Master of Science, The Ohio State University, 2009, Mechanical Engineering

The natural history of focal cartilage defects is not entirely understood, but defect size is believed to be a critical factor in the success of surgical repair procedures. Clinical repair algorithms have identified 2 cm2 as the threshold area between marrow-stimulation techniques and cartilage restoration techniques, although there is little evidence to support this threshold. Studies examining this threshold size have used circular defects, while narrow, elongated defects are more clinically relevant. Furthermore, our clinical experience suggests that two defects of approximately equal size, but oriented differently, will exhibit different repair outcomes. We first sought to identify how cartilage defect area, location, and orientation influence subchondral bone contact within oval-shaped defects. We used cylindrical punches to create bilateral oval defects with areas between 0.73 cm2 and 2.88 cm2 on the femoral condyles of twelve bovine knees. Four defect groups were examined, each comprised of defects in one of two orientations, anterior-posterior or medial-lateral, on the medial or the lateral femoral condyle. We statically loaded fully-extended joints in a uniaxial testing system, while thin-film sensors recorded joint contact, and we calculated the area within the defect demonstrating subchondral bone contact. We then performed a three-way analysis of variance (ANOVA) and determined that defect area, location, and orientation each had a significant effect on subchondral bone contact, and significant interactions were found between defect area and both location and orientation. We also determined that each defect group exhibited a different area threshold where significant contact first occurred. The findings of this study challenge current clinical algorithms that use defect area alone to dictate one cartilage surgery over another. Cartilage defect size, location, orientation may impact the treatment of focal cartilage defects, but there are no methods to ac (open full item for complete abstract)

Committee: Robert Siston PhD (Advisor); Ajit Chaudhari PhD (Committee Member) Subjects: Biomedical Research; Engineering; Mechanical Engineering; Surgery

Master of Science, The Ohio State University, 2024, Biomedical Engineering

The objective of this study was to quantify how costal cartilage affects rib properties. Fifteen bilateral pairs of 5th human ribs were included in this study. One rib within each pair was tested without costal cartilage while the other rib within each pair was tested with costal cartilage. All ribs underwent AP loading until failure at 2 m/s to simulate that of a frontal impact. Results showed a significant difference in peak force, structural stiffness, CSG2 strain at yield, and PSG2 strain at yield between ribs with costal cartilage and ribs without costal cartilage. On average, the ribs with costal cartilage had a lower force but higher displacement and longer time to fracture compared to the ribs without costal cartilage. This study shows the effect costal cartilage has on both the rib and thorax properties and why it is critical to include the costal cartilage in ATDs and human body models.

Committee: Yun-Seok Kang (Advisor); Amanda Agnew (Advisor) Subjects: Biomedical Engineering

Master of Science (MS), Ohio University, 2023, Biomedical Engineering (Engineering and Technology)

A study on a solution to repair osteochondral defects was investigated. This work contained the use of a novel collagen-based biomaterial that was structured to mimic the composition and structure of osteochondral tissue. Collagen extraction from the bovine achilles was optimized in terms of atelocollagen yield and stability. It was found that collagen enzymatically digested at a 1.25:10 pepsin to tendon weight ratio in the superior tendon region, gave optimal results in terms of atelocollagen quantity and hydrogel formation. Mineralized collagen scaffolds were fabricated to reflect the composition of subchondral bone. Controlled freezing was applied, which successfully oriented collagen fibers mimicking those in each native zonal tissue. Multiple approaches were attempted to replicate the collagen orientations of osteochondral tissue, ultimately a T-shaped mold was designed to guide directional freezing, resulting in an anisotropic scaffold structure. Native composition of bone hydroxyapatite and cartilage hyaluronic acid were also taken into consideration when fabricating such multizonal scaffolds.

