Doctor of Philosophy, The Ohio State University, 2024, Biomedical Engineering

The lens is the pivotal tissue of the eye allowing accommodation, the process by which the eye adjusts focal distance. Presbyopia and cataract, age-associated lens dysfunctions, prevent proper accommodative function and focusing of light as it passes through the lens. As the eye ages, lenses continue to grow in size and stiffen. As these properties change with age, lenticular dysfunctions arise. Presbyopia is incredibly common, impairing near vision in nearly all people by 40 to 50 years of age. A significant portion of the population lives with imperfect near vision due to presbyopia. The exact causes of presbyopia are yet to be explained, and additionally, there remain no effective therapies capable of restoring, or preventing the loss of, full accommodative function in aged lenses. It is now understood that both lens stiffening and lens geometric change due to continual lens growth, lead to presbyopia. Recent studies have demonstrated that mechanical force transduction, through the zonular fibers to the lens capsule, increases lens epithelial cell proliferation. These findings offer an avenue of study that could reveal mechanisms governing lens growth and guide future lens treatment options. Some clinical practitioners consider presbyopia and cataract to be entirely treated through the use of spectacles and implanted artificial intraocular lenses; however, no preventative therapy exists and no current treatment is capable of restoring accommodation. Advancement in the understanding of lens cell biology, mechanics, and the lens epithelial cell (LEC) mechanobiological response is necessary for the improvement of clinical treatment for age-associated lens dysfunction. This dissertation seeks to describe a new branch in the field of lens study with hopes of expanding fundamental knowledge focusing on LEC growth and mechanobiology. First, a novel method of simulating accommodation-like forces in a murine eye model is detailed. The methods described here demo (open full item for complete abstract)

Committee: Katelyn Swindle-Reilly (Committee Member); Cynthia Roberts (Committee Member); Heather Chandler (Committee Member); Matthew Reilly (Advisor) Subjects: Biology; Biomechanics; Biomedical Engineering; Biomedical Research; Ophthalmology; Optics

Doctor of Philosophy, Case Western Reserve University, 2022, EMC - Mechanical Engineering

Cellular processes strongly regulate the biophysical and biomechanical properties of each blood cell including density, adhesion, and motility, all of which can rapidly change during various healthy and pathological states. To have a better understanding of the cellular processes, an assessment of the biophysical and biomechanical signatures of single cells is needed. Microfluidics has the remarkable ability to mimic the physiological environment of microvasculature, providing a means to better characterize biomechanical and biophysical signatures of blood cells, such as adhesive interactions between different blood cells. As a result, microfluidics has found applications in studies of many different pathophysiologies that stem from altered biomechanical and biophysical properties of blood cells. Despite the advances in microfluidics for the characterization of the biophysical and biomechanical properties of blood cells, the use of microfluidics for mechanistic and mechanobiology studies remains limited due to a lack of standardization and single-cell level imaging. Microfluidics can harness image analysis for standardized characterization of fundamental properties of single cells and reveal subpopulations in heterogeneous cell populations to unfold the mechanobiology and mechanisms of physiology reliably. This dissertation presents the design and engineering of standardized microfluidic systems that utilize image analysis at various technical complexity levels (i.e., manual pixel-to-pixel distance measurements, and automated computer vision with and without machine learning). These microfluidic single-cell level imaging systems demonstrate effective multi-variate measurement of blood cells' biophysical and biomechanical properties and inform the investigation of microcirculatory cellular action mechanisms. The specific aims of this dissertation were: 1) To develop a microfluidic magnetic levitation platform that can perform size and density measurements of single r (open full item for complete abstract)

Committee: Umut Gurkan (Advisor); Bryan Schmidt (Committee Chair); Michael Hinczewski (Committee Member); Ozan Akkus (Committee Member) Subjects: Biomechanics; Biomedical Engineering; Biophysics

