Doctor of Philosophy, University of Akron, 2019, Biomedical Engineering

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an elusive disease that presents as exposed necrotic bone following tooth extraction. It occurs in patients undergoing bisphosphonate therapy for metastasizing cancers and osteoporosis. Experts believe the condition is caused by a defect in bone remodeling, the process by which osteoclasts resorb bone and osteoblasts form new bone, within the oral cavity. Its complexity requires a multicellular model to address the net effects of two key risk factors: tooth extraction (overload) and inflammation associated with bacterial infection. In this work, a system comprised of a deformable polymeric chip and mechanical loading device is used to expose bisphosphonate-treated osteocytes, the mechanosensing bone cells, to overload. Osteocyte viability is evaluated as a function of load, and soluble activity is assessed. Effects of these factors on bone resorption by osteoclasts and bone formation by osteoblasts are quantified. Osteoclast activity is also quantified in the presence of inflammatory agents, lipopolysaccharide and interferon gamma. Results support a role for osteocyte mechanotransduction in suppressing osteoblast bone formation within a BRONJ environment. They also suggest inflammation may inhibit resorption of necrotic bone by osteoclasts. These findings provide insights into BRONJ that may contribute to its elucidation. This dissertation also lays the foundation for a biomimetic lab-on-a-chip platform for the study of bone turnover and remodeling-related disease. Fabrication techniques are developed, and osteocyte, osteoclast and osteoblast characterizations are performed on relevant substrates within microfluidic devices. Culture conditions, including seeding densities, feeding requirements and time points for analyses are determined. This work will enable the development of a controlled multicellular lab-on-a-chip capable of quantifying the aggregate response of bone cells to disease cofactors.

Committee: Marnie Saunders PhD (Advisor); Hossein Tavana PhD (Committee Member); Ge Zhang PhD (Committee Member); Jiang Zhe PhD (Committee Member); Sailaja Paruchuri PhD (Committee Member) Subjects: Biomedical Engineering

MS, University of Cincinnati, 2017, Engineering and Applied Science: Aerospace Engineering

To better understand skull response after surgeries in patients born with an alveolar cleft, a finite element method (FEM) has been designed to predict how bone is strained during normal loading cycles of mastication. To test the effectiveness of treatment utilizing stem cells on resorbable scaffolds, a juvenile swine was operated by a surgically created alveolar cleft. Then, the FEM model of the pig skull was built based from pre- and post-surgery computed tomography (CT) to estimate strain dynamics in the healing bone. Scan resolutions were insufficient to visualize bone at the scale of trabeculae, a necessary item to determine how depositional fields in healing and growing bone will respond to loading. This is important because bone deposition is sensitive to both strain and material properties of depositional substrates. Hence, a detailed model is urgently needed with more accurate skull structure and mechanical properties. In this thesis, a new semi-automated method is proposed to build a more accurate skull model with microCT (µCT) scans. In addition to applying the new model in alveolar cleft repair, this new method can also be used to estimate remodeling algorithms incorporated with three dimensional (3D) finite element methods (FEM) script. In this way, finite element method (FEM) can been used to predict how mature bone partially remodels under mechanical loadings.

Committee: Gui-Rong Liu Ph.D. (Committee Chair); Yao Fu (Committee Member); Donna Jones Ph.D. (Committee Member) Subjects: Biomechanics

Bachelor of Science (BS), Ohio University, 2017, Biological Sciences

Osteoporosis is a disease characterized by diminished bone strength, resulting in an increased risk for fracture with minimal trauma. Though osteoporotic fractures present severe consequences for patients and health communities alike, there remains to be an accurate diagnosis for this disease. There are many characteristics that influence bone strength, ranging from mechanical, microstructural, to geometrical in nature. This project specifically aimed to assess cortical porosity, diameter, and bending stiffness as predictors of bending strength in the human radius. Data was collected from thirty cadaveric human radii from men and women between the ages of 17-99 years. Bending strength and bending stiffness were measured by the gold standard three-point bending method, quasi-static mechanical testing (QMT). Interosseous diameter was measured from both higher resolution µCT and lower resolution CT scans. Finally, cortical porosity was measured from µCT scans in the NIH image-processing software ImageJ. These measurements were guided by 3D Avizo models. Simple linear regression analyses revealed that bending stiffness predicted bending strength with the least amount of uncertainty (SEE=3.2 Nm). Cortical porosity demonstrated the weakest relationship with bending strength (SEE=12.0 Nm). Predictions of bending strength by µCT diameter were not different from those made by CT diameter (p=0.37). In comparisons of cortical porosity in the radius and ulna as imaged from the same arms, porosity at the 55%L of the ulna was the only unbiased predictor of radius porosity adjacent to the QMT fracture site (p=0.12). Thus, at the midshaft, cortical porosity of the ulna and radius appear to be indistinguishable.

