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Browsing by Author "Donahue, Seth, advisor"

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    Are lines of arrested growth in bone indicative of seasonal metabolic suppression in bears?
    (Colorado State University. Libraries, 2016) Hinrichs, Jason, author; Donahue, Seth, advisor; Norrdin, Robert, committee member; Popat, Ketul, committee member
    Large hibernators such as bears have seasonal metabolic suppression, hibernation (Tøien et al. 2012). During hibernation bear's activity is very low; to the point most other animals would exhibit disuse bone resorption. However bears do not exhibit disuse bone resorption during this time (McGeeLawrence et al. 2008). Are lines of arrested growth (LAGs) in bone indicative of seasonal metabolic suppression in bears? Through the use of toluidine blue stain light microscopy slides and backscattered scanning electron microscopy images (SEM), LAGs were counted and correlated with age. LAGs have a strong correlation with age. This is indicative of LAGs formation once per year, during set hibernation cycles. LAGs are metabolic markers, in bears with set hibernation cycles. These metabolic markers could be used to identify the specific time in which there is metabolic suppression, in bears. This identification could be used in the future to track blood serum and other chemical markers in an attempt to understand bear's natural resistance to disuse bone resorption. Bears ability to not exhibit disuse bone resorption could be biomimetically studied, in an attempt to adapt this protection to humans. Since humans experience disuse osteoporosis (extended bed rest and spaceflight) and osteoporosis (older population specifically women).
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    Efficacy of locally delivered parathyroid hormone for treatment of critical size bone defects
    (Colorado State University. Libraries, 2018) Wojda, Samantha J., author; Donahue, Seth, advisor; Yaszemski, Michael, committee member; Popat, Ketul, committee member; Reynolds, Melissa, committee member
    Large segmental defects in bone (e.g., due to trauma or tumor resection) commonly have complications or fail to heal properly, resulting in delayed or non-union. Around 2.2 million orthopaedic procedures utilize autografts or allografts each year to repair large defects; however, neither is without disadvantages. Disability due to orthopaedic injury has a significant impact on both the patient and the healthcare system. Quality of life for these patients can be severely impacted as healing time may exceed 9 months and multiple treatment attempts may be required if the first is unsuccessful. Research into bone graft substitutes, like Infuse® and OP-1® (Bone Morphogenetic Protein and a collagen sponge), has become prominent. PTH is another bioactive molecule that may promote bone regeneration and provide an alternative to autograft and BMP use for treatment of large segmental defects and non-unions. Daily injections of PTH are well known to have an anabolic effect on bone and are presently FDA approved for use as an osteoporosis treatment that results in increases in both bone mineral density and bone volume. Off label PTH 1-84 treatment also resulted in the healing of a non-union fracture that was unresponsive to BMP. Current FDA approval is for daily injections of PTH (intermittent administration), as continuously elevated PTH often has a catabolic effect on bone. However, post-menopausal women with mild primary hyperparathyroidism (PTH levels are not as severely elevated) demonstrate trabecular bone preservation. Low levels of continuous PTH have also been shown to increase bone formation rate and marrow vascularity in mice. Thus, there is some evidence to suggest that low dose continuous PTH could be beneficial as an anabolic therapy in bone and may enhance bone regeneration. Continuously released, locally delivered PTH has been shown to improve healing/formation around dental implants in dogs and drill defects in sheep. However, dose response to local continuously delivered PTH is still unknown. Whether or not the benefits of PTH treatment observed in these models translate to critical size defect models is also unknown. The contribution of the research described in this dissertation increases understanding of the effects of locally delivered PTH on osteoblasts as well as its potential to enhance bone regeneration in a critical size long bone defect. This contribution is significant because presently the effects of low dose continuous PTH are not well understood. Continued development of the approaches described herein could lead to improved therapies for treatment of non-union and critical size defects in bone. Bone regeneration through locally delivered parathyroid hormone has the potential to improve functional restoration, even beyond that of allografts and without the drawbacks of current treatments, which would improve the quality of life for patients.
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    Evaluation of parathyroid hormone and zoledronic acid in promoting bone healing after stereotactic radiation therapy for local control of osteosarcoma in an orthotopic rat model
    (Colorado State University. Libraries, 2014) Curtis, Ryan C., author; VandeWoude, Sue, advisor; Donahue, Seth, advisor; Custis, Jamie, committee member; Ehrhart, Nicole, committee member; Ehrhart, EJ, committee member
    Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have achieved similar median survival times in patients as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptably high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA , 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and polar moments of inertia within the region of interest (distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to canine osteosarcoma.
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    Exploration of unique porous bone materials for candidacy in bioinspired material design
    (Colorado State University. Libraries, 2018) Seek, Timothy W., author; Donahue, Seth, advisor; Bradley, Thomas, committee member; Florant, Gregory, committee member
    Bioinspired material design draws inspiration for improved technologies from unique functional adaptations found in nature. Grizzly bear (Ursus arctos horribilis), cave bear (Ursus spelaeus), edmontosaur (Edmontosaurus annectens) (Edmontosaurusregalis), and bighorn sheep (Ovis canadensis) exhibit unique functional examples of porous bone structures. Grizzly bear trabecular bone does not lose bone density during long periods of disuse. Cave bears, being larger than grizzly bears, give a unique perspective of trabecular bone property scaling relationships in animals from the near past. Edmontosaurs were expected to have grown to gigantic sizes weighing 7936±1991 kg creating a unique high force loading environment in dinosaur trabecular bone. Bighorn sheep butt heads during the mating season routinely generating near 100g accelerations and approximately 3400N forces in their horn core bone during impact. Morphological trabecular bone properties of bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), and trabecular number (Tb.N) were examined using micro-computed tomography (µCT) imaging for the underlying trabecular bone in the proximal tibias of grizzly bear, cave bear, and edmontosaurus animals. Morphological bone properties were compared against body mass scaling relationships from extant mammals. Cave bear trabecular bone was found to have larger BV/TV and Tb.Th than modern grizzly bears. The larger BV/TV may indicate environmental drivers on cave bear trabecular bone properties. To our knowledge, the measurement of dinosaur trabecular bone properties is a novel concept. Adult edmontosaur BV/TV was measured at an average greater than 60% which was significantly different from extant species BV/TV values. Additionally, adult edmontosaurus Tb.Th, and Tb.Sp were measured at comparable values to small mammals. The difference in edmontosaur BV/TV from extant mammals may be a potential clue in why extant terrestrial animals do not reach the same levels of gigantism as dinosaurs. Additionally, mimicking the continuum properties of edmontosaur trabecular bone in an engineered foam may have potential usage in optimized high strength foams. Bighorn sheep horn core bone exhibits observational and morphological properties different from typical trabecular bone in thickness, separation and number. Due to these differences, the bighorn sheep horn core bone is being considered as a new type of porous bone architecture referred to as 'velar' bone. The velar bone morphology indicates that it is highly adapted to resist high impact bending through widely separated and thick bone formations. Future bioinspired engineering foam designs mimicking the structures of porous bone outlined in this research could be useful for energy absorption in repeated high impact loading. The work presented here does not include efforts to create a bioinspired structural foam. However, this research focuses on the quantification of porous bone structural properties optimized for unique mechanical environments for the purposes of guiding future research towards structural foam design.