Off-campus WSU users: To download campus access dissertations, please use the following link to log into our proxy server with your WSU access ID and password, then click the "Off-campus Download" button below.
Non-WSU users: Please talk to your librarian about requesting this dissertation through interlibrary loan.
Access Type
WSU Access
Date of Award
January 2023
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Biomedical Engineering
First Advisor
Howard Matthew
Abstract
Post-traumatic osteoarthritis (PTOA) is a degenerative joint condition that develops subsequent to sustaining a traumatic injury. Rupture of the anterior cruciate ligament (ACLR), an injury commonly suffered by athletes and military personnel, has been highly associated with the onset and progression of PTOA. With incidence rates up to 50% regardless of surgical intervention, there remains a need to develop therapeutic strategies that delay or mitigate the onset of PTOA. Recent investigations aim to harbor the immunomodulatory capacity of bone marrow derived mesenchymal stem cells (BM-MSCs). Specifically, one immunomodulatory factor of interest is indoleamine 2,3-dioxygenase (IDO). IDO, a soluble factor secreted by MSCs, is known to play an enzymatic role in the degradation of tryptophan to kynurenines. This reaction has been shown to have a downstream effect on Treg, Th17, and natural killer cell regulation. The influence of IDO has been investigated in the setting of several immune based medical conditions including pregnancy, malignant tumors, rheumatoid arthritis and osteoarthritis). Utilizing the immunomodulatory properties of IDO in conjunction with BM-MSCs may provide a viable therapeutic strategy to combat PTOA. The purpose of this dissertation was to develop and evaluate a novel therapeutic regimen utilizing locally delivered IDO liposomes in combination with systemic mobilization agent AMD3100. Following in vitro characterization of the therapeutic duo, we employed a noninvasive rat model of ACLR to characterize the post-rupture endogenous expression of IDO by mobilized MSCs and measure the effect of mobilized MSCs on intra-articular cytokine profile. The results confirmed ACLR curates a highly inflammatory environment characterized by increased cytokine production. Acute treatment with AMD3100 is capable of inflammatory intervention displayed by reduced cytokine production. Coinciding observed increases in synovial fluid IDO with AMD3100 treatment may be indicative of MSC-mediated modulation. Finally, we applied an established rat model of PTOA to assess the individual and combined in vivo effects of exogenous IDO and AMD3100 to mitigate the onset and progression of PTOA. Our results indicate that ACLR-induced changes in articular cartilage, subchondral bone, and epiphyseal bone are delayed with independent treatment of IDO or AMD. This is characterized by restoration of gait parameters (swing time, propulsion time, paw placement etc) towards baseline values. Articular cartilage morphology (surface roughness and cartilage thickness), and bone morphology (BV/TV, subchondral thickness, and trabecular number) were also maintained at the early time point compared to the uninjured contralateral. However, when the combined treatment is administered, the anti-inflammatory properties are not capitalized suggesting inflammation may be over regulated interfering with the bodies innate healing processes. However, because these therapeutics have demonstrated individual efficacy there may be an opportunity to adjust dosage and time of delivery to administer a more appropriate combination in the setting of PTOA.
Recommended Citation
Fleischer, Mackenzie Marie, "A Novel Immunomodulatory Approach To Ptoa Mitigation Via Msc-Mediated Expression Of Indoleamine-2,3 Dioxygenase" (2023). Wayne State University Dissertations. 3795.
https://digitalcommons.wayne.edu/oa_dissertations/3795