electron beams at room temperature in the air. Their effects are characterized by measuring gel content percentage, tensile testing, Differential Scanning Calorimetry (DSC), nanoindentation, and nano scratch test. Crosslinked LLDPE heart valve leaflet tested in in vitro flow loop and wear tester to determine valve performance and durability, respectively. Low energy electron beam (LEEB) forms 28% xylene insoluble gel whereas high energy electron beam (HEEB) forms 58 % gel at 100 kGy doses. LEEB does not affect mechanical properties, but HEEB significantly increases stiffness and yield strength. A slight reduction of melting temperature is found for LLDPE crosslinked by both of the energy sources. Nanomechanical tests show crosslinking improves hardness and coefficient of friction, an indication of improving surface wear resistance, which can explain durability improvement. Heart valve durability can also be improved by strengthening the leaflet with fiber reinforcement. A thin plastic sheet is assembled into a cylindrical form by welding two ends, which never fails. The weld at the commissure post is found to be mechanically stronger than the rest of the leaflet, which protected this region. Braided fibers are embedded on the leaflet regions of the commissure post perpendicular to the valve circumference, mimicking the weld but at a much higher strength. Leaflet durability skyrockets from a few million ISO 5840-2005 cycles to 73 million. The entire cardiac cycle of the heart valve with embedded fibers of varying angles, lengths, and numbers is simulated in Finite Element Analysis (FEA) to study their effects on leaflet maximum principal stress and leaflet opening dynamics. Horizontal fibers wrap the leaflet 360° to relax the leaflet completely during peak diastolic. However, the leaflet has a higher coaptation gap and delayed opening. The heart valve with embedded horizontal fibers is physically manufactured and tested in an in vitro flow loop and wear tester, which showed improved durability, but compromised hemodynamics. Finally, strategically crosslinked leaflet was simulated in FEA where leaflet regions of the commissure post and stent line are assigned with stiff crosslinked LLDPE material property, but the rest of the cusps undergo maximum bending are assigned with uncrosslinked LLDPE material property. Results show that strategically crosslinked leaflets open more easily than fully crosslinked leaflets. The final chapter discusses 3D shaped LLDPE leaflet bio enhancement process. Leaflets are 3D shaped in a vacuum thermoformer followed by the HA enhancement. Whole blood clotting resistance, platelet adhesion, activation, and cytotoxicity studies are conducted to determine at 10-4 µmol/mm2 ranged HA population density is required to achieve the best biocompatibility. Generally, water contact angle, Toluidine Blue O (TBO) elution assays, ATR-FTIR are used to determine overall HA presence on the leaflet. This study reports TBO staining and elution is the most effective and accurate measurement tool for determining HA population density. Fiber-reinforced LLDPE, and crosslinked LLDPE are HA-treated, and TBO staining predicts heavily populated HA surface density.Item Open Access Image-based development of three-dimensional finite element models(Colorado State University. Libraries, 2018) Huang, Xin, author; Heyliger, Paul R., advisor; Atadero, Rebecca A., committee member; McGilvray, Kirk, committee memberIn the finite element method (FEM), constructing three-dimensional (3D) models of irregular geometries of structures can be technically difficult and cost-inefficient due to the requirement for expensive equipment such as three-dimensional laser scanner. Along with the rapid development of photogrammetry in 3D modeling, an appropriate application of advanced photogrammetric technologies in FEM can greatly facilitate productivity where analysis of a large number of irregular geometries is needed. In this study, a quasi-automatic, user-friendly approach to construct 3D finite element models using advanced techniques in the field of photogrammetry is introduced and successfully applied to example geometries of structural mechanics. The 3D models were constructed in a photogrammetric program from 2D photo sequences taken by ordinary commercial cameras and then analyzed in a FEM software package. General guidance of using photogrammetric approach to acquire feasible 3D models for FEM analysis was also included. Convergence of stresses and deformation of the structure were found in the analyses with increasing number of discretized elements. The approach introduced in this thesis is recommended for the FEM analyses of structures with irregular geometries and homogeneous materials when conventional methods are less effective due to the difficult modeling process.Item Embargo Investigation into the mechanisms of bone loss in a sheep model of osteoporosis(Colorado State University. Libraries, 2024) Bisazza, Katherine T., author; Easley, Jeremiah T., advisor; Anthony, Russell V., committee member; McGilvray, Kirk, committee member; Goodrich, Laurie R., committee member; Nelson, Bradley B., committee memberOsteoporosis is the most common metabolic bone disease in humans and the leading cause of fragility fractures in the aging population. Given the invasiveness of researching bone diseases in people, appropriate animal models are essential to both build our understanding of the disease as well as examine novel therapeutics. While small animals and rodents are more commonly used as models in bone research, large animal models offer the ability to perform robust, long-term studies on bone quality with higher translational impact. Ovariectomized sheep are a well-established large animal model for osteoporosis because of the comparable bone size and microarchitecture that is shared with humans. While the ovariectomized