Committee: Anne B Loucks PhD (Advisor) Subjects: Anatomy and Physiology; Biology; Cellular Biology; Endocrinology; Kinesiology; Medical Imaging; Molecular Biology; Morphology; Physiology

Doctor of Philosophy, The Ohio State University, 2015, Comparative and Veterinary Medicine

Cathepsin K (CatK), a cysteine protease, has been implicated in the process of bone resorption and inflammation. Selective inhibitors of CatK are promising therapeutic agents for the treatment of diseases associated with excessive bone loss and osseous inflammation, such as osteoarthritis, rheumatoid arthritis, periodontitis, osteoporosis, and multiple myeloma. Multiple reports have emerged over the last several years demonstrating the effect of different CatK inhibitors on osteo-inflammatory conditions. Therefore, the study of CatK inhibition as a target to prevent bone loss and inflammation, and influence bone marrow osseous progenitor cells, in a large animal model, is the subject of this dissertation. The horse was selected as the large animal model because this species suffers from ailments of adaptive bone remodeling in their sport performance and CatK inhibitors may serve as therapeutics in this species as well as serve as a large animal model for human applications. In the first phase of this work, we determined an optimal dose and dose interval for a CatK inhibitor (CatKI), VEL-0230, in healthy adult horses. Plasma pharmacokinetic (PK) and bone resorption biomarker [carboxy-terminal cross-linking telopeptide of type I collagen (CTX-1)] analyses were performed following single and multiple oral dose protocols of a CatKI (VEL-0230) in horses. Weekly administration of VEL-0230, at a dose of 4 mg/ kg body weight, provided effective inhibition of bone resorption in young exercising horses that returned to baseline within 7 days after drug withdrawal even after multiple doses. In the second phase of this work, we evaluated bone structure and turnover in healthy young exercising horses receiving repeated oral dosing of a CatKI in a randomized, controlled, double-blinded, prospective, sufficiently powered clinical trial. With the objectives of: 1. To determine whether repeated dosing of a CatKI produced a desired inhibition of the bone resorption biomarker (open full item for complete abstract)

Committee: Alicia Bertone PhD (Advisor); Maxey Wellman PhD (Committee Member); Prosper Boyaka PhD (Committee Member); Teresa Burns PhD (Committee Member) Subjects: Biology; Biomedical Research; Cellular Biology

Master of Science, The Ohio State University, 2015, Dentistry

Objective: The objective of the current study was to examine whether peri-implant bone tissue properties at the buccal region are different from those at the lingual region as a result of growth factor treatments at post-implantation healing periods. Methods: Four dental implant groups were used: titanium (Ti) implants, alumina-blasted zirconia implants (ATZ-N), alumina-blasted zirconia implants with demineralized bone matrix (DBM) (ATZ-D), and alumina-blasted zirconia implants with rhBMP-2 (ATZ-B). These implants were placed in mandibles of six male dogs. Nanoindentation elastic modulus (E) and plastic hardness (H) were measured for the buccal and lingual bone tissues adjacent and away from the implants at 3 and 6 weeks post-implantation. A total of 2281 indentations were conducted for 48 placed implants. Results: The peri-implant buccal region had less bone quantity resulting from lower height and narrower width of bone tissue than the lingual region. Buccal bone tissues had significant greater mean values of E and H than lingual bone tissues at each distance and healing period (p<0.007). Nearly all implant treatment groups displayed lower mean values of the E at the lingual bone tissues than at the buccal bone tissues (p<0.046) although the difference was not significant for the Ti implant group (p=0.758). Conclusions: The DBM and rhBMP-2 treatments stimulated more peri-implant bone remodeling at the lingual region, producing more immature new bone tissues with lower E than at the buccal region. Clinical Significance: This finding suggests that the growth factor treatments to the zirconia implant system may help balance the quantity and quality differences between the peri-implant bone tissues.

