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Author:
Abbott, Rosalyn D.
Dept./Program:
Biomedical Engineering Program
Year:
2012
Degree:
Ph. D.
Abstract:
Low back pain (LBP) is the second most common cause of disability in US adults with 50-80% of adults experiencing an episode at some point during their lives. Many tissues are implicated in the pathogenesis of LBP; with approximately 40% of patients having LBP related to intervertebral disc (IVD) pathology, and the rest being classified as 'non-specific'. Although it affects a large population, the etiology of LBP is still being elucidated, and effective minimally invasive treatments targeting LBP processes for both IVD related and non-specific LBP are still in early stages of development. In the IVD, treatments with injectable agents have potential to slow or stop degeneration. However, it is unknown whether human degenerated cells that would be targeted in the center gelationous region ofthe IVD, the nucleus pulposus (NP), have regenerative potential, and what the most effective stimulus is. The causes ofreduced cellularity in degenerated IVDs are also only patially known, and mechanical causes (for example due to high strains adjacent to herniation, fissure, or other defect in the AF) have not been explored. For the non-specific low back pain cases, it is unknown whether mechanotransduction is altered in the denser connective tissues of patients with low back pain.
The goals of this dissertation were therefore to determine 1) if soluble factors released by notochordal cells, important in the developing IVD, are capable of 'recueing' human degenerated NP cells; 2) if degree of degeneration (moderate vs. severe) affects the regenerative potential of NP cells, and if matricellular proteins are sufficient to stimulate a reparative response; 3) determine whether the AF cells in two dimensional culture can adapt to high axial strains, as might be expected adjacent to a herniation or during needle puncture injury; and in order to explore mechanisms for non-specific back pain, to 4) determine the effect of stretch on areolar and dense loose connective tissue cells in stiffand compliant matrices in order to test the hypothesis that fibroblasts have a diminished response to stretch in dense connective tissues. Overall NP cells exhibited regenerative potential and degree of degeneration was an important factor foresponsiveness of cells. Taken together the first two goals demonstrated that an optimal treatment will need to combine mitogenic/anti-catabolic agents with cyto-active constituents to increase overall GAG synthesis, that notochordal cell conditioned media needs further optimization to stimulate an anabolic response, and that growth factor treatments are more effective at promoting anabolism in severely degenerated states than matricellular proteins alone.
AF cells were shown to be mechanically responsive and reoriented their cytoskeleton in response to cyclic uniaxial stretch when they were allowed to spread on a uniform coating of collagen, with no changes in matrix or catabolic gene expression, or apoptosis. However, they staininged positive for cleaved caspase 3 staining (indicative ofapoptosis) when restricted from orienting, as might be the case in the highly structured dense matrix ofthe native AF. Finally, it was demonstrated that there is a decrease in cytoskeletal remodeling in dense, stiff gels subjected to uniaxial tensile strain that was more dependent on the density of the matrix than the stiffness, and was not related to the tissue of origin of the fibroblasts. These results suggest that fibroblasts within abnormally dense, fibrosed or scarred connective tissue may lack cytoskeletal responsiveness contributing to the pathophysiology of chronic LBP.