The use and efficacy of biomimetic proteoglycans for cartilage repair and regeneration

Shaili Sharma, Purdue University

Abstract

Osteoarthritis (OA), a debilitating disease starts at the articular surface of cartilage and deteriorates the entire joint. This clinical need has yet to see a conclusive treatment. While etiologies and exact molecular mechanisms that cause this chronic disease remain elusive, key pathophysiological changes occurring during the degradation process have been identified. Of these, loss of aggrecan, a major proteoglycan in cartilage, is considered to occur first, after which other cartilage matrix components become extremely susceptible to enzymatic degradation. Therapies that protect the matrix from degradation have been proposed as ideal candidates to mitigate the inflammatory cycle of OA. To address this clinical need, our laboratory has designed molecules, coined peptidoglycans, modeled to functionally mimic proteoglycans and limit proteolytic degradation. This dissertation studied the efficacy of two such peptidoglycans, consisting primarily of a chondroitin-6-sulfate backbone functionalized with either hyaluronan or collagen type II binding peptides, as a potential therapy to prevent cartilage degradation and promote repair. These peptidoglycans are able to directly adhere to cartilage extracellular matrix components and are less prone to proteolytic cleavage. The efficacy of these peptidoglycans were tested in three different cartilage degradation models: type I collagen scaffolds seeded with chondrocytes and stimulated with interleukin-1β, trypsin treated cartilage explants stimulated with interleukin-1β and cartilage explants treated with synovial fluid from OA patients. Our findings indicated the ability to enhance bulk mechanical properties in collagen scaffolds and aggrecan depleted cartilage explants. In addition the mimic shows the ability to prevent cytokine induced degradation and modulate anabolic (collagen type II and aggrecan) and catabolic (MMP-13 and ADAMTS 5) gene expression of chondrocytes. The findings in this dissertation support our hypothesis that by reducing fragmentation of matrix components during the early stages of OA, the inflammatory cycle can be curbed. This technology shows promising potential to be pursed further as a treatment in early stage OA, preventing excessive cartilage damage and providing a healthy environment for tissue repair and regeneration.

Degree

Ph.D.

Advisors

Panitch, Purdue University.

Subject Area

Biomedical engineering

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