Master of Science, The Ohio State University, 2022, Biomedical Engineering

The motor-clutch model is a mechanosensing model that enables cells to probe their extracellular environment via interactions between myosin motors and molecular clutches through actin filaments. While two substrate-dependent behaviors have emerged from this model, there has been a third type of behavior that has also been discovered, characterized by high molecular clutch engagement with actin and prolonged bond lifetimes, which was described as super-loading. While it has been theorized that it can occur on super soft substrates in the absence of clutch reinforcement mechanisms, it can also occur on intermediate to stiff substrates when clutches undergo reinforcement, as shown from previous studies. In this study, the mechanisms influencing super-loading behavior were examined focusing exclusively on intermediate to stiff substrates through analysis of the effects of the initial binding rate, the reinforcement rate, and changes in the clutch-to-motor (CMR) ratio. It was found that the initial binding rate is able to influence what types of behaviors the motor-clutch model can exhibit and can even prevent certain behaviors from occurring, regardless of the incorporation of clutch reinforcement. While reinforcement rates were able to shift cell traction, spreading velocity, and clutch engagement as well, they did so mostly on intermediate to stiff substrates. Because reinforcement rates had to be increased 10-fold from the base parameter values to induce super-loading on stiff substrates, it was additionally sought to determine if modifying the CMR could allow for super-loading to occur under minimally increased rates of reinforcement and initial binding rates. Ultimately, super-loading could be observed on both intermediate and stiff substrates at higher CMR ratios and in most initial binding rates. In cases where the initial binding rate was increased, higher CMRs could achieve a near-stalled system, characterized by super-loading on all substrate stiffne (open full item for complete abstract)

Committee: Seth Weinberg (Committee Member); Keith Gooch (Advisor) Subjects: Biomedical Engineering; Biomedical Research

Doctor of Philosophy, The Ohio State University, 2021, Biophysics

A defining characteristic of complex life is the capacity to integrate a variety of stimuli from the environment and, through the interaction of a dizzying array of biomolecules, to properly interpret and respond to such stimuli. Gene duplications and random mutations, when filtered through the sieve of natural selection, provides living organisms with the creative power needed to produce the suite of highly specialized molecules required to perform the vital task of sensing environmental cues. From maintaining balance by harnessing the power of gravity in vertebrates, to the detection of a dangerous shift from diffusive equilibrium in yeast cells, proteins play a vital role in detecting changes in the environment of all living organisms. Central to the function of many of these proteins is the transmission or detection of mechanical forces applied to the proteins themselves, or to surrounding cellular structures and tissues in which they are embedded. Such force sensitive proteins are thus ideal subjects of single-molecule, quantitative biophysical approaches to better understand the molecular basis of force transduction. Examples of such proteins are cadherin-23 (CDH23) and protocadherin-15 (PCDH15), two proteins required for vertebrate hearing; desmoglein (DSG) and desmocollin (DSC), two proteins that are vital for maintaining tissue integrity in the presence of constant mechanical stress; and transient receptor potential yeast 1 (TRPY1), a mechanically-sensitive ion channel in yeast that restores osmotic balance in response to hyperosmotic shock. While these proteins are involved in unrelated biological processes, they all have evolved the ability to detect and respond to force generated by environmental sources, and their proper function is vital to the survival of the host organism. Here, a multidisciplinary approach is used to provide fundamental insights into the structure, mechanical properties, and dynamics of these specific proteins, as well as into pro (open full item for complete abstract)

Committee: Marcos Sotomayor Dr. (Advisor); Steffen Lindert Dr. (Committee Member); Rafael Brüschweiler Dr. (Committee Member); Charles Bell Dr. (Committee Member) Subjects: Biochemistry; Biophysics

PhD, University of Cincinnati, 2021, Engineering and Applied Science: Chemical Engineering