sheep has been utilized for decades as a model for the study of bone, many gaps in the model characterization remain. Based on results from a preliminary literature search, we developed study objectives and hypotheses to expand upon current knowledge gaps in the characterization of the sheep model of osteoporosis. In order to test these aims, we performed a single 12-month in vivo study utilizing sixteen ewes. Osteoporosis was induced experimentally in ten of these ewes via ovariectomy followed by a 24-week regimen of high dose corticosteroids, while six ewes were used as healthy seasonal controls. In our first aim, we compared the bone density and microarchitectural changes in the osteoporotic animals as compared to healthy controls over the course of a year. Dual-energy x-ray absorptiometry (DXA) scans revealed significant bone density loss in the osteoporotic animals in both the lumbar spine and tibia as compared to control animals. We also noted significant microarchitectural changes in iliac crest bone biopsies of osteoporotic animals as indicated by micro-computed tomography (microCT), including decreased bone volume fraction, trabecular thickness, and trabecular number, as well as increased trabecular spacing. Additionally, we compared the use of quantitative computed tomography (QCT) and DXA to measure bone mineral density and correlated those findings with microarchitectural parameters in the osteoporotic animals. We demonstrated superior QCT sensitivity and specificity to subtle bone changes in the lumbar spine as compared to DXA, as well as demonstrated a higher correlation of QCT with iliac crest biopsy microarchitectural changes. The second aim of our study was to explore the systemic and clinical impacts of osteoporosis model development in our ten sheep compared to the healthy control animals. To test this aim, we collected blood, bone marrow, and body weights throughout the course of the year-long study. Osteoporotic animals demonstrated significant impacts to hematology and serology blood levels over the course of model development, primarily at 3 and 6-months when corticosteroids were at peak use. In particular, we note significant reductions in monocytes, lymphocytes, and eosinophils at 3-months with accompanying neutrophilia, as well as an increase in platelet count and volume. We also observed an increase in serum phosphorus and electrolytes, decrease in kidney enzymes and total protein, and an increase in select liver enzymes at 3 and 6-months in the same animals. Serum cortisol and estradiol were significantly depleted at 3 and 4-months, respectively, in the osteoporotic animals. However, estradiol levels were maintained to control levels for the remainder of the study. All these changes indicate disruptions to multiple physiologic systems over the course of osteoporosis induction in sheep which may highlight the acute effects of administering high-dose glucocorticoids. In the third and final aim of this study, we investigated the morphometrical and proteomic changes in the bone of sheep following osteoporosis induction over the course of a year. Histomorphometry of iliac crest bone biopsies revealed decreases in trabecular bone area in osteoporotic model animals compared to healthy controls, while negligible differences were observed in cortical bone morphometry. Initial global untargeted proteomic outputs identified a total of 4,765 proteins from the iliac bone biopsy samples, 909 of which were determined to be differentially expressed over the course of model development in our osteoporotic sheep. Pathway analysis of differentially expressed proteins (DEPs) revealed unique enriched pathways at all time points. Enrichment of biological processes such as monocyte differentiation, metabolic processes, regulation of chromosome condensation, and immune responses were noted throughout osteoporosis development. When comparing the 909 DEPs between time points, we identified seven downregulated proteins shared between all time points as compared to baseline in the osteoporotic animals (CTR9, INPP5D, CDK6, PPP2R5C, NUP133, ITPRIPL1, W5PH60_SHEEP). Pathway analysis of these shared proteins revealed enrichment of p53 signaling, mRNA surveillance, sphingolipid signaling, and P13K-Akt signaling pathways. This study was the first to report on the proteomic changes of bone in conjunction with morphometry assessments in a sheep model of osteoporosis. All three of our described experiments allowed us to successfully fill in some of the knowledge gaps in the characterization of a large animal model of osteoporosis by further assessing both macro and micro changes in ovariectomized and steroid-dosed sheep over the course of a year. Large animal preclinical models offer researchers the ability to compare bone changes in the same animals over time, allowing for a more comprehensive insight into the progression of postmenopausal and age-related bone loss. Understanding the mechanisms driving bone loss and systemic changes in osteoporosis disease progression could aid in future cellular therapy research and investigation of novel pathway targets for osteoporosis treatment in humans.Item Open Access Numerical simulations of binary mixtures under gravity deposition using the discrete element method(Colorado State University. Libraries, 2021) Jiang, Chao, author; Heyliger, Paul, advisor; Bareither, Christopher, committee member; Ellingwood, Bruce R., committee member; Venayagamoorthy, Karan, committee member; McGilvray, Kirk, committee memberBinary granular mixtures are frequently used in manufacturing, geotechnical engineering, and construction. Applications for these materials include dams, roads, and railway embankments. The mixing process requires dealing with particles with varying sizes and properties, and the complex composite nature of these mixtures can bring unpredictable results in overall performance. At