Previous decades of cartilage research have predominantly focused on decoupling the solid and fluid interactions of the mechanical response. The resulting biphasic and triphasic models are widely used in the biomechanics community. However, a simple viscoelastic model is able to account for the stress-relaxation behavior of cartilage, without the added complexity of solid and fluid interactions. Using a viscoelastic model, cartilage is considered a single material with elastic and dissipative properties. A mechanical characterization is made with fewer material parameters than are required by the conventional biphasic and triphasic models. This approach has tremendous utility when comparing cartilage of different species and varying healths. Additionally, the viscoelastic models can be easily extended in dynamic analysis and FEA programs. Cartilage primarily experiences compressive motion during exercise. Therefore, to mimic biological function, a mechanical test should also compress the cartilage. One such test is a viscoelastic stress-relaxation experiment. The Prony and fractional calculus viscoelastic models have shown promise in modeling stress-relaxation of equine articular cartilage. The elastic-viscoelastic correspondence principle is used to extend linear viscoelasticity to the frequency domain. This provides a comparison of articular cartilage based on stored and dissipated moduli. The storage and loss moduli metrics are hypothesized to serve as benchmarks for evaluating osteoarthritic cartilage, and provide guidelines for newly engineered bio-materials. The main goal of the current study is to test the applicability of modeling articular cartilage with viscoelastic models. A secondary goal is to establish a rigorous set of harvesting techniques that allows access to fresh explants with minimal environmental exposure. With a complex substance like cartilage, it is crucial to avoid unnecessary emph{in vitro} environmental exposure. Additional areas of study include: determining the strain-dependency of the mechanical response, exploring the response of cartilage in different fluid mediums such as saline, synovial fluid, and synthetic substitutes, and studying the time-dependent properties of cartilage during stress-relaxation experiments. Equine stifle joints, which are mechanically analogous to human knees, are harvested and used for analysis in this study. It is believed that the proposed viscoelastic models can model other articulating joints as well. If viscoelastic theory can be used to characterize cartilage, then comparisons can be drawn between real and artificial cartilage, leading to better joint replacement technology.

An ultrasonic nondestructive evaluation (NDE) technique has been developed to characterize the superficial layer of articular cartilage. The technique utilizes the unique properties of surface waves to detect changes in mechanical properties of the surface layer of the test sample. Experiments were performed first on poly(vinyl alcohol) (PVA) hydrogels, a material used to model articular cartilage, to examine repeatability and the ability of wave propagation parameters to reflect changes in material properties. Dynamic shear and compression tests were performed on 20% and 25% PVA by weight hydrogels to examine the difference in material properties. Ultrasonic NDE tests with longitudinal, shear and surface waves were performed on the hydrogels. Wave speeds in the 20% and 25% hydrogels were compared. Results showed that ultrasonic NDE with surface waves was repeatable and the technique was able to detect material property changes in hydrogels. Ultrasonic NDE tests with surface waves were then performed on healthy and damaged bovine articular cartilage. Wave speeds in the healthy cartilage were compared to speeds in enzymatically digested cartilage. Results showed that ultrasonic NDE with surface waves was repeatable and the technique was able to detect material property changes in the superficial layer of articular cartilage. Findings suggest that the technique has potential to be a tool in diagnosing diseases involving cartilage degeneration, such as osteoarthritis.

In pathological states such as osteoarthritis, the complex metabolic balance of cartilage is disrupted, leading to a loss in the integrity and biomechanical function of cartilage. Osteoarthritis affects more than 20 million Americans, costing the United States economy over $60 billion yearly. Risk factors for osteoarthritis include age, excessive joint loading, and joint injury. Tissue engineering offers a potential solution for the replacement of diseased and/or damaged cartilage. Unfortunately, plentiful donor cell populations are difficult to assemble, as chondrocytes have a well characterized lack of expansion potential. Mesenchymal progenitor cells offer an alternative with a high expansion potential capable of supplying large quantities of cells. Using an immature bovine model, the chondrogenic differentiation of articular chondrocytes and bone marrow stromal cells was found to be scaffold, media and mechanical stimulation dependent. TGF-beta signaling participated in the response of articular chondrocytes to dynamic compressive loading, as well as enhanced the chondrogenesis of bovine BMSCs, through interactions between loading and TGF-beta/Smad signaling. Also, dynamic loading altered gene expression, matrix synthesis rates and intracellular phosphorylation for bovine BMSCs. However the response of the cells to dynamic loading depends on both media supplementation and the duration of unloaded culture. These studies establish signaling through the TGF-beta pathway as a mechanotransduction pathway for chondrocytes and chondroprogenitors in 3D culture.

Arthritis includes many conditions of the joints characterized by inflammation, pain, and loss of joint function that affect 66 million people in the U.S. alone. During arthritic degeneration, chondrocytes exhibit downregulated synthesis of extracellular matrix molecules and upregulation of proteolytic enzymes. Fibrochondrocytes, found in meniscal fibrocartilage, appear to behave in a similar way. Metalloproteinases, including matrix metalloproteinases (MMP) and a disintegrin and metollproteinase with thrombospondin motif (ADAMTS) class enzymes have demonstrated efficient, distinct aggrecan degradation in models of arthritis. ADAMTS-4 and ADAMTS-5 are thought to be primary mediators of pathologic aggrecan catabolism, while MMP-17 may be involved in ADAMTS activation. There is also growing evidence of metalloproteinase-independent mechanisms in aggrecan catabolism. The cysteine endopeptidase m-calpain has been detected in cartilage from arthritic joints, and chondrocytes can secrete this protease. The overall objective of this work was to investigate metalloproteinases and m-calpain as comediators of aggrecan turnover in articular cartilage and meniscal fibrocartilage. The central hypothesis was that metalloproteinases cooperate with m-calpain to mediate cytokine-induced aggrecan turnover and associated changes in tissue mechanics. Experiments involved using inhibitors to perturb protease systems, antibodies targeting aggrecan neoepitopes to characterize enzyme activity, and established methods of evaluating tissue compressive and shear properties. Models of degradation and de novo tissue assembly were used to investigate tissue-specific differences in aggrecan turnover. The results of this work demonstrate tissue-specific differences in the abundance and structure of aggrecan, and indicate that the mechanisms and extent of aggrecan processing in the meniscus is dependent on location within the tissue. The relationships between aggrecan structure and tissue material properties are discussed, along with implications for development, disease, and repair.