Committee: Mei Wei (Advisor); Shouan Zhu (Committee Member); Doug Goetz (Committee Member); Andrew Weems (Committee Member) Subjects: Biomedical Engineering; Biomedical Research

PHD, Kent State University, 2022, College of Arts and Sciences / School of Biomedical Sciences

The human ilium is significantly shorter and broader than are those of all other primates. In addition, it exhibits an anterior inferior iliac spine that emerges via a secondary center of ossification. It is also unique to hominins. Here we track the ontogeny of the ilium in human and subadult primate ossa coxae. We find that its ontogeny is exclusive among primates from anlagen to adulthood and that the fusion of the anterior inferior iliac spine is a capstone event of a unique growth process that repositions the anterior gluteal muscles for control of pelvic drop during upright walking. This novel growth process is therefore a hominin synapomorphy that can be used to assess the presence of bipedal locomotion in extinct taxa. We recently reported that a unique physis modulates broadening of the hominin ilium and shortening of its isthmus. We report here the discovery of a large, constant vascular foramen which lies close to the novel growth plate and serves as a central structure in the hominin ilium's vascular network. No likely homologues appear in Old World Monkeys but are sometimes present in African great ape pelves. However, the human foramen (the Anterior Iliac Foramen) is significantly larger than the same individual's nutrient foramen, and when corrected for body size, the human anterior iliac foramen is substantially larger than are those of apes. Those of Pan and Gorilla do not differ significantly from one another when so corrected, establishing that a small foramen is primitive and that its enlarged state is derived in hominins. This likely reflects amplification of the blood supply to the novel hominin physis during growth. Its presence in hominin fossil ilia can therefore provide evidence of iliac ontogenetic specialization for bipedality. The unique presence of this synapomorphy provides robust evidence that non-saltatory bipedality is a singular adaptation restricted to hominins, and that it has occurred only once in known primates.

Committee: C. Owen Lovejoy (Advisor); Tobin Hieronymus (Committee Member); Richard Meindl (Committee Member); Mary Ann Raghanti (Committee Member) Subjects: Biology; Biomechanics; Developmental Biology; Evolution and Development; Forensic Anthropology; Paleontology; Physical Anthropology; Radiology; Zoology

Doctor of Philosophy, University of Toledo, 2021, Biomedical Engineering

Load-bearing soft tissue (LBSTs) injuries are multi-causal, resulting from physical activities, infection, and aging, affecting a wide array of patients. These injuries are expensive to treat and require long-term care, increasing the health care cost burden by billions of dollars annually in the United States. Commonly reported injuries of LBSTs, such as damage to knee menisci and nucleus pulposi, could be addressed by a tissue-engineered scaffold. This study investigated a novel PVA/alginate composite scaffold as a potential tissue-engineered construct that can be used to treat LBST injuries. PVA with embedded alginate beads was physically crosslinked by repeated freezing and thawing to produce composite scaffolds (PVA-ALG scaffolds). After crosslinking, bovine articular chondrocytes were seeded in these constructs. All the constructs maintained cell viability and had compressive properties similar to nucleus pulposi. Among the PVA concentrations used, 10% PVA produced constructs with a high compressive modulus (5.49 kPa) that could be handled easily during the fabrication process. Further characterization of 10% PVA-ALG showed that the scaffolds promoted cell growth. SEM micrographs and nitrogen adsorption analysis showed that the PVA-ALG scaffolds are mostly macroporous. These constructs also contained a significant amount of micropores and some mesopores. As the PVA concentration increased, the surface area of the scaffolds increased, and the porosity decreased in the scaffolds. In addition, the swelling decreased with the increase in the PVA concentration. However, the material properties in all the constructs were favorable for cell growth. After 11 weeks in PBS, 10% PVA-ALG scaffolds showed 68% degradation (reduction in weight in the swollen state) with neutral degradation products. Cell proliferation studies showed that the chondrocytes expanded well in both alginate beads and PVA regions, even though the cell growth was higher in alginate. While liv (open full item for complete abstract)

Committee: Arunan Nadarajah (Advisor); Patricia Relue (Committee Member); Halim Ayan (Committee Member); Kelly Marbaugh (Committee Member); R. Mark Wooten (Committee Member) Subjects: Biomedical Engineering; Materials Science; Polymers

PHD, Kent State University, 2021, College of Arts and Sciences / School of Biomedical Sciences