Committee: Damian Lee DDS, MS (Advisor); William Brantley PhD (Advisor); DoGooyn Kim PhD (Advisor) Subjects: Biomechanics

Master of Arts, The Ohio State University, 2010, Anthropology

Researchers have implemented many histomorphometric techniques to estimate age at death for human skeletal remains. While previous studies have reported relations between osteon size and age, few studies have focused on the shape of secondary osteons. Osteon circularity (On.Cr) is a factor potentially affecting histological estimations. Additionally, with age the numbers of observable osteons and osteon fragments increase and an asymptotic value for osteon population density (OPD) is eventually achieved. The cortex of bones reaches asymptote by 60 years of age, but it can occur as early as age 50. Once asymptote is reached, histological methods can no longer produce reliable age at death estimations. The purpose of this study is to establish if circularity differs between young and old age groups, and whether observed On.Cr is due to the effects of increasing OPD per unit area and osteon size (area; On.Ar) on the shape of osteons. To determine circularity, osteons were measured from thin (~100µm) cross-sections of femora and ribs of 29 individuals under and over the age of 50 from a modern cadaver sample of known age at death. The observed results support the observations of Currey (1964) and Britz et al. (2009) that osteon cross-sectional shape becomes more circular with age. With the increase in the number of osteons and their fragments per unit area (OPD) with age, the probability of eccentric and larger osteons surviving to be measured decreased considerably. This finding may be useful to help identify if a bone has reached its OPD asymptote, or even help refine our ability to estimate age for older individuals.

Committee: Sam D. Stout PhD (Committee Chair); Douglas E. Crews PhD (Committee Member); Clark Spencer Larsen PhD (Committee Member) Subjects: Biology; Microbiology; Physical Anthropology

Master of Science, The Ohio State University, 2008, Veterinary Clinical Sciences

Fracture of the right central tarsal bone (CTB) is a common injury in racing greyhounds. The aim of this study was to use standard radiography, computed tomography (CT), and histology to evaluate changes in CTB of racing greyhounds to determine an underlying cause of fracture. Paired tarsi from 12 racing greyhounds were evaluated; six dogs had sustained fractures to the right CTB. Radiographs and CT were evaluated on intact tarsi and dissected CTB. The bone mineral density gradient was calculated in the sagittal plane of each bone and on either side of fracture planes. Fractured right CTB had greater bone mineral density, in the dorsal and mid body regions, when compared to the contralateral CTB and non-fractured right CTB. Dorsal slab fractures occurred though zones of uniform density. Data from this study are the first to support the phenomenon of site specific remodeling in fractured right CTB of racing greyhounds.

Committee: Kenneth Johnson MVSc, PhD, DACVS, DECVS (Advisor); Valerie Samii DVM, DACVR (Committee Member); Steven Weisbrode VMD, MS, PhD, DACVP (Committee Member) Subjects: Veterinary Services

Bachelor of Science, Miami University, 2010, School of Engineering and Applied Science - Mechanical Engineering

This thesis investigates the factors influencing bone remodeling within the human skeleton with a focus on developing methods for constructing prosthetic bone scaffolds containing cells to progenerate into living bone upon implantation in the body. These porous scaffolds would ideally regulate events such as cellular proliferation and intracellular signaling after surgical implantation. The overarching goal is to identify materials, geometries, and other properties of the scaffold design in order to generate replacement tissue that replicates the original bone structure and geometry.Bone remodeling is the process of simultaneous removal of old bone and replacement with new bone powered by the coupled actions of osteoclasts and osteoblasts, cells that resorb bone and produce bone, respectively. While bone remodeling occurs more intensely during skeletal development, it continues throughout a human's lifetime, repairing microscopic damage resulting from stress and fatigue on the body. There are many different models that describe how remodeling may occur as well as what initiates the remodeling response to damaged bone. Historically, biologists explored tissue development primarily in terms of chemical and electrical signal pathways controlled by genes. However, recently published studies have implied that bone cells may be able to sense and react to mechanical forces. These forces likely have a crucial role in stimulating remodeling to occur based on the existing three-dimensional geometry of the bone and how well suited it is to handle the forces. Many independently published studies have investigated singular mechanical factors in the stimulation of bone remodeling as well as the resulting implications for the design of implanted skeletal scaffolds. However there remains a lack of publications that analyze multiple studies in order to examine their similarities and discrepancies. Reviews linking multiple studies are valuable tools for moving bone engineering theori (open full item for complete abstract)