Peripheral nervous system (PNS) injuries currently lack effective treatments for regaining full functional recovery, and thus remain a major challenge in healthcare. Schwann cells (SCs) as the principal glial cells within the PNS, play a vital role in peripheral nerve regeneration due to their inherent capacity for altering phenotype to enhance the regenerative capacity of the PNS post injury. However, the regenerative phenotype of SCs is challenging to maintain through the time-period needed for regeneration and can be impacted by the properties of the surrounding extracellular matrix (ECM) such as protein composition and stiffness. Furthermore, the properties of the ECM also regulate cell morphology including spreading area and cellular elongation, which directly impact SC regenerative capacity. Therefore, deciphering the complex interplay between SCs and the ECM to provide alternative therapeutic solutions for enhancement of regenerative potential in SCs leader to functional recovery in traumatic nerve injury is essential. To address the role the ECM plays in SC phenotype, this research mechanistically analyzes how matrix stiffness, cell morphology, and protein composition cooperatively control regenerative phenotype. In this work, ECM proteins were adsorbed onto mechanically tunable polydimethylsiloxane (PDMS) substrates, which provided a cell culture platform where stiffness and protein composition can be modulated. SCs were cultured on tunable substrates as critical cellular functions and transcriptional factors that represent the dynamics of SC phenotypes were assessed at differing time points. To illustrate the dynamic reciprocity between a regenerative phenotype and cell morphology, single-cell microcontact-printed cell adhesive patterns and line-patterned substrates were utilized, and SC regenerative phenotypes were characterized by immunofluorescence (IF) staining, western blot, and microarray assay. Lastly, SCs were grown on tunable or patterned sub (open full item for complete abstract)

Committee: Greg Harris Ph.D. (Committee Chair); Yoonjee Park Ph.D. (Committee Member); Aashish Priye (Committee Member); Jason Shearn Ph.D. (Committee Member) Subjects: Cellular Biology

Doctor of Philosophy, The Ohio State University, 2021, Biomedical Engineering

The human body is a complex mechanical environment that exposes cells to variations in both passive and active forces, where forces vary depending on tissue type, location, and function. Recent work has been done to analyze how the mechanical environment changes in different disease states and the effects of these changes on organ and cellular function. As a result, there are several well-known changes in in vitro cellular behavior in response to perturbations in the mechanical environment including: cell shape, size, phenotype, and differentiation. While other groups have begun to distinguish key components related to cell sensing of the mechanical environment, the exact mechanism remains poorly understood. The motor-clutch biophysical model describes cytoskeletal dynamics as a balance between substrate adhesion, myosin contractility, and actin polymerization. Initially, the model was hypothesized as a mechanism to explain cellular traction force generation and resultant actin flow. An initial computational formulation of the motor-clutch system demonstrated that it accurately predicts changes in neuronal cell behavior as a function of changes in extracellular substrate stiffness. Here we adapt the computational motor-clutch model to include external substrate motion as a means of simulating cyclic substrate deformation. We then use this adapted model to study the combined effect of cyclic substrate deformation and substrate stiffness on actin cytoskeleton organization and dynamics. The goal of this work was to demonstrate that the motor-clutch model can be used to predict and explain distinct cellular responses to applied cyclic strain. Furthermore, the adapted model allows for the study of experimental parameter spaces that are otherwise difficult to re-create experimentally. We found that the model predicts that applied cyclic stretch significantly impacts actin traction force generation and adhesion dynamics. Importantly, adhesion dynamics are finely co (open full item for complete abstract)

Committee: Keith Gooch PhD (Advisor); Aaron Trask PhD (Committee Member); Thomas Hund PhD (Committee Member); Seth Weinberg PhD (Committee Member) Subjects: Biomedical Engineering

Master of Sciences (Engineering), Case Western Reserve University, 2020, Biomedical Engineering