Osteoarthritis (OA) is a degenerative disease of articular cartilage that causes cartilage degradation, osteophyte formation, synovial inflammation, angiogenesis, and subchondral bone alteration. OA causes chronic disability in older people. Various factors are associated with its pathogenesis, including aging, obesity, joint instability, and joint inflammation. In healthy conditions, cartilage remodeling involves balanced interactions of synthesis and degradation to achieve homeostasis of the extracellular matrix (ECM) However, in OA this process becomes unbalanced, leading to pathologic changes in the affected joint. OA is also a highly prevalent rheumatic musculoskeletal disorder, that affected 303 million people globally in 2017. In the U.S. only, OA affects more than 32.5 million adults and is estimated to affect approximately 70 million more (i.e., 25% of the U.S. population) by 2030. Multiple OA factors might lead to stimulate the chondrocytes in the articular cartilage to produce the proteolytic enzymes which include matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) which work together to degrade joint articular cartilage leading to osteophyte formation and stiffening of joints. So far, there are no medications that can treat OA and all medicines such as analgesics, corticosteroids, and non-steroid anti-inflammatory drugs (NSAIDs) are used to reduce pain and inflammation. Trafficking protein particle complex subunit 9 (TRAPPC9) is a protein subunit part of the Transport Protein Particle II (TRAPPII), a highly conserved trafficking pathway from yeast to human. Not only TRAPPC9 is implicated in protein trafficking, but it has been also reported that TRAPPC9 regulates/potentiates multiple cellular activities such as prefiltration, differentiation, and function for several cell types through NF-kB mediation. To emphasize the relationship between TRAPPC9 and NF-kB, a study showed that TRAPPC9 physica (open full item for complete abstract)

Committee: Fayes Safadi Ph.D. (Advisor); Moses O. Oyewumi Ph.D. (Committee Member); Min-Ho Kim Ph.D. (Committee Member); Soumitra Basu Ph.D. (Committee Member); Mohammad Ansari Ph.D. (Committee Member) Subjects: Biology; Biomedical Research

Doctor of Philosophy, Case Western Reserve University, 2021, Genetics

Injury to articular cartilage is common, often progresses to a degenerative cycle of dysfunction and inflammation, and can ultimately result in degenerative joint diseases. The inability to repair defects, which cannot heal on their own within avascular cartilage, is a growing and costly unmet clinical need. The engineering of cartilage tissue is a promising technology that might finally meet this need, but current efforts have so far failed to generate cartilage that mimics native articular cartilage. Improvements must be made to both the cellular phenotype and the biomechanical properties of engineered cartilage. Using Next Generation Sequencing of RNA (RNA-seq), the transcriptomes of healthy, young, and human articular cartilages have been comprehensively characterized herein. These native tissues were contrasted with a standard model of cartilage differentiation using human bone marrow derived mesenchymal stem cells as source cells. Key regulatory elements such as the epigenetic factor TET1, the transcription factors TBX4 and RORC, and microRNA miR-99a-5p are highlighted as missing components throughout the chondrogenesis within this model. MicroRNAs miR-21-5p and miR-143-3p were demonstrated as persistent and dominant regulatory elements within this model that native tissue does not express, and their destabilizing effects on cartilage mRNAs are bioinformatically predicted and validated via antagomir inhibition in vitro. Collectively, these studies and the resulting databases and analyses should serve as valuable references to those seeking to generate articular cartilage ex vivo.

Committee: Arnold Caplan PhD (Advisor); Paul Tesar PhD (Committee Chair); Thomas LaFramboise PhD (Advisor); Hua Lou PhD (Committee Member) Subjects: Bioinformatics; Biomedical Engineering; Genetics

PHD, Kent State University, 2020, College of Arts and Sciences / School of Biomedical Sciences

Osteoarthritis (OA) is one of the leading causes of disability and is caused by a combination of mechanical and biochemical factors. Accumulating evidence suggests that inflammation has a key role in the pathogenesis of OA, and nitric oxide (NO) is considered as one of the major inflammatory mediators in OA that drives many pathological changes during the development and progression of OA. Excessive production of NO in chondrocyte promotes cartilage destruction and cellular injury, and its synthesis in chondrocytes is catalyzed by inducible nitric oxide synthase (iNOS), which is thereby an attractive therapeutic target for the treatment of OA. A number of direct and indirect iNOS inhibitors, bioactive compounds, and plant-derived small molecules have been shown to exhibit a chondroprotective effect by suppressing the expression of iNOS. Currently, there is no effective disease-modifying drug available for OA. Small molecules have proved to be powerful tools for modulating important molecular pathways in development and disease. Our preliminary screening of selected small molecules led us to select imperatorin (IMP) and peretinoin (PRT), which exhibit anti-inflammatory properties; however, their effect in chondrocytes is unknown. IMP is a plant-derived compound, while PRT is an acyclic retinoid and is currently in clinical trials for its efficacy to treat hepato-carcinoma. We found that IMP, as well as PRT, inhibited IL-1β induced expression of iNOS and production of NO in primary human OA chondrocytes by modulating the activation of mitogen-activated protein kinase (MAPK) pathway. Additionally, PRT inhibited matrix degradation by suppressing the expression of matrix metalloproteinase-13 (MMP-13). The work described in this dissertation demonstrates that PRT inhibits the expression of iNOS and production of NO in primary human OA chondrocytes and cartilage explants, identifies the mechanism, and shows OA suppressive effects in a mouse OA model.

