Injury to bone is one of the most prevalent and costly medical conditions. Clinical treatment of volumetric bone loss or hard-to-heal bony lesions often requires the use of proper bone grafting materials, with or without adjuvant anabolic therapeutics. Despite significant problems associated with autografting (donor site morbidity, limited supplies) and allografting (disease transmissions, high graft failure rates) procedures, synthetic bone grafts remain the least utilized clinically. Existing synthetic orthopaedic biomaterials rarely possess a combination of bone-like structural and biochemical properties required for robust osteointegration, scalable and user-friendly characteristics indispensable for successful clinical translations. This thesis tests the hypothesis that by recapitulating key structural elements and biochemical components of bone in 3- and 2-dimensional biomaterials, scalable synthetic bone grafts can be designed to enable expedited healing of hard-to-heal volumetric bone loss. Specifically, FlexBone, a 3-dimensional hydrogel scaffold encapsulating 50 wt% of structurally well integrated nanocrylstalline hydroxyapatite, the main inorganic component of bone, was developed. The large surface area of nanocrystalline hydroxyapatite combined with its intrinsic affinity to proteins and its excellent structural integration with the hydrogel matrix enabled FlexBone to both sequester endogenous protein signals upon press-fitting into an area of skeletal defect and to deliver exogenous protein therapeutics in a localized and sustained manner. We demonstrated that FlexBone enabled the functional healing of critical-size long bone defects in rats in 8 – 12 weeks with the addition of a very low dose of osteogenic growth factor BMP-2/7. This promising synthetic bone graft is now being explored for the delivery of multiple growth factors to expedite the healing of diabetic bony lesions. In addition, a 2-dimensional electrospun cellulose fibrous mesh was chemically modified with sulfate residues to mimic sulfated polysaccharide ECM components of skeletal tissues to enabled progenitor cell attachment and differentiation as well as controlled retention and localized/sustained delivery of protein therapeutics. This sulfated fibrous mesh is currently explored as synthetic periosteum to augment the osteointegration of devitalized structural allografts. Finally, a rat subcutaneous implantation model developed to examine the biocompatibility of newly developed biodegradable shape memory polymer bone substitutes is also presented.

Indiana University-Purdue University Indianapolis (IUPUI) / Bone is a dynamic tissue that is constantly remodeling to repair damage and strengthen regions exposed to loads during everyday activities. However, certain conditions, including long-term unloading of the skeleton, hormonal imbalances, and aging can disrupt the normal bone remodeling cycle and lead to low bone mass and osteoporosis, increasing risk of fracture. While numerous treatments for low bone mass have been devised, dynamic mechanical loading modalities, such as axial loading of long bones and lateral loading of joints, have recently been examined as potential methods of stimulating bone formation. The effectiveness of mechanical loading in strengthening bone is dependent both on the structural and geometric characteristics of the bone and the properties of the applied load. For instance, curvature in the structure of a bone causes bending and increased strain in response to an axial load, which may contribute to increased bone formation. In addition, frequency of the applied load has been determined to impact the degree of new bone formation; however, the mechanism behind this relationship remains unknown. In this thesis, the application of mechanical loading to treat osteoporotic conditions is examined and two questions are addressed: What role does the structural geometry of bone play in the mechanical damping of forces applied during loading? Does mechanical resonance enhance geometric effects, leading to localized areas of elevated bone formation dependent on loading frequency? Curvature in the structure of bone was hypothesized to enhance its damping ability and lead to increased bone formation through bending. In addition, loading at frequencies near the resonant frequencies of bone was predicted to cause increased bone formation, specifically in areas that experienced high principal strains due to localized displacements during resonant vibration. To test the hypothesis, mechanical loading experiments and simulations using finite element (FE) analysis were conducted to characterize the dynamic properties of bone. Results demonstrate that while surrounding joints contribute to the greatest portion of the damping capacity of the lower limb, bone absorbs a significant amount of energy through curvature-driven bending. In addition, results show that enhanced mechanical responses at loading frequencies near the resonant frequencies of bone may lead to increased bone formation in areas that experience the greatest principal strain during vibration. These findings demonstrate the potential therapeutic effects of mechanical loading in preventing costly osteoporotic fractures, and explore characteristics of bone that may lead to optimization of mechanical loading techniques. Further investigation of biomechanical properties of bone may lead to the prescribing of personalized mechanical loading treatments to treat osteoporotic diseases.