Committee: Mr. Robert Setlock (Advisor); Dr. Osama Ettouney (Committee Member); Dr. James Moller (Committee Member) Subjects: Biomedical Research; Cellular Biology; Engineering; Materials Science; Mechanical Engineering; Mechanics

Master of Sciences (Engineering), Case Western Reserve University, 2011, EMC - Mechanical Engineering

Resorption cavities result from the activity of osteoclasts, cells that remove old or damaged tissue during bone remodeling. These cavities are believed to act as stress risers, potentially impairing bone strength and increasing fracture risk. Estrogen depletion has been associated with an increase in bone remodeling, but it is unclear whether the change is due to an increase in the number of cavities, surface area of individual cavities, or both. The distribution of stress concentration due to cavities may be related to their number and size, independent of the amount of bone remodeling. Here we present and validate the first, 3D approach to measuring individual resorption cavities in cancellous bone. Additionally, cavity number and surface area are compared in a standard animal model of post-menopausal osteoporosis, the ovarietomized rat.

Committee: Christopher Hernandez PhD (Committee Chair); Clare Rimnac PhD (Committee Member); Joseph Mansour PhD (Committee Member) Subjects: Biochemistry; Biology; Biomechanics; Biomedical Engineering; Biomedical Research; Cellular Biology; Health Care; Mechanical Engineering; Mechanics; Medical Imaging; Molecular Biology

Master of Sciences (Engineering), Case Western Reserve University, 2008, EMC - Mechanical Engineering

Osteoporosis is a disease characterized by high fracture risk and low bone mass. Bone mineral density is modified by a process known as bone remodeling. Bone remodeling is the resorption of bone by osteoclasts followed by deposition of new bone by osteoblasts. Because the resorption phase precedes formation, remodeling results in the formation of temporary cavities known as resorption cavities. Resorption cavities act as stress risers and are believed to impair fatigue properties and increase fracture risk. To better understand how bone remodeling affects the biomechanical properties of cancellous bone, images of bone and fluorescent markers of bone formation are collected through serial block face imaging. Images are collected using a computer numerically controlled mill with an attached fluorescence microscope. The techniques described here address factors contributing to imaging imprecision inherent to serial block face imaging using epifluorescence microscopy and allow direct measurement of resorption cavities.

Committee: Christopher Hernandez PhD (Committee Chair); Clare Rimnac PhD (Committee Member); Melissa Knothe-Tate PhD (Committee Member) Subjects: Biomedical Research; Computer Science; Electrical Engineering; Engineering; Mechanical Engineering

MA, University of Cincinnati, 2012, Arts and Sciences: Anthropology

Injury may be a significant locomotor cost, in that a severely injured animal may be unable to secure enough food to maintain normal activities, avoid predation, or find mates. Thus, safety is as likely as energetics to be the impetus of natural selection, and both have potential to impact reproductive fitness (Pontzer and Wrangham, 2004; Thorpe, 2005). The purpose of this study is twofold. First, to assess fracture patterns relative to variation in locomotion, ecology, and body mass among suspensory apes. Second, to quantify change in compact bone geometry associated with bone fracture and bone remodeling in suspensory apes. To obtain the first goal, fracture frequency, severity, and remodeling are examined in limb bones from skeletons of 141 wild-caught primates according to four major predictions. First, the suspensory genera will show a greater percentage of limb bone fractures than quadrupedal baboons. Second, among suspensory apes, the brachiating gibbons will have the highest fracture frequency and the most severe fractures, the quadrumanus orangutans will have frequent and severe fractures, but fewer than the brachiators, and the climbing and knuckle-walking chimpanzees will have the lowest fracture occurrence and severity. As a corollary, terrestrial quadrupedal baboons will have the lowest fracture frequency and severity. Third, fractures will be more prevalent in species with larger bodies. Fourth, fracture rate and severity will be greatest in species that travel on substrates higher in the forest canopy. The results show that body size is a significant predictor of fracture frequency. Increases in body size increase the likelihood of fracture. Travel height and locomotor strategy are not significant predictors of fracture frequency. However, the dual locomotor strategy and low travel heights used by Pan have a negative relationship with deformity and remodeling. Such strategies may provide an evolutionary advantage, as fractures incurred by Pan are le (open full item for complete abstract)