Committee: Tariq Haqqi (Advisor); Fayez Safadi (Committee Member); Moses Oyewumi (Committee Member); Mohammad Ansari (Committee Member); Christine Crish (Committee Member) Subjects: Biomedical Research

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

Degeneration/calcification of the cartilage endplate (CEP) has been linked to the onset and progression of intervertebral disc (IVD) degeneration yet the CEP remains under characterized and understudied. The aims of this dissertation were to evaluate the effect of in vitro cell culture conditions, including biochemical hypertrophic stimuli (10% fetal bovine serum (FBS) and Wnt agonist), oxygen tension (Aim 1), and substrate stiffness (Aim 2), on hypertrophic differentiation, a possible mechanism of degeneration/calcification, in human CEP cells and to characterize the human CEP on the molecular, cell and tissue level (Aim 3) and compare it to the CEP of animal models commonly used to study IVD degeneration, specifically bovine and canine species (Aim 4). For Aim 1, isolated human CEP cells were cultured as pellets for 21 days at either 5% or 20.7% O2 and treated with 10% FBS or Wnt agonist, two biochemical stimuli known to induce hypertrophy in articular chondrocytes. CEP cells did not exhibit a hypertrophic morphology in response to hypertrophic stimuli but did display other hallmarks of chondrocyte hypertrophy and degeneration including hypertrophic gene and protein expression, and a decrease in healthy proteoglycans (glycosaminoglycan (GAG)) and increase in fibrous collagen accumulation. For Aim 2, human CEP cells were cultured in either 2% (soft) or 4.5% (stiff) agarose gels at 5% O2 for 11 days. No significant differences in cell morphology, or protein expression of hypertrophic cell markers were observed between substrate stiffnesses. For Aims 3 and 4, isolated human, bovine and canine CEP, nucleus pulposus (NP), annulus fibrosus (AF) and articular cartilage (AC) tissue and cells were evaluated for cell morphology, matrix composition/structure, GAG content, and gene and protein expression. Significant differences in matrix and cell marker gene expression were observed between human CEP and NP or AF, with greatest differences between the human CEP and AC. W (open full item for complete abstract)

Committee: Devina Purmessur (Advisor); Alan Litsky (Committee Member); Sarah Moore (Committee Member); Gregory Lafyatis (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2018, Comparative and Veterinary Medicine

Osteoarthritis (OA) is a progressive disease associated with cartilage injury and is the most common form of arthritis, affecting millions of people worldwide. Most common cartilage healing and treatments have unsatisfactory outcomes due to the inherently limited repair capability of cartilage. The goal here was to produce a sConstruct from decellularized synovial-derived extracellular matrix (sECM) seeded with synovial-derived mesenchymal stem cells (sMSCs) that could house normal or engineered sMSC with little immune reaction while improving cartilage healing. The first part of this work investigates the sMSC migration, differentiation, and distribution into the sECMs as determined by CD90, viability, histologic morphology, expression of GFP, BMP-2, hyaluronic acid (HA), and proteoglycan (PG). At day 14, sMSCs were viable, had multiplied 2.5-fold in the sECMs, had a significant decrease in CD90 expression and significant increases in HA and PG expression. Seeding with BMP-2-sMSCs enhanced the expression of BMP-2, and increased soluble HA and PG. These results indicate sMSC produce anabolic agents and differentiate in the sECM. The second portion of the thesis has two parts; 1) an in vitro model where the sConstructs were co-cultured with chondrocytes, and 2) in vivo, placing sConstructs adjacent to a cartilage lesion in a rat knee. The in vitro study showed increased chondrocyte proliferation, viability, and Col II production, greatest in BMP-2-sConstructs. Chondrocyte co-cultures increased the sConstruct sMSC production of HA, PG, and BMP-2 in a positive feedback loop. 2) In the in vivo study, sECM alone, GFP- or BMP-2-sConstructs were implanted adjacent to clinically created full-thickness rat-knee cartilage lesions. At 5 weeks, the lesion area was resected and gross anatomy, adjacent articulate cartilage growth and subchondral bone repair were scored and peripheral, central and cartilage lesion measurements taken. For all scores and measurements, sConstruct im (open full item for complete abstract)

