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Doctor of Philosophy with a Major in Bioengineering
Doctor of Philosophy with a Major in Bioengineering
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ItemThe effects of aging and remodeling on bone quality and microdamage(Georgia Institute of Technology, 2011-05-16) O'Neal, JessicaOne indication of increasing fragility of bone is the accumulation of microscopic cracks, or microdamage, within the bone matrix. Microdamage accumulates in bone of the elderly, when changes in bone material properties and matrix architecture coupled with a decrease in bone repair mechanisms compromise bone integrity. To preserve bone mass and reduce fracture risk, therapeutics such as alendronate are prescribed which increase bone volume fraction by decreasing the rate of bone turnover. However, concerns over adverse effects of prolonged turnover suppression have been reinforced by findings of increased microdamage density with alendronate use. Microdamage formation is not always pathologic, but extensive accumulation of damage can be an indicator of reduced bone quality. The work in this thesis explores the hypothesis that microdamage in bone of lower quality will form more easily and progress more extensively than in bone of higher quality. Microdamage initiation stresses and strains were obtained for trabecular bone from older females, older males, and younger females to determine whether thresholds for damage initiation were lower in older females. Results suggest that the stress threshold for damage initiation in older females may indeed be lower compared with younger females, and that normalized strain thresholds for severe damage formation in older males may be decreased compared with older females. Damage propagation was evaluated as a function of age and sex to determine whether damage in older women progressed more extensively than in younger women or men. Results suggest that bone from older individuals had decreased resistance to crack propagation evidenced by an increased number of severely damaged trabeculae which expanded in area under cyclic loading; however no sex differences were uncovered. Finally, the stress/strain thresholds for damage initiation were investigated in alendronate-treated bone, and results indicate that a decreased stress threshold was needed to initiate damage formation of a linear and severe morphology after one year of treatment. After three years of treatment, however, micromechanical properties recovered, perhaps due to increased matrix mineralization which increased tissue level stiffness.
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ItemDelivery of BMP-2 for bone tissue engineering applications(Georgia Institute of Technology, 2010-01-04) Johnson, Mela RonelleBone defects and fracture non-unions remain a substantial challenge for clinicians due to a high occurrence of delayed union or non-union requiring surgical intervention. The current grafting procedures used to treat these injuries have many limitations and further long-term complications associated with them. This has resulted in research efforts to identify graft substitution therapies that are able to repair and replace tissue function. Many of these tissue engineered products include the use of growth factors to induce cell differentiation, migration, proliferation, and/or matrix production. However, current growth factor delivery methods are limited by poor retention of growth factors upon implantation resulting in low bioactivity. These limiting factors lead to the use of high doses and frequent injections, putting the patients at risk for adverse effects. The goal of this work was to develop and evaluate the efficacy of BMP-2 delivery systems to improve bone regeneration. We examined two approaches for delivery of BMP-2 in this work. First, we evaluated the use of a self-assembling lipid microtube system for the sustained delivery of BMP-2. We determined that sustained delivery of BMP-2 from the lipid microtube system was able to enhance osteogenic differentiation compared to empty microtubes, however did not demonstrate a significant advantage compared to a bolus BMP-2 dose in vitro. Second, we developed and assessed the functionality of an affinity-based system to sequester BMP-2 at the implant site and retain bioactivity by incorporating heparin within a collagen matrix. Incorporation of heparin in the collagen matrix improved BMP-2 retention and bioactivity, thus enhancing cell-mediated mineralized matrix deposition in vitro. Lastly, the affinity-based BMP-2 delivery system was evaluated in a challenging in vivo bone repair model. Delivery of pre-bound BMP-2 and heparin in a collagen matrix resulted in new bone formation with mechanical properties not significantly different to those of intact bone. Whereas delivery of BMP-2 in collagen or collagen/heparin matrices had similar volumes of regenerated mineralized tissue but resulted in mechanical properties significantly less than intact bone properties. The work presented in this thesis aimed to address parameters currently preventing optimal performance of protein therapies including stability, duration of exposure, and localization at the treatment site. We were able to demonstrate that sustained delivery of BMP-2 from lipid microtubes was able to induce osteogenic differentiation, although this sustained delivery approach was not significantly advantageous over a bolus dose. Additionally, we demonstrated that the affinity-based system was able to improve BMP-2 retention within the scaffold and in vitro activity. However, in vivo implantation of this system demonstrated that only delivery of pre-complexed BMP-2 and heparin resulted in regeneration of bone with mechanical properties not significantly different from intact bone. These results indicate that delivery of BMP-2 and heparin may be an advantageous strategy for clinically challenging bone defects.
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ItemDevelopment of a small animal model to study tissue engineering strategies for growth plate defects(Georgia Institute of Technology, 2007-07-10) Coleman, Rhima M.The growth plate is a cartilaginous tissue responsible for the longitudinal growth of long bones. It is a complex tissue composed of chondrocytes whose maturation and proliferation is tightly regulated by a biochemical feedback loop. Injury to this tissue can result in a limb length discrepancy or angular deformity that may lead to life long disability. Given the recent rise in the number of growth plate injuries and the variability in success of current therapies, there is a significant need for a greater understanding of growth plate injury pathology and the development of improved treatment strategies. Cartilage tissue engineering strategies offer an attractive alternative to regenerating growth plate tissue and restoring growth function. Bone marrow-derived stem cells (BMSCs) have been shown to be able to undergo chondrogenic differentiation and in vitro and in vivo and therefore offers an appealing and abundant cell resource for developing tissue engineering strategies for the treatment of growth plate defects. However, the dependence of chondrogenic differentiation and matrix accumulation on monolayer expansion protocols and three-dimensional (3D) culture environment has received little attention. Prior to developing treatment strategies for growth plate injury repair, it is essential to first understand the interconnection between alterations in growth plate morphology and subsequent limb deformities. To that end, we have established a surgical defect model of growth plate injury in Sprague Dawley rats and developed a novel technique to quantitatively monitor growth plate morphology in health and disease using microcomputed tomography (micro-CT) imaging. In an effort to develop a tissue engineering treatment strategy for growth plate injury, the role of monolayer expansion, 3D scaffold, and growth factor regimen in the chondrogenic differentiation of rat BMSCs was also examined. This research study has demonstrated the utility of micro-CT as a non-invasive imaging modality for assessing growth plate injury and repair. This work has also provided an improved understanding of the interrelationship of monolayer expansion, 3D culture environment, and growth factor regimen in BMSC chondrogenic differentiation. Finally, this work suggests that an injectable in situ gelling hydrogel is a feasible method for decreasing limb length discrepancies, however, neither implantation of agarose alone into the defect nor the inclusion of BMSCs fully corrects growth disruption.