Indiana University-Purdue University Indianapolis (IUPUI) / Mechanical loading associated with exercise is known to benefit bone health; however, most studies explore exercise benefits on bone mass independent of bone structure and strength. The purpose of this dissertation is to explore the response of the skeleton to exercise across the translational divide between animal- and human-based studies, with a particular emphasis on exercise-induced changes in bone structure and estimated strength. To explore the skeletal benefits of exercise, models were used wherein loading is introduced unilaterally to one extremity. Unilateral exercise enables the contralateral, non-exercised extremity to be used as an internal control site for the influences of systemic factors, such as genetics and circulating hormones. In study 1, a dose response between load magnitude and tibial midshaft cortical bone adaptation was observed in mice that had their right tibia loaded in axial compression at one of three load magnitudes for 3 d/wk over 4 weeks. In study 2, the ability of peripheral quantitative computed tomography to provide very good prediction of midshaft humerus mechanical properties with good short-term precision in human subjects was demonstrated. In study 3, collegiate-level jumping (long and/or high jump) athletes were shown to have larger side-to-side differences in tibial midshaft structure and estimated strength between their jump and lead legs than observed in non-jumping athletes. In study 4, prepubertal baseball players followed for 12 months were shown to gain more bone mass, structure and estimated strength in their throwing arm relative to their nonthrowing arm over the course of 12 months. These cumulative data using a combination of experimental models ranging from animal to cross-sectional and longitudinal human models demonstrate the ability of the skeleton to adapt its structure and estimated strength to the mechanical loading associated with exercise. Study of these models in future work may aid in optimizing skeletal responses to exercise.

Indiana University-Purdue University Indianapolis (IUPUI) / PTH increases osteoclasts by upregulating RANKL in cells of the osteoblastic lineage, but the precise differentiation stage of the PTH target cell remains undefined. Recent findings demonstrate that PTH regulates gene expression in osteocytes and that these cells are an important source of RANKL. We therefore investigated whether direct regulation of the RANKL gene by PTH in osteocytes is required to stimulate osteoclastic bone resorption. To address this question, we examined bone resorption and RANKL expression in transgenic mice in which PTH receptor signaling is activated only in osteocytes (DMP1-caPTHR1) crossed with mice lacking the distal control region regulated by PTH in the RANKL gene (DCR -/-). Longitudinal analysis of circulating C-terminal telopeptide (CTX) in male mice showed elevated resorption in growing mice that progressively decreased to plateau at 3-5 month of age. Resorption was significantly higher (~100%) in DMP1-caPTHR1 mice and non-significantly lower (15-30%) in DCR -/-mice, versus wild type littermates (WT) across all ages. CTX in compound DMP1-caPTHR1; DCR -/-mice was similar to DMP1-caPTHR1 mice at 1 and 2 months of age, but by 3 months of age, was significantly lower compared to DMP1-caPTHR1 mice (50% higher than WT), and by 5 months, it was undistinguishable from WT mice. Micro-CT analysis revealed lower tissue material density in the distal femur of DMP1-caPTHR1 mice, indicative of high remodeling, and this effect was partially corrected in compound vi mice. The increased resorption exhibited by DMP1-caPTHR1 mice was accompanied by elevated RANKL mRNA in bone at 1 and 5 months of age. RANKL expression levels displayed similar patterns to CTX levels in DMP1-caPTHR1; DCR -/-compound mice at 1 and 5 month of age. The same pattern of expression was observed for M-CSF. We conclude that resorption induced by PTH receptor signaling requires direct regulation of the RANKL gene in osteocytes, but this dependence is age specific. Whereas DCR-independent mechanisms involving gp130 cytokines or vitamin D 3 might operate in the growing skeleton, DCR-dependent, cAMP/PKA/CREB-activated mechanisms mediate resorption induced by PTH receptor signaling in the adult skeleton.

The evolution of jaws in cichlid fishes of the East African Great Lakes is a textbook example of adaptive radiation in vertebrates. Karl Liem postulated that this adaptive radiation has been possible due to the functional decoupling of two cichlid functional units – the pharyngeal jaw (PJ) and the oral jaw (OJ). This functional decoupling of the jaws has enabled the OJ to be relieved of its dual role of prey capturing and processing and has allowed the PJ to take on the role of prey processing. As a result, African cichlids have adapted the morphology of their functional units (i.e., oral jaws) to specialize in a feeding mechanism best suited for their habitat. However, global morphological changes (across the OJ and PJ) are understudied, especially, at the genetic level. In this study, two rock dwelling species of African Cichlids from Lake Malawi were used - Labeotropheus fuelleborni (LF) and Tropheops “red cheek” (TRC). Both species have distinct craniofacial morphologies for specialized benthic feeding (LF) and for generalized feeding (TRC). This morphological variation allowed us to investigate the functional decoupling of the jaws by studying differences in bone shape and muscle volumes in an F5 hybrid population. Strong phenotypic correlations were observed between and within the tissues of the OJ and PJ. Further, to identify phenotype to genotype associations, a Quantitative Locus (QTL) analysis and a fine mapping analysis was conducted. The results show some evidence of overlapping genetic control (i.e., pleiotropy) suggesting some genetic coupling between the two jaws.