The project goal is to dissect the mechanical feedback of cells onto the extracellular matrix (ECM) using De Novo ECM synthesis and traction force microscopy (TFM). In this thesis, we devised a method to apply traction force microscopy to De Novo ECM. We first stimulated 3T3s to synthesize ECM (>=20μm in 10days) using ascorbic acid with experimental conditions of hyperglycemia. After cell removal by lysis, the ECM was measured with AFM and fresh cells were replated for TFM. To achieve TFM on de novo ECM, we developed a serial labeling approach to deposit carboxylated fluorescent beads during multi-day ECM synthesis. We observe that ECM stiffness is increased in high vs low glucose. We also observe a unimodal response of cell traction to increasing stiffness in polyacrylamide substitutes. With the generated TFM bead displacement data, we plan to analyze 3t3s replated onto bead-labeled de novo ECM to better understand the mechanical response of cells.

Committee: Samuel Senyo PhD (Committee Chair); Zheng-Rong Lu PhD (Committee Member); Ozan Akkus PhD (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2020, Biomedical Engineering

The lens is a pivotal organ in the eye; playing a crucial role in the process of accommodation, by which the eye is able to alter its focal distance. The lens continuously grows in size throughout the lifetime, unlike the globe which maintains a constant size from adulthood. This growth is a result of lens epithelial cell (LEC) proliferation, which ultimately leads to an increase in the number of fiber cells. Changes in the size, stiffness, and shape of the lens contribute to the etiology of age-related refractive issues in the lens, namely presbyopia, and cataracts. Additionally understanding the forces that control the proliferation of LECs has implications in developing therapies for posterior capsule opacification (PCO) and translational research in clinical applications for lens regeneration. The processes governing the growth of the lens are therefore of great clinical interest; however, they are not fully understood. This dissertation considers the broadest context of the translational utility of understanding lens growth, beginning with the long-term goal of regenerating a lens following cataract extraction. This review is followed by the first basic science studies investigating mechanobiological regulation of lens growth. This represents a significant step towards understanding lens biology since, to date, all such studies have been conducted without consideration for the refractive state of the lens. In the first study, and for the first time, LECs were found to be mechanosensitive in vitro using a bespoke stretching device. The LEC proliferation rate was found to depend strongly on the amplitude and frequency of stretching. This dependence was effectively eliminated via chemical inhibition of yes-associated protein (YAP) activation using verteporfin. These findings suggest that zonular tension is a major driving force for lens growth. The second study investigated the localization of proliferative activity. This spatial distribution of prolif (open full item for complete abstract)

Committee: Matthew Reilly PhD (Advisor); Cynthia Roberts PhD (Committee Member); Heather Chandler PhD (Committee Member) Subjects: Biomedical Engineering; Ophthalmology

Doctor of Philosophy in Engineering, Cleveland State University, 2019, Washkewicz College of Engineering

Development of nervous system has been greatly explored in the framework of genetics, biochemistry and molecular biology. With the growing evidence that mechanobiology plays a crucial role in morphogenesis, current studies are geared towards understanding the role of mechanical cues in nervous system development and progression of neurological disorders. Formation, maturation and differentiation of various development related cells are sensitive to extrinsic and intrinsic perturbations. Based on this hypothesis, the objective of this study was to investigate the effects of environmental toxicants, mutations in molecular clutch proteins, and matrix stiffness cues on the biophysical, biomechanical, and phenotypic changes in brain-derived neural progenitor cells (NPCs) and microglia. In the first aim, we established the utility of biophysical and biomechanical properties of NPCs as indicators of developmental neurotoxicity. Significant compromise (p < 0.001) in NPC mechanical properties was observed with increase in concentration (p < 0.001) and exposure duration (p < 0.001) of four distinct classes of toxic compounds. We propose the utility of mechanical characteristics as a crucial maker of developmental neurotoxicity (mechanotoxicology). In the second aim, we elucidated the critical role of molecular clutch proteins, specifically that of kindlin-3 (K3) in murine brain-derived microglia, on the cell membrane mechanics and physical characteristics. Using genetic knockouts of K3 and AFM analysis, we established the role of K3 in regulating microglia membrane mechanics.Mutation at the K3-β1 integrin binding site revealed that the connection serves as the major contributor of membrane to cortex attachment (MCA). Finally, in aim 3, we identified the molecular mechanisms (non-muscle myosin II) by which NPCs transduce mechanical input from external substrate into fate decisions such as differentiation and phenotype. We established cell mechanics as a label-free marker of d (open full item for complete abstract)