No description available.

<p>The aim of this dissertation was to develop new techniques for producing electrospun scaffolds for use in the tissue engineering of articular cartilage. We developed a novel method of imparting mechanical anisotropy to electrospun scaffolds that allowed the production of a single, cohesive scaffold with varying directions of anisotropy in different layers by employing insulating masks to control the electric field. We improved the quantification of fiber alignment, discovering that surface fibers in isotropic scaffolds show similar amounts of fiber alignment as some types of anisotropic scaffolds, and that cells align themselves in response to this subtle fiber alignment. We improved previous methods to improve cellular infiltration into tissue engineering scaffolds. Finally, we produced a new material with chondrogenic potential consisting of native unpurified cartilage which was electrospun as a composite with a synthetic polymer. This work provided advances in three major areas of tissue engineering: scaffold properties, cell-scaffold interaction, and novel materials.</p> / Dissertation

Articular cartilage is the translucent, heterogeneous three-component biological load processing gel that overlays the end of the articulating bones of mammalian joints. Normally, healthy intact articular cartilage performs two biomechanical functions very effectively. These are (i) redistribution of stresses due to loads acting on the joint; (ii) act as a near-frictionless interface between contacting bone ends. These principal functions are enabled by its highly elastic properties. Under normal physiological conditions, these essential biomechanical functions are provided over the lifetime of a mammalian joint with little or no degenerative changes. However, certain levels of physiological and traumatic loads and degenerative processes induced by activities such as running, walking, extreme sport, and aging can alter the composition and structure of the tissue, leading to changes in its biomechanical properties. This, inturn, influences its functional characteristics. The most common degenerative change in articular cartilage is osteoarthritis and the management and treatment of this disease is pivotal to all research targeted toward articular cartilage. Several scientific groups around the world have developed models of articular cartilage to predict its fundamental and functional responses to load and altered biochemical conditions through both in vivo and in vitro studies. The most predominant of these models are the biphasic and triphasic models, which are based on the conceptualisation of articular cartilage as a dispersed mixture of its three main components namely collagen fibrils proteoglycan aggregates and water. The triphasic model is an extension of the biphasic model and incorporates swelling as a separate identifiable component of the tissue's biomechanical response. While these models are capable of predicting the elastic and viscoelastic behaviour and certain aspects of the swelling characteristics of articular cartilage, they are incapable of accounting for its short-term responses where the fluid component is the main carrier of the applied pressure. The hydrostatic and swelling components of the fluid content determine the manner of stress-sharing and hence transient load processing within the matrix as stress is transmitted to the underlying structure. Furthermore, the understanding of the nature of this stress-sharing between fluid and solid components of the tissue is fundamental to the comprehension of the nature of degeneration and its biomechanical consequence in the function of the articulating joint. The inability of the biphasic and triphasic theories to predict, in accordance with experimental results, the transient behaviour of the loaded matrix fluid requires a more representative model. This imperative therefore forms the basis for the research work presented in this thesis. In this thesis, a new mathematical model of articular cartilage load carriage is presented which can predict the transient load-induced responses. The model is based on a continuum framework invoking the principle of mechanical consolidation of fluid-saturated, swollen porous elastic materials. The cartilage matrix is conceptualised as a heterogeneous anisotropic fluid-saturated porous material in which its solid component responds to load as a hyperelastic material and whose interaction with the swelling component produces a partially distributed time-varying permeability. In accordance with the principle of consolidation, a phenomenological approach is adopted for developing both analogue/engineering models and mathematical models for the tissue. The models are then used to predict both bulk matrix responses and the properties of the hypothetical layers of the tissue when subjected to physiological loading conditions. Ultimately, the generalized mathematical model is used to analyse the effect of superficial layer laceration on the stress-processing or stress-sharing characteristic of normal healthy articular cartilage. Finally, predicted results are shown to compare with experimental data demonstrating that the new models for swelling deformation, the hyperelastic law for solid skeletal structure and the distributed, time-dependent permeability are representative of the articular cartilage.

Errata tipped inside back end paper. / Bibliography: leaves 150-190. / vi, 190 leaves : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Insulin-like growth factors (IGFs) and inflammatory cytokines (e.g. IL-1) affect cartilage metabolism in opposite ways. The actions of IGFs in biological systems are modulated by locally produced IGF binding proteins (IGFBPs). This thesis investigated the effects of the IGFs and inflammatory cytokines on IGFBPs produced by chondrocytes and the subsequent interplay of these factors on proteoglycan production in vitro. To do this, a primary culture of ovine articular chondrocytes was used as an in vitro experimental model system. It was concluded that the IGFBP-5-mediated decrease in proteoglycan synthesis could be a relevant in vivo mechanism by which IL-1 exerts its catabolic effect and disturbs the balance between the synthesis and degradation of cartilage matrix macromolecules in pathological conditions. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1998?

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Western Australia, 2007.