Committee: Alicia Bertone (Advisor) Subjects: Animal Sciences; Veterinary Services

Master of Sciences (Engineering), Case Western Reserve University, 2017, Biomedical Engineering

Hydrogels allow chondrocytes to maintain their morphology and provides an ideal environment for the chondrocytes to produce cartilage. Hydrogels have been widely used in three- dimensional (3D) printing to create scaffold for tissue engineering. There are various methods in additive manufacturing however, for this study we have decided to use stereolithography because of its high accuracy. In this study, we created a new hybrid biocompatible resin using a combination of natural and synthetic polymers (chitosan and polyethylene glycol diacrylate (PEGDA), respectively) by varying feed-ratios and photo-initiator concentration. Ear-shaped hybrid scaffolds were fabricated by a stereolithographic method using a low cost commercially available 3D printer. Hybrid hydrogel mixture of chitosan (50–190 kDa) and PEGDA (575 Da) were mixed at different feed-ratios. The formulations that were made were ideal in terms of mechanical properties and cell viability. However, the lyophilizing the scaffold affected the porosity that resulted in uneven cell adhesion. Therefore, an alternative formulation of Chitosan and PEGDA mixture was created which subsequently improved the scaffold porosity by CAD printing of the scaffold. This is the first report of stereolithographic printing using a commercially available low cost 3D printer hybridizing cell adhesive properties of chitosan with mechanical robustness of PEGDA in scaffolds suitable for regenerative process of the cartilage.

Committee: Ozan Akkus (Committee Chair); Dominique Durand (Committee Member); Eben Alsberg (Committee Member) Subjects: Biomedical Engineering; Biomedical Research

Doctor of Philosophy, The Ohio State University, 1966, Graduate School

Committee: Not Provided (Other) Subjects: Biology

Doctor of Philosophy (Ph.D.), Bowling Green State University, 2016, Photochemical Sciences

We present the formulation and study of light-responsive materials based on carboxylate-containing polysaccharides. The functional groups in these natural polymers allow for strong interactions with transition metal ions such as Fe(III). The known photochemistry of hydroxycarboxylic acids in natural waters inspired us in exploring the visible light induced photochemistry of the carboxylates in these polysaccharides when coordinated to Fe(III) ions. Described in this dissertation are the design and characterization of the Fe(III)-polysaccharide materials, specifically the mechanistic aspects of the photochemistry and the effects that these reactions have on the structure of the polymer materials. We present a study of the quantitative photochemistry of different polysaccharide systems, where the presence of uronic acids was important for the photoreaction to take place. Alginate (Alg), pectate (Pec), hyaluronic acid (Hya), xanthan gum (Xan), and a polysaccharide extracted from the Noni fruit (NoniPs), were among the natural uronic acid-containing polysaccharide (UCPS) systems we analyzed. Potato starch, lacking of uronate groups, did not present any photochemistry in the presence of Fe(III); however, we were able to induce a photochemical response in this polysaccharide upon chemical manipulation of its functional groups. Important structure-function relationships were drawn from this study. The uronate moiety present in these polysaccharides is then envisioned as a tool to induce response to light in a variety of materials. Following this approach, we report the formulation of materials for controlled drug release, able to encapsulate and release different drug models only upon illumination with visible light. Furthermore, hybrid hydrogels were prepared from UPCS and non-responsive polymers. Different properties of these materials could be tuned by controlling the irradiation time, intensity and location. These hybrid gels were evaluated as scaffolds for ti (open full item for complete abstract)

Committee: Alexis Ostrowski Ph.D. (Advisor); Michael Geusz Ph.D. (Committee Member); George Bullerjahn Ph.D. (Committee Member); R. Marshall Wilson Ph.D. (Committee Member) Subjects: Chemical Engineering; Chemistry; Materials Science; Polymer Chemistry; Polymers