Committee: Katherine Whitcome PhD (Committee Chair); Brooke Crowley PhD (Committee Member) Subjects: Physical Anthropology

Doctor of Philosophy, The Ohio State University, 2023, Mechanical Engineering

Finite element method (FEM) is a numerical method that is widely used for obtaining approximate solutions to various engineering and research problems. In material science, FEM is used to simulate the mechanical response of materials under dierent loadings and to guide the design of materials with targeted properties. Generating high-delity nite element (FE) models of materials with complex microstructures, such as composite materials, requires generating realistic virtual microstructures of materials that are statistically equivalent to the actual microstructure and converting them to high-delity FE meshes. Choosing appropriate mechanical models and material properties for materials is also a fundamental challenge to obtaining an accurate simulation result. In this thesis, advanced computational frameworks are introduced to overcome these challenges, including creating realistic virtual microstructures of materials by algorithm, developing new damage models, and applying articial intelligence (AI) techniques to the model of materials with complex microstructures. Several numerical techniques are presented to model materials and analyze their micromechanical behaviors. Two new high-cycle fatigue damage models are introduced for modeling mechanical performance under cyclic loading to predict the fatigue life of heterogeneous adhesives, one for the matrix and the other for the particle-matrix interfaces. An automated computational framework is developed to simulate the performance of adhesives under cyclic loading. High-delity nite element models of this adhesive's representative volume elements (RVEs) are generated using an automated computational framework, enabling the virtual reconstruction of the microstructure and mesh generation. These 3D FE models are used to calibrate the fatigue damage model parameters with fatigue test data under dierent loading conditions. Another example presents a high-delity FE model, constructed based on (open full item for complete abstract)

Committee: Soheil Soghrati (Advisor); William Marras (Committee Member); Alok Sutradhar (Committee Member) Subjects: Mechanical Engineering

Doctor of Philosophy, The Ohio State University, 2012, Anthropology

During skeletal growth, long bones must change in size, shape, and relative position. This is accomplished diametrically by a process called bone modeling, which has been evidenced microscopically by patterned remnants of periosteal and endosteal bone distributions. It is the asymmetry of these distributions, or modeling drift, that accomplishes morphological change in the diaphysis. Until now, human modeling drift histomorphometry has received little attention. Previous research demonstrated a collection of specific histomorphological features could be used as a meta-feature, indicating the microscopic remnants of drift. This meta-feature, the endosteal lamellar pocket (ELP), is characterized by hemicircumferential lamellar orientation, primary Volkmann's canals, and a relative decrease in the number of osteons compared to surrounding internal tissues. The current study provides a novel tissue level perspective, assessing human skeletal variation via quantification of ELP presence, position, and morphology in the humerus in order to discuss drift among individuals. Two distinct skeletal populations are compared: one archaeological, and the other, a modern control sample with known age and sex. Mid-diaphyseal, thin ground cross-sections are analyzed using custom point-count and hand-drawn techniques. Results provide: 1) an evaluation of the use of endosteal tissue, specifically the ELP, as a summary of drift; 2) an comparative assessment of the two methods used in the analysis; 3) a comparison between the position of Imax, as an indicator of adaptation to mechanical loading, with the drift direction suggested by the position of the ELP; and 4) a baseline for variance in ELP characteristics against the background of periosteal and secondary bone distributions by region across subgroups generated by sex, age category, and population sample. Results indicate the ELP is a viable means of measuring and comparing modeling drift among subgroups. Both techniques work well u (open full item for complete abstract)