Committee: Chandra Kothapalli (Advisor); Moo-Yeal Lee (Committee Member); Nolan Holland (Committee Member); Xue-Long Sun (Committee Member); Parthasarathy Srinivasan (Committee Member) Subjects: Biomechanics; Biomedical Engineering; Biomedical Research; Biophysics; Engineering; Materials Science; Mechanics; Neurosciences

Doctor of Philosophy, The Ohio State University, 2017, Biomedical Engineering

Glioblastoma is a highly lethal brain tumor for which patient survival times have remained around 14 months for the past 40 years. The lethality of the disease is driven by the invasive nature of the tumor, which results in substantial infiltration throughout the brain parenchyma. These cells that are migrating further from the tumor are able to avoid surgical resection and radiotherapy. As a result, this places a greater burden on chemotherapy to eradicate the remaining tumor cells. Most often, temozolomide(TMZ), the gold standard chemotherapeutic, fails to meet this objective and a treatment-resistant tumor recurs, to which the vast majority of patients will succumb. The problem with chemotherapy is two-fold. First, TMZ is a genotoxic drug, so tumor cells that are resistant to DNA damage-induced apoptosis are able to survive and serve as the genetic basis of the recurrent tumor. In order to eliminate enough tumor cells to prevent a recurrent tumor, new drug targets are needed. Combination therapy has been the most effective approach to cancer treatment (i.e. surgery, radiation, and chemotherapy) and it is likely that the future of glioblastoma research will involve additional chemotherapies. Second, drug delivery to the brain is poor because of the blood-brain barrier (BBB). Therefore, this dissertation has characterized and probed the mechanical microenvironment to build towards new drug targets for patient treatment. Additionally, a drug carrier is characterized for its ability to cross the BBB, to improve drug delivery to the brain.

Committee: Jessica Winter PhD (Advisor); Jose Otero MD, PhD (Committee Member); Samir Ghadiali PhD (Committee Member); Keith Gooch PhD (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2017, Anthropology

The objective of this research was to test the hypotheses that ontogenetic patterns of change in tibial subchondral trabecular and cortical bone microstructure are age and condyle site-specific due to differential loading associated with changing joint kinetics and body mass. High-resolution computed tomography (HR-CT) images were acquired for 31 human tibiae, ranging in age from 8 to 37.5 years. The skeletal samples are from Norris Farms #36 site, a cemetery mound in the central Illinois River valley associated with the Oneota culture, dating to A.D. 1300. This bioarchaeological sample was chosen for this study because of its cultural and biological homogeneity, high number of subadult individuals, extensive archaeological context, and excellent preservation. Proximal epiphyses were digitally isolated for analysis as regions of interest (ROIs) using Avizo Fire 6.2 and 8.1.1. 3D resolution-corrected morphometric analysis of subchondral bone architecture was performed for 11 cubic volumes of interest (VOIs) using the BoneJ plugin for ImageJ. VOIs were positioned within and between the tibial condyles within the epiphyseal region. The analysis of the subchondral cortical plate was accomplished through dual-threshold cortical masking. Ontogenetic patterns in the epiphysis of the proximal tibia were described using eight 3D morphological parameters: bone volume fraction (BV/TV), mean trabecular thickness (Tb.Th), mean trabecular spacing (Tb.Sp), structure model index (SMI), connectivity density (Conn.D), degree of anisotropy (DA), trabecular number (Tb.N), and cortical thickness (Ct.Th) in the subchondral cortical plate. Kruskal-Wallis and Wilcoxon signed rank tests were used to examine the association between region, age, and each of the eight structural parameters. For analysis, individuals were divided into four age categories: child, adolescent, young adult, and middle age. The findings of this study indicate that age-related changes in mechanical loading have (open full item for complete abstract)