Master of Science, University of Akron, 2016, Polymer Science

Osteoarthritis (OA) is the most common articular disease and the most prevalent condition resulting in disability among the United States adult population. According to the U.S. Department of Health and Human Services, from 2010-2012, 52.5 million (22.7%) of adults aged > 18 years had self-reported doctor-diagnosed arthritis, and 22.7 million (9.8%) reported arthritis-attributable activity limitation, which indicates not only an ethical, but also economic importance of this disease. OA is characterized by progressive loss of articular cartilage and leads to chronic pain and functional restrictions in the affected joint. Although current treatments are successful in some aspects to provide short-term pain relief and recovered joint mobility, their long term benefits remain elusive and there is still no cure for the disease. The limited capacity for treatment is mainly due to the cartilage`s inability to repair itself. Regenerative medicine using tissue-engineered cartilage has the potential to address this issue, but a remaining challenge is the development of a feasible large scale cell expansion process, since during the expansion in monolayer cultures, chondrocytes undergo the process of dedifferentiation. Several surface-engineering approaches with bioactive factors and surface chemistry have been previously studied to look at increasing the interfacial interaction between the materials and cells. This project aimed to study the effects of various concentrations of surface functional groups on chondrocyte behavior. The cell proliferation and phenotype maintenance within continuously variable one-dimensional concentration gradients were examined. This method included fabrication of functionalized gradients by a vapor deposition technique that provided a fast, efficient, and reliable strategy by incorporating a series of concentrations in single substrates. Finally, human primary chondrocytes density and cellular survival were studied as response of amine and hydro (open full item for complete abstract)

Committee: Matthew Becker Dr. (Advisor); Abraham Joy Dr. (Committee Member) Subjects: Biomedical Research; Polymers

Doctor of Philosophy, Case Western Reserve University, 2016, Biomedical Engineering

There is a critical need for cartilage regeneration therapies. Not only is cartilage necessary for proper joint function, as deterioration of cartilage leads to osteoarthritis, but it also serves important roles in other places in the body, like in the trachea. Specifically in the articular and tracheal niches, replacement cartilage should have adequate mechanical properties and specific geometries to restore native function. To address these needs, novel strategies to engineer high-density human mesenchymal stem cell (hMSC)-derived cartilage tissues are presented in this dissertation. Bioactive microspheres loaded with chondrogenic transforming growth factor beta 1 (TGF-ß1) were incorporated within some of these tissues for enhanced chondrogenesis. First, scaffold-free cartilage rings and tubes with controlled dimensions were successfully fabricated using custom-made culture wells and a ring-to-tube assembly approach, respectively. The use of TGF-ß1 microspheres in the hMSC rings and tubes significantly improved the quality and quantity of generated cartilage tissue. Next, localized TGF-ß1 presentation within cartilaginous tissues facilitated organized fusion and culture of cartilage tissue building blocks with engineered epithelial and prevascular tissues. Successful development and/or maintenance of tissue-specific phenotypes in this co-culture approach with localized presentation of cues guiding cell differentiation is a promising step toward engineering a functional replacement trachea. Next, extracellular matrix (ECM) scaffolds fabricated from high-density hMSC condensates with and without TGF-ß1 microspheres were shown to support chondrogenesis of re-seeded hMSCs. Importantly, addition of microspheres to hMSC condensates significantly enhanced ECM production and consequently yielded 50% more scaffolds. Additionally, ECM scaffolds were demonstrated to drive chondrogenesis when TGF-ß1 was loaded into them, which suggests improved potential for clinical translat (open full item for complete abstract)

Committee: Eben Alsberg (Advisor); Horst von Recum (Committee Chair); Ozan Akkus (Committee Member); Guang Zhou (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2016, Allied Medical Professions

Articular cartilage defects (ACD) in the knee are isolated lesions in the articular cartilage of the knee, surrounded by healthy cartilage. Most common in young, active adults, ACDs are often accompanied by pain, swelling, and muscle weakness that leads to activity restriction and reduced participation in desired activities. For this reason, individuals with ACDs report low knee-related quality of life, on par with older individuals preparing for total knee replacements. Unfortunately, the presence of the ACD can alter the stress distribution within the existing cartilage, raising concern that individuals with ACDs in the knee may develop osteoarthritis at an accelerated pace compared to individuals with healthy knees. While numerous surgical interventions have been developed in efforts to restore the friction-free and resilient cartilage surface, conservative and palliative treatments remain the most common choice. However, little is known regarding individuals with ACDs without or prior to a cartilage restoration procedure in a manner that can inform the development of rehabilitation interventions. As a first step toward understanding modifiable factors affecting individuals with ACDs, the overall objective of this dissertation is to evaluate muscle activation and joint loading patterns in individuals with ACDs during walking, with specific interest in its relationship to kinesiophobia (fear of movement/reinjury). Chapter 1 reviews the pertinent background regarding ACDs and presents a conceptual framework that links the subsequent chapters. Chapter 2 presents the results of systematic review of the kinesiophobia, as measured by the Tampa Scale for Kinesiophobia, across individuals with knee pathologies that found while kinesiophobia is generally low, there are many gaps in our current understanding. Chapter 3 finds that individuals with ACDs demonstrate muscle co-contraction during gait to a similar extent as healthy individuals, and is largely influenced by (open full item for complete abstract)