Committee: Sam Stout Ph.D. (Advisor); Clark Larsen Ph.D. (Committee Member); Paul Sciulli Ph.D. (Committee Member) Subjects: Archaeology; Biology; Histology; Physical Anthropology

Master of Science, The Ohio State University, 2010, Dentistry

Objective: The purpose of this study was to quantify the bone remodeling in the jaws of skeletally immature dogs, specifically in the bone surrounding fully erupted primary teeth. Information on skeletal turnover in a young age group is important to better understand bone metabolism during health and disease, growth and development, and tooth eruption. Methods: Four skeletally immature (5 month old) beagle dogs were used to examine bone turnover. Thirty-two bone sections total were obtained bilaterally in each jaw from the bone supporting the primary molars of the maxilla and mandible. Histomorphometric methods were used to estimate the intracortical secondary osteonal remodeling. The following variables were calculated: mineral apposition rate (MAR, µm/day), mineralizing surface/bone surface (MS/BS, %), erosion surface/bone surface (ES/BS, %), and bone formation rate (BFR, %/year), and compared between jaws (maxilla vs mandible) and bone types (alveolar vs. basal). BFR, %/year was the variable of greatest interest as it can be compared to other data and includes mineral apposition rate and mineralizing surface in its calculation. These measurements were also compared to existing data from skeletally mature dogs (1-2 years). Results: The mean (SD) BFR were as follows: Md. Alveolar: 44.10(26.89), Mx. Alveolar: 3.54(3.57), Md. basal: 22.65(14.65), Mx. basal: 12.33(7.11). The mandibular BFR was significantly (p<0.05) higher than the maxillary bone. The BFR of the alveolar bone of the skeletally immature dogs was not significantly (p=0.48) different from skeletally mature dogs. Conclusion: The remodeling rate of alveolar bone in skeletally immature dogs was greater in the mandible than in the maxilla and remained constant between primary and permanent dentitions.

Committee: Sarandeep Huja DDS, PhD, Associate Professor (Advisor); Zongyang Sun DDS, MS, MSD, PhD, Assistant Professor (Committee Member); F. Michael Beck DDS, MS (Committee Member) Subjects: Biology

Doctor of Philosophy, Case Western Reserve University, 2011, EMC - Mechanical Engineering

It has been suggested that bone remodeling targeted to microscopic tissue damage can impair trabecular bone biomechanical properties, potentially modifying overall bone strength. In this study, we evaluate microscopic tissue damage and remodeling cavities using experimental and computational methods. Cyclic loading experiments were performed on isolated rat caudal vertebrae (n=24) to evaluate the progression of microscopic tissue damage in trabecular bone in-vitro. Vertebrae were potted in bone cement and subjected to cyclic loading between 0 – 260N. Cyclic loading was terminated at secondary and tertiary phases of the creep-fatigue curve. Trabecular microfracture was the primary form of damage in trabecular bone and the number of microfractures increased with the amount of cyclic loading. Only small amounts of microscopic tissue damage were observed in the cortical shell, demonstrating that the damage occurs in trabecular bone prior to complete fracture of vertebrae. Modifications to the rat tail loading model developed by Chambers and colleagues were considered to evaluate the feasibility of using the model to generate microscopic tissue damage in trabecular bone without fracturing the vertebrae in-vivo. Protocols were developed to apply cyclic loading to caudal 8th vertebrae (C8) in-vivo (n=20) or in-situ (n=15). Two pin types: smooth and threaded, two pin sizes: 1.6mm and 2.0mm dia. and four time points after the surgery: 0, 1, 2 and 4 weeks were considered. Our results indicated that the rat tail loading model may not be used for generating microscopic tissue damage in trabecular bone in-vivo. Finite elements models of idealized trabeculae were generated to determine a potential range for stress concentrations factors of remodeling cavities. Two types of trabecula: rod-like and plate-like and two types of loading conditions: pure tension and pure bending were considered. Finite element models of two rod-like and three plate-like rat trabeculae were generated (open full item for complete abstract)

Committee: Christopher Hernandez (Committee Chair); Clare Rimnac (Committee Member); Joseph Mansour (Committee Member); Eben Alsberg (Committee Member) Subjects: Biomechanics; Biomedical Engineering; Mechanical Engineering