Committee: Samuel Stout PhD (Advisor); James Gosman M.D, PhD (Committee Member); Mark Hubbe PhD (Committee Member); Clark Larsen PhD (Committee Member); Scott McGraw PhD (Committee Member) Subjects: Aging; Anatomy and Physiology; Archaeology; Behavioral Sciences; Biology; Biomechanics; Evolution and Development; Microbiology

Doctor of Philosophy, The Ohio State University, 2016, Anthropology

The significance of the microstructural interface between trabecular and cortical bone in the long bone metaphyses as a mechanically-adapted feature of skeletal morphology is largely unexplored, despite the role of these structures as critical for the transmission of axial loads from the trabecular network to the cortical diaphysis. These cortical-trabecular junctions (CTJs) are studied here within the context of bone ontogeny and from the perspective of mechanobiology, which seeks to interpret skeletal morphology as a product of its mechanical-functional demands. Aligned to the theoretical paradigm of bone functional adaptation, which states that bone adapts to its mechanical environment during life, this study tests several hypotheses regarding various associations between body mass and age on the one hand and various measures of CTJ structure on the other, including elements of cortical-trabecular connectivity and bone volume distribution. Anatomical site variability and mechanical adaptability in CTJ ontogeny was further addressed by examining these skeletal features in two separate skeletal elements with vastly different mechanical functions. This study was performed conducted using the Norris Farms (NF) No. 36 skeletal series, an archaeological sample of skeletons derived from a late-prehistoric group of Oneota Native Americans living in present day west-central Illinois ca. 1300 A.D. Micro-computed tomography was used to acquire high-resolution images of NF adult and sub-adult tibiae and humeri for non-invasive and non-destructive analysis of internal bone microstructure. Two computer image analysis programs (Avizo Fire 8.1.1 and ImageJ 1.49v) were used to isolate and quantify volumes of interest, and all statistical analyses were carried out in SPSS v.22. Results show a complicated picture of CTJ ontogeny in which mechanical adaptability appears to be an important driver of CTJ structural development, but not to the exclusion of other, less clear factors. (open full item for complete abstract)

Committee: Clark Larsen (Advisor); James Gosman (Committee Member); Amanda Agnew (Committee Member); Paul Sciulli (Committee Member); Sam Stout (Committee Member) Subjects: Anatomy and Physiology; Archaeology; Biomechanics; Human Remains; Physical Anthropology; Soil Sciences

Doctor of Philosophy, The Ohio State University, 2014, Biomedical Engineering

Cells in vivo are constantly exposed to mechanical stimuli originated from their extracellular environment, such as the contraction from cardiac muscle and the laminar shear from blood flow. These mechanical stimuli are essential for maintaining cellular functions and regulating cellular behaviors in many physiological processes. Hence, it is important to understand how mechanical stimuli induce cellular responses. This requires specific tools that can deliver controllable mechanical signals in magnitude, duration, frequency, and direction. To this end, many engineered cell loading tools have been developed for applying different types of mechanical loads to in vitro cultured cells to trigger different types of cellular responses. By using these tools, it has been demonstrated that cyclic mechanical loads can regulate cell alignment, migration, proliferation, apoptosis, and can affect stem cell differentiation. Nonetheless, current cell loading tools still have many limitations. For example, tools with conventional-scale loading sites are often with low throughput, since few loading site can be arranged onto the limited space of a tool. Moreover, the large loading site inevitably leads to unnecessary consumption of precious cells and reagents, especially when the study requires parallel and multiplexed loading parameters. Tools with miniaturized loading sites can largely increase the loading throughput. However, device fabrication and assembly are increasingly challenging when the dimension of the loading site decreases. Moreover, the magnitudes of the simultaneously applied mechanical loads at different loading sites are not well controllable, especially at the dynamic loading conditions. Besides, most of the tools are designed for loading 2D cultured cells, while specific tools for loading 3D cells are still in need. To address these limitations, this thesis describes the development of elastomeric-membrane-based cellular micromechanical stimulators for mec (open full item for complete abstract)