present, there are no specifications for mixing these materials that can be used to quantify the levels of mixing and give estimates of the overall bulk properties. In this study, the Discrete Element Method (DEM) is used to examine the mechanics of the mixing process and give guidelines on how to achieve a well-mixed aggregate. A comprehensive non-linear visco-elastic damping collision model was developed to better represent the interactions between two dissimilar particles. A general Hertz model was applied for describing the normal force but a refined non-linear spring model was generated to imitate the friction force behavior without having to consider the entire loading history. A transition zone revealing the interactions between static and dynamic friction forces was shown in our numerical results. A moment resistance model was also added to capture the behavior of particle surface asperities and the damping force was calculated using relative motion. An alternative condition was applied to determine the end of a collision. Excellent agreement was found with well-established benchmark solutions and new results are also provided for future comparisons. Using this new DEM model, the mixing process of binary unbonded particles was studied using the effects of the number and position of geometric mixing obstacles and the number of mixing iterations. It was found that the mixing degree can be best quantified by measuring the spatial variation of the volume ratio φv. It was also found that small adjustments in the geometric position of the mixing obstacles could have a significant impact on the final mixing parameters. Surprisingly, the results indicate that two mixing iterations provided almost identical levels of mixing regardless of the number and nature of mixing obstacles. Estimates of the bulk elastic constants were provided and showed a high level of anisotropy as measured by the Poisson ratios for the horizontal versus vertical planes of the control volume. Particle crushing is a typical characteristic of many granular materials and can influence the mixing process, and it is possible to model non-particulate materials by bonding individual spheres together. The particle interactions and possibly impact with mixing barriers can result in the fracture of these solids as the allowable bond strength is exceeded. Therefore, the strength of the bond between individual particles that can be part of the mixing process is a critical parameter. The parallel bond model of Potyondy and Cundall (2004) was extended with the present DEM model was used to study the effects of bond strength on the mixing and mechanical properties of binary mixtures. Three types of particle blocks were studied for this purpose: unbonded, weakly bonded, and strongly bonded particles. The bonded particles result in a wider range of reflection angles as the particles interact with geometric mixers and simultaneously change and improve the level of mixing. Overall, these simulations serve to established specific guidelines and provide a basis for field-level mixing operations. They also provide some levels of expectation for the final mixing and bulk elastic behavior for the final aggregates.Item Open Access The right ventricle—the forgotten chamber that deserves more love(Colorado State University. Libraries, 2022) Nguyen-Truong, Michael, author; Wang, Zhijie, advisor; Chicco, Adam, committee member; Li, Yan Vivian, committee member; McGilvray, Kirk, committee member; Popat, Ketul, committee memberRight ventricle failure (RVF) is associated with serious cardiac and pulmonary diseases that contribute significantly to the morbidity and mortality of patients. The prevalence of RVF is significantly increased in the later stages of pulmonary hypertension, congenital heart disease, and left heart failure with preserved ejection fraction. Moreover, the mortality rate of these patients has not improved with currently limited treatment options. The persistent clinical challenge is mainly due to an incomplete understanding of the structure-function relationships of the RV, partly attributed to the lack of large animal models, as well as the lack of RV-specific therapies. Therefore, the overall goal of the study is to fill knowledge gaps in the biomechanics of right ventricle failure secondary to pressure overload and in the regenerative potential of mesenchymal stromal cells (MSCs) regulated by RV mechanics. The specific aims are: 1. Assess the unique ex vivo biomechanics of the RV free wall in contrast to the LV free wall. 2. Assess the ex vivo biomechanics of the "significant other" of the RV chamber – the septum wall. 3. Establish a novel ovine model of RV failure and investigate RV biomechanical changes during RV failure progression. 4. Investigate the pro-angiogenic paracrine effect in the context of mesenchymal stromal cell mechanobiology to ultimately improve RV therapy. From ovine models, there was distinct anisotropic mechanical behavior of the RV compared to the left side in healthy adults, and the low-strain mechanical behavior was correlated to collagen III. Multiscale computational model indicated softer collagen fibers in the RV. The investigation on the septal wall originally revealed transmural biomechanical changes and a significantly more compliant wall than the ventricular free walls. A new adult RV failure was established, and there was stiffening of the RV in the outflow tract direction and altered tissue anisotropy with RV failure progression. Finally, from prior and our own RV mechanical data, biomimetic scaffolds that represent healthy and diseased RV mechanics were fabricated for the first time. The pro-angiogenic potentials of MSCs on these scaffolds were assessed by cytokine production and neovessel formation. There were synergistic effects of matrix stiffness and anisotropy on MSC pro-angiogenic functionality.