В диссертационном исследовании проанализированы нарушения опорно-двигательного аппарата у женщин старше 40 лет, а также механизмы лечебного воздействия средств оздоровительной гимнастики ушу на опорно-двигательный аппарат. Разработана, обоснована и определена эффективность программы физической реабилитации женщин старше 40 лет с нарушениями опорно-двигательного аппарата средствами оздоровительной гимнастики ушу. / The dissertation analyses the musculoskeletal system disorders in women over 40 years old, as well as the mechanisms of therapeutic effects of Wushu recreational gymnastics on the musculoskeletal system. The effectiveness of physical rehabilitation program for women over 40 years old with disorders of musculoskeletal system by means of wushu health gymnastics has been identified, explained and developed.

<p>Dedicated to the memory of Dr. Colin E. Webber</p> / <p>This comparative study of peripheral (p) QCT, high-resolution pQCT (hr-pQCT) and 1.0 Tesla pMRI technologies quantified short-term test-retest reproducibility, validity, one-year detection limit and clinical sensitivity of each modality’s derived bone measures. Select bone outcomes were evaluated from scans performed on Hamiltonian women above 50 years old and externally validated in a population-based cohort. In the local cohort (age: 74 ± 9 years and BMI 27.65 ± 5.74 kg/m²), Tb.Sp measured on pMRI, Ct.Th and vBMD from pQCT showed significant correlations (r²=0.52-0.85) with hr-pQCT, yielding slopes near unity. Bland-Altman analyses revealed significant relationships between pQCT and pMRI bone outcome values (Tb.Th(-), Tb.N(+), BV/TV(-)) and agreement with hr-pQCT. Short-term reproducibility was < 5% for pQCT but only BV/TV was < 5% for pMRI. Co-registration and excluding individuals with fractures mildly reduced precision error and one-year change. In the local cohort, only Ct.Th and cortical vBMD associated with fractures (OR: 1.09-3.28) using hr-pQCT, which was externally validated in the national cohort. Certain trabecular measures on pMRI and pQCT erred towards increased odds for fractures locally. For pQCT, these became significant in the national cohort (OR:1.04-3.81). This Canadian reference dataset for hr-pQCT showed larger Tb.Sp and smaller Tb.N compared to Americans but age-related decline in Ct.Th and BV/TV was faster in Europeans. This study demonstrated validity of pMRI and pQCT-derived volumetric bone outcomes and reasonable short- and long-term precision error for pQCT but not 1.0T pMRI. A single CT slice from pQCT was comparable to 110 slices from hr-pQCT in associations with fractures.</p> / Doctor of Philosophy (Medical Science)

Necessary for effective ambulation, head stability affords optimal conditions for the perception of visual information during dynamic tasks. This maintenance of head-in-space equilibrium is achieved, in part, by the attenuation of the high frequency impact shock resulting from ground contact. While a great deal of experimentation has been done on the matter during steady state locomotion, little is known about how head stability or dynamic visual acuity is maintained during asymmetric walking. In this study, fifteen participants were instructed to walk on a split-belt treadmill for ten minutes while verbally reporting the orientation of a randomized Landolt-C optotype that was projected at heel strike. Participants were exposed to the baseline, adaptation, and washout conditions, as characterized by belt speed ratios of 1:1, 1:3, and 1:1, respectively. Step length asymmetry, shock attenuation, high (impact) and low (active) frequency head signal power, and dynamic visual acuity scores were averaged across the first and last fifty strides of each condition. Over the course of the first fifty strides, step length asymmetry was significantly greater during adaptation than during baseline (p d =2.442). Additionally, high frequency head signal power was significantly greater during adaptation than during baseline (p d =1.227), indicating a reduction in head stability. Shock attenuation was significantly lower during adaptation than during baseline (p d =-0.679), and a medium effect size suggests that dynamic visual acuity was lower during adaptation than during baseline as well (p =0.052; d =0.653). When comparing the baseline and adaptation conditions across the last fifty strides, however, many of these decrements were greatly reduced. The results of this study indicate that the locomotor asymmetry imposed by the split-belt treadmill during the early adaptation condition is responsible for moderate decrements to shock attenuation, head stability, and dynamic visual acuity. Moreover, the relative reduction in magnitude of these decrements across the last fifty strides underscores the adaptive nature of the locomotor and visuomotor systems.

