Osteoarthritis (OA) is a debilitating, degenerative joint disease that affects over 32.5 million adults in the United States and nearly 595 million people globally. OA is a major cause of pain and disability and is among the most expensive conditions to treat, carrying an annual healthcare cost of over $16.5 billion. The disease has classically been characterized by the degradation of articular cartilage and subchondral bone; however, changes to the synovium have recently garnered appreciation as synovitis has been linked to OA symptoms and progression. While the importance of the synovium in diarthrodial joint health and pathology is now widely accepted, quantitative structure-function data remains sparse. There is a need to investigate synovium structure-function relationships to better understand the synovium’s role in joint homeostasis and disease. The role of sex-based differences in OA has gained attention as epidemiological studies reveal that the incidence and prevalence of OA is higher in women than in men. Sex as a variable has rarely been considered in preclinical animal studies and in vitro laboratory experiments that explore the mechanisms of OA development and progression. Furthermore, therapeutic approaches for the treatment of OA have not adequately considered sex-based differences. As the population of those at risk for OA grows, the influence of sex-based differences in OA warrants more attention, particularly in the regenerative strategies for cartilage repair.
This dissertation seeks to address persistent questions regarding OA etiology and the mechanisms underlying disease progression, as well as strategies to enhance cartilage tissue engineering therapies. The objectives of this dissertations are three-fold: (1) to further the understanding of synovium tribology (2) to develop a tissue-engineered (TE) human synovium to facilitate the study of synovium structure-function relationships and (3) to elucidate sex-based differences in cartilage regenerative medicine strategies.
In Chapter 2, we assess the hypothesis that tissue glycosaminoglycan (GAG) content contributes to the low friction properties of the synovium. Bovine and human synovium tribological properties were evaluated using a custom friction testing device. Following proteoglycan depletion, synovium friction coefficients increased while GAG content decreased. In a second study, synovium samples were treated with interleukin-1 (IL) to observe inflammatory-induced structural changes. IL treatment elevated GAG concentration and decreased friction coefficients. No changes to collagen content were observed following IL treatment. For the first time, a relationship between synovium friction coefficient and GAG concentration was demonstrated. The study of synovium tribology is necessary to fully understand the mechanical environment of the healthy and diseased joint.
Chapter 3 documents the development of a human TE synovium and its ability to recapitulate native tissue properties and responses to chemical stimuli. A mixed donor population of primary human fibroblast-like synoviocytes was combined with a commercially available extracellular protein mixture to fabricate TE synovium constructs. At baseline, mature TE synovium exhibited characteristics of native synovium such as the formation of an intimal lining and the expression of critical proteins like lubricin, cadherin-11, and collagen type IV. In response to IL and dexamethasone treatment, TE synovium underwent biochemical changes that mimicked the changes observed in human explants. In addition, solute transport measurements were performed to highlight the relationship between synovium extracellular matrix (ECM) composition and its functional properties, resulting in a proposed link between tissue GAG content and diffusion coefficient. A human TE synovium enables the investigation of synovium structure-function relationships in a controlled manner and can serve as a platform for disease modeling and drug screening, which may accelerate the development of new treatments for maintaining joint health that specifically target the synovium.
In Chapter 4, sex-based differences in the ECM properties of canine engineered cartilage and in its degradative response to IL insult are evaluated. Isolated chondrocytes from male or female cartilage donors were encapsulated in agarose to create cylindrical cartilage constructs. Mechanical and biochemical measurements demonstrated that the sex of the donor chondrocytes did not influence intrinsic, de novo tissue formation after 42 days of tissue maturation. Following IL treatment, the mechanical, biochemical, and media analyses revealed that the sex of the donor cells did not influence the engineered cartilage’s response to IL insult. By understanding how sexual dimorphism impacts cartilage growth and susceptibility to proinflammatory cytokine insult, we may better direct cell-based strategies for cartilage repair that are personalized to account for patient sex.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/hhzs-2333 |
| Date | January 2024 |
| Creators | Gangi, Lianna R. |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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