Committee: Laura Schmitt (Advisor); Thomas Best (Committee Member); David Flanigan (Committee Member); Ajit Chaudhari (Committee Member); Robert Siston (Committee Member); Zhiwei Hu (Other) Subjects: Physical Therapy

MS, University of Cincinnati, 2015, Engineering and Applied Science: Biomedical Engineering

Cartilage rings in the trachea are primarily responsible for structural stability of the trachea and to prevent its collapse over the range of intrathoracic pressures encountered in-vivo. The underlying biomechanical properties of the cartilage rings critical to this function are unknown. This study was designed to determine the zero stress state, structural properties – initial and tangent stiffness, and load relaxation (% of initial load) of the tracheal rings and material properties of the tracheal cartilage. These properties would eventually be used to create the biomechanical design requirements for a tracheal exostent which would then be used in pediatric patients suffering from long segment congenital tracheal stenosis. Primary goal of this study was to determine the inter-animal variations of these properties for 3-6 month old lamb and to determine if these properties vary within animals with the anatomical location of the ring on the trachea. Cartilage rings were isolated from the cranial, mid and caudal sections of tracheas from eight lambs (3-6 month old). The rings were cut posteriorly to allow them to reach zero stress state and corresponding opening angles were measured. The rings at zero stress state were further tested either in radial tension or radial compression at a constant rate of deformation. The rings tested in radial tension were held at a constant radial displacement at the end of the test and load relaxation was recorded over 15 minutes. The data from these tests was used to calculate the initial and tangent stiffness and load relaxation of the rings. Modulus was calculated from analytical models for the ring test configurations based on curved beam theory. The results obtained showed large inter-animal variations in the tracheal ring major and minor diameters, width and thickness of rings (geometry at no-load), opening angle (zero stress state geometry), initial and tangent stiffness, load relaxation and modulus. Moreover, the minor d (open full item for complete abstract)

Committee: Balakrishna Haridas PH.D. (Committee Chair); Farhan Zafar M.D. (Committee Member); Vasille Nistor Ph.D. (Committee Member); Marepalli Rao Ph.D. (Committee Member) Subjects: Engineering

Doctor of Philosophy, The Ohio State University, 2015, Molecular, Cellular and Developmental Biology

The study of the molecular basis of exercise adaptations in the field of exercise physiology is relatively new, as evidenced by the surge in articles citing molecular techniques over the last decade. This focus on molecular indicators is not surprising given the efforts to improve upon preventative healthcare and reduce healthcare cost burden in our country. The ability to exploit molecular indicators of exercise effectiveness as well as discover novel therapeutic options are clear advantages to studying molecular exercise physiology that could impact healthcare. In the studies described here, we used an integrative approach, building from a molecular basis to mice to human subjects, to develop a more comprehensive understanding of the molecular mechanisms mediating the effects of exercise. To study the effects of exercise on a physiological systems-wide level, we used microarray technology to characterize global upregulation and downregulation of genes in response to walking exercise in rat cartilage. We found temporal gene expression changes over 15 days of exercise. The networks of genes affected were responsible for directing extracellular matrix; cell metabolism; cytoskeleton; cell signaling, growth, and differentiation; and inflammatory pathways. It was evident from this study that integration of multiple physiological systems occurs in response to an exercise stimulus. We then aimed to isolate and study selected systems using molecular and physiological techniques. The objective of one particular study was to determine the role of exercise as an integrator of bone and muscle health. One of the genes that was observed during the microarray analysis to be upregulated by exercise by more than 1.5 fold was follistatin-like3 (FSTL3). FSTL3 belongs to the follistatin family of molecules which also includes follistatin (FST). Previous studies showed that FSTL3 is required for exercise driven bone formation. This protein also binds and inhibits myos (open full item for complete abstract)