Orbital blowout fractures are a particular facial fracture occurring within the inner eye orbits of the face caused by blunt force trauma to the eyeball or the lower orbital rim. This fracture is common in modern clinical contexts due to physical assaults, but examining this fracture in skeletal material can also provide insights into the patterns of interpersonal violence within the fields of bioarchaeology and forensic anthropology. Issues with analyzing this fracture in skeletal material arise due to the clinical assessment practices of blowout fractures, where medical practitioners are highly focused on the soft tissue presentations of the fracture in a patient. In this study, standard clinical criteria for defining an orbital blowout fracture were analyzed and translated into criteria that could be used to assess skeletal material where no soft tissue is present. A set of scoring criteria was developed to analyze skeletal material based on four traits commonly observed in this fracture pattern, and the material was examined for any post-mortem taphonomy that could be mistaken for perimortem trauma. In this study, thirteen individuals were selected from online osteological databases and examined to score the possible presence of orbital blowout fractures. The scoring results of this study were further tested using positive and negative likelihood ratio tests (LRT) and indicated that eight individuals were highly likely to have blowout fractures present. The presence of nasal fractures was noted in 69.2% of individuals utilized in this study and presents a possible correlation with blowout fractures that should be further explored. The scoring sheet developed in this study establishes a standardized methodology for reporting orbital blowout fractures in contexts lacking soft tissue, providing a valuable tool for the consistent analysis of orbital trauma in bioarchaeology.

Thesis (MScPhysio)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Aims: To assess the effect of a vertical height adjustment of the chair and visual display unit (VDU) on work related upper quadrant musculoskeletal pain (WRUQMP) and sitting comfort in computer users. The upper quadrant refers to the occiput, cervical and upper thoracic spine including the clavicles and scapulae. Methods: An N=1 study was conducted using the ABC design whereby an ergonomic workstation adjustment, of VDU and chair height, was compared to the subject’s usual workstation settings. Pain and sitting comfort were measured using visual analogue scales (VAS). The subject was assessed over the four week phases as she performed her typical VDU work. The results were compiled and tabulated. Results: Both the mean and variance in pain intensity decreased after the workstation intervention. A deterioration was noted in sitting comfort. Conclusion: The vertical height adjustment of the chair and VDU may have contributed to a decrease in WRUQMP in this subject. This safe, economical workstation intervention may be a practical management option for the computer user suffering from WRUQMP. Further research into the measurement of comfort whilst sitting at a computer workstation, is recommended. / AFRIKAANSE OPSOMMING: Doelwitte: Om die effek te bepaal van n vertikale aanpassing van die stoel en beeldskerm van rekenaargebruikers op werksverwandte boonste kwadrant muskuloskeletale pyn en sitgemak. Die boonste kwadrant verwys na die oksiput, servikale en boonste torakale werwelkolom en sluit ook die klavikel en skapula in. Methode: Die N=1 studie is onderneem met gebruik van die ABC ontwerp in terme waarvan n ergonomiese aanpassing van stoel en beeldskerm vergelyk is met die normale gebruik van die deelnemer. Pyn en sitgemak is gemeet deur die gebruik van die Visueel analoogskaal. Die interwensies is ge-evalueer oor vierweekfases tydens normale rekenaar gebruik van die deelnemer. Die resultate is saamgestel en getabuleer. Uitkoms: Beide die gemiddelde en veranderlike pynintensiteit het verminder nadat die werkstasie aangepas is. Geen verbetering in sitgemak is opgemerk nie. Gevolgtrekking: Die vertikale hoogte-aanpassing van die stoel en beeldskerm het moontlik bygedra tot die verminderde pynvlakke in hierdie deelnemer. Hierdie veilige, ekonomiese verstelling is moontlik n praktiese beheeropsie vir rekenaargebruikers wat werksverwandte boonste kwadrant muskuloskeletale pyn verduur. Verder studie in die meet en waarneming van sitgemak tydens rekenaarwerk is nodig.