No description available.

Current cartilage repair methods are ineffective in restoring the mechanical and biological functions of native hyaline cartilage. Therefore, using the paracrine actions of stem cell therapies to stimulate endogenous cartilage regeneration has gained momentum. Adipose stem cells (ASCs) are an attractive option for this endeavor because of their accessibility, chondrogenic potential, and secretion of factors that promote connective tissue repair. In order to use the factors secreted by ASCs to stimulate cartilage regeneration, the signaling pathways that affect postnatal cartilage development and morphology need to be understood. Next, approaches need to be developed to tailor the secretory profile of ASCs to promote cartilage regeneration. Finally, delivery methods that localize ASCs within a defect site while facilitating paracrine factor secretion need to be optimized. The overall objective of this thesis was to develop an ASC therapy that could be effectively delivered in cartilage defects and stimulate regeneration via its paracrine actions. The general hypothesis was that the secretory profile of ASCs can be tailored to enhance cartilage regeneration and be effectively delivered to regenerate cartilage in vivo. The overall approach used the growth plate as an initial model to study changes in postnatal cartilage morphology and the molecular mechanisms that regulate it, different media treatments and microencapsulation to tailor growth factor production, and alginate microbeads to deliver ASCs in vivo to repair cartilage focal defects.

Injuries to connective tissues such as ligaments and tendons are common, and rather than healing, repair typically results in fibrosis, or the formation of mechanically inferior and disorganized scar tissue. This fibrotic repair response is due in part to inflammation, during which the injury site is invaded by a number of cell types, including macrophages, neighboring fibroblasts, and homed stem cells or progenitor cells. Activation of macrophages is believed to be modulated by communications with fibroblasts and stem cells, prompting either a pro-fibrotic or a pro-regenerative response. Beyond changes to the cellular microenvironment, fibrosis also results in changes to the organization and mechanical properties of the matrix microenvironment. For healthy fibrous connective tissues, the matrix is comprised of aligned collagen fibers, while scar tissue is disorganized and exhibits weaker mechanical properties than healthy tissue. To date, the nature of the cell-cell and cell-matrix interactions and their relevance in tissue healing or repair remain understudied. To better understand the cellular and matrix-based cues that direct scar formation versus tissue regeneration, and using anterior cruciate ligament (ACL) injuries as a model, Aim 1 of this thesis tests the hypothesis that in vitro models of cellular communications between fibroblasts, macrophages, and mesenchymal stem cells (MSC) can be used to determine the effects of cellular interactions on macrophage activation and fibrosis. In Aim 2, the contribution of matrix-based cues (alignment and mechanical properties) to the inflammatory and fibrotic response, as well as their modulation of cellular interactions, were examined. Findings from these two aims reveal that 1) communications between native tissue fibroblasts and macrophages drive inflammation and fibrosis, while stem cells modulate the repair process through a combination of trophic signaling and immunomodulatory roles, and 2) matrix alignment and mechanical properties exert combined regulation on cell response during inflammation. From a clinical application perspective, stem cells delivered in conjunction with an engineered matrix that provides the critical cues for driving stem cell immunomodulation and trophic signaling will be essential for promoting tissue regeneration and minimizing fibrosis. In particular, an aligned matrix with an elastic modulus similar to that of developing connective tissue may serve to further minimize inflammation and scar formation, and activate stem cell-guided regeneration of mechanically functional connective tissue.

Intramuscular connective tissue is critical in maintaining muscle structure and the transfer of force from contractile elements to the bone. We examined intramuscular connective tissue characteristics in young and old men and women, as well as men and women subjected to simulated microgravity. We hypothesized that intramuscular collagen content, collagen cross-linking and formation of advanced glycation endproducts of old individuals would be greater than young, and that intramuscular collagen content would be elevated following prolonged periods of unloading spanning 35, 60 and 90 days. Vastus lateralis muscle biopsies revealed that intramuscular collagen (Young: 9.6±1.1, Old: 10.2±1.2 ug•mg muscle wet wf-') and collagen cross-links (hydroxylysylpyridinoline, HP) (Young: 395±65, Old: 351±45 mmol HP•mol collagen-1) were unchanged (p>0.05) with aging. The advanced glycation endproduct, pentosidine, was increased (p<0.05) by 203% (Young: 5.2±1.3, Old: 15.9±4.5 mmol pentosidine•mol collagen"') with aging. With unloading, collagen content of the vastus lateralis was unchanged (p>0.05) following all time periods but was found to be elevated (p<0.05) in the soleus following 90 days of unloading. Furthermore, baseline collagen content was found to greater (p<0.05) in the soleus compared to the vastus lateralis. These results suggest the age related decline in whole muscle function is not related to increases in intramuscular collagen content or cross-linking but may be related to the accumulation of advanced glycation endproducts. Muscle function following unloading does not appear to be impacted by collagen content in the vastus lateralis but may play a role in the soleus. / School of Physical Education, Sport, and Exercise Science

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Thesis (Ph.D.) -- University of Adelaide, Dept. of Anatomical Sciences, 2003. / "June 2003" Includes bibliographical references (leaves 408-457).

Thesis (M.S.)--University of Michigan, 1985.

Thesis (M.S.)--University of Michigan, 1985.

Thesis (Ph. D.)--University of Washington, 1998. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.