Committee: Noah Weisleder (Advisor); Tim Hewett (Advisor); Sudha Agarwal (Advisor); Tim Eubank (Committee Member) Subjects: Cellular Biology; Molecular Biology

Doctor of Philosophy, The Ohio State University, 2015, Biomedical Engineering

Osteoarthritis (OA) is a huge disease burden in United States, affecting almost 30 million Americans, and is the leading cause of disability in the elderly. Knee and hip replacements cost over $40 billion annually, but may be avoided through early detection of at risk cartilage and early intervention. There are abundant MRI tools for non-invasive, quantitative imaging that reveal characteristics of cartilage structure and physiology such as collagen alignment, molecular content, and health of subchondral bone vasculature. However, no quantitative MRI technique has been added to clinical standard of care for cartilage imaging because of lack of specificity and technical difficulty. Chemical exchange saturation transfer (CEST) MRI is a promising technique to detect small metabolites such as glutamate, creatine and glucose, as well as large soluble molecules such as protein, proteoglycans, and glycogen. It has been demonstrated that CEST MRI can detect glycosaminoglycan (GAG), a proteoglycan crucial to the functioning of healthy articular cartilage, however only with high-field non-clinical scanners (> 3 Tesla). In osteoarthritis development, reduction in GAG content is a preliminary step before gross changes in cartilage thickness and joint space, and therefore clinical methods to detect GAG may have a tremendous impact on OA prevention. In this dissertation, we discuss multiple quantitative MRI techniques used to characterize articular cartilage, but then focus on CEST MRI. A miniature horse model of cartilage injury is used to evaluate several MRI techniques through serial imaging of the healing process over the course of one year. While promising, the techniques lack specificity and are technically challenging to perform, especially delayed gadolinium enchance MRI of cartilage (dGEMRIC), a technique used to detect GAG content. To meet the challenge of GAG detection at 3 Tesla, we hypothesized that a variant of CEST, using a novel variable saturation power (vCES (open full item for complete abstract)

Committee: Michael Knopp MD, PhD (Advisor); Seth Smith PhD (Committee Member); Orlando Simonetti PhD (Committee Member); Jun Liu PhD (Committee Member) Subjects: Biomedical Engineering; Medical Imaging

PhD, University of Cincinnati, 2015, Engineering and Applied Science: Biomedical Engineering

The anterior cruciate ligament (ACL) plays a complex role in knee stability. Injury to this structure can cause abnormal joint kinematics and loadings which may lead to the early onset of osteoarthritis (OA) and joint degeneration. While surgeons are able to restore joint laxity in the short to medium term, long term OA development is currently not prevented in patients who have undergone surgical repair. In order to slow or stop the progression of OA following ACL injury, we hypothesize that reconstruction techniques must achieve a greater degree of native ligament functionality. The principles of Functional Tissue Engineering state that a ligament's functionality may be defined as its in vivo loading characteristics. While this information remains impossible to measure directly in human patients in vivo, in vitro testing can serve as an alternative as long as the following conditions are met: 1) Loads are measured in 6 degrees-of-freedom (DOFs); 2) Loads are measured during activities of daily living (ADLs); 3) Loads are measured within a realistic environment, which may include knees sustaining injury to structures influencing ACL functionality. Due to the invasive nature of in vivo load sensing, researchers have turned to robotics to simulate ADLs kinematics on biological tissue. This technique allows open access to the joint to measure contact forces and 6 DOF ligament loads throughout physiologic motion paths, fulfilling the first 2 requirements for in vitro testing. By using an animal model, specimen-specific kinematics may be collected and applied to the same tissue, overcoming several limitations of cadaveric testing, including specimen quality and kinematic mis-matches. It also allows for consideration of biologic effects and controlled testing of various knee pathologies, fulfilling the 3rd requirement for in vitro testing. Because of these advantages, this work utilized robotics in combination with the sheep knee model to study in vivo AC (open full item for complete abstract)

Committee: Jason Shearn Ph.D. (Committee Chair); Vasille Nistor Ph.D. (Committee Member); Marepalli Rao Ph.D. (Committee Member); Grant Schaffner Ph.D. (Committee Member) Subjects: Biomedical Research