Committee: Yi Zhao (Advisor); Derek Hansford (Committee Member); Xiaoming He (Committee Member) Subjects: Biomedical Engineering

Master of Sciences (Engineering), Case Western Reserve University, 2012, Biomedical Engineering

The periosteum serves as a stabilizing boundary membrane to the bone it envelopes and contains mechanosensitive progenitor cells capable of promoting new bone formation. Knowledge of the structure-function relationships underlying the dynamic mechanical and regenerative properties of the periosteum is lacking. The following work investigates the structure-function relationships present in periosteum at both the tissue and cellular level. At the tissue level, periosteum permeability is characterized and found to exhibit barrier membrane properties. Subsequently, cell scale studies investigate the molecular characteristics of periosteum cells responsible for enabling tissue-level barrier membrane properties. Lastly, a biomimetic membrane system for investigating cell-cell adhesions of periosteum cells is developed. Culture of periosteum cells on the model membrane system results in signs of early osteogenic lineage commitment. Characterization of structure-function relationships in periosteum across multiple lengths scales provides knowledge valuable for the development of predictive computational models and tissue engineered periosteal replacement membranes.

Committee: Melissa Knothe Tate PhD (Committee Chair); Gerals Saidel PhD (Committee Member); Joseph Mansour PhD (Committee Member) Subjects: Biomechanics; Biomedical Engineering; Biomedical Research

Doctor of Philosophy, Case Western Reserve University, 2010, Biomedical Engineering

Mechanical forces are hypothesized to modulate periosteal bone generation during development, growth, healing and aging, in health and disease. A multi-scale understanding of periosteal osteochondroprogenitor cells and the periosteum tissue environment allows researchers and clinicians to develop surgical techniques, post-surgical physical therapies, and implants that harness the regenerative capacity of the periosteum and periosteal cells to repair tissue damage such as fractures or critical-sized defects. This research aims to bridge the gap between cellular, tissue, and organ levels using cellular and tissue studies as well as clinical models. Using in vitro to ex vivo models, the following work identifies the mechanosensitivity of progenitor cells, the mechanical properties of the periosteum, and the prevailing loads that promote periosteal de novo bone generation in a critical-sized defect. Progenitor cells are incredibly sensitive to the mechanics of their environment (i.e. cell density and three-dimensionality of culture) and applied shear stress. In vitro experiments demonstrate that genes associated with the first stages of skeletogenesis are significantly up- and down-regulated in response to both factors. In fact, shear stresses two orders of magnitude less than those needed to stimulate differentiated osteogenic cells can alter genetic expression in progenitor cells in as little as 30 minutes. The tissue environment periosteal progenitor cells inhabit, the periosteum, is also remarkably responsive to different mechanical stimuli. Mechanical testing reveals that the periosteum is highly prestressed in situ and anisotropic. Upon removal from the underlying bone, periosteal samples will shrink to approximately half of their in situ area. Most of the shrinkage occurs in the axial direction. Likewise, when large strains are applied the periosteum is five fold stiffer in the axial direction than in the circumferential direction. Finally, ex vivo clinical mo (open full item for complete abstract)

Committee: Melissa Knothe Tate PhD (Advisor); Edward Greenfield PhD (Committee Member); Horst von Recum PhD (Committee Member); Clare Rimnac PhD (Committee Member); Joseph Mansour PhD (Committee Member) Subjects: Biomechanics; Biomedical Engineering; Biomedical Research