Osteoarthritis (OA) is a degenerative joint disease which has yet no complete treatment with medication. Doxycycline, a well-known antibiotic, has been shown to prevent matrixmetallopreoteinases-MMPs, indicating potency on OA treatment. However, long term systemic use can cause side effects on other tissues. This study aimed to develop controlled drug delivery systems of doxycycline/doxycycline-chondroitin sulfate (D/D-CS) in the form of PCL microspheres for providing a better and new treatment approach via local application. After optimization studies for size, loading efficiency, surface/structure and release properties, microspheres of low Mw PCL (14 kDa) was decided to be more suitable than those of high Mw (65 kDa). The release profile of former was also more compatible with diffusion model than that of latter. The bio-effectiveness of the microspheres was evaluated with three-dimensional in vitro model / osteoarthritic-rabbit chondrocytes embedded in agarose and subjected to interleukin-1&beta / throughout incubations. In vitro treatments with D/D-CS microspheres showed significant reduction in MMP-13 activity compared with untreated OA controls for 15 and 24-day incubations. Although collagen and GAG analysis results showed no enhancement of synthesis with MS treatments, significant decrease in GAG and collagen release from D/D-CS MS treated groups and from D MS treated ones respectively. Overall evaluations of the efficacy using in vivo rabbit OA model showed better radiographic scores and histological outcomes for D/D-CS MS groups compared to only hyaluronan injected and/or untreated controls in 8 weeks. The ex-vivo biomechanical properties of cartilages demonstrated improved hardness with values comparable to healthy group upon application of D-CS MS.
| Identifer | oai:union.ndltd.org:METU/oai:etd.lib.metu.edu.tr:http://etd.lib.metu.edu.tr/upload/12613470/index.pdf |
| Date | 01 August 2011 |
| Creators | Aydin, Ozlem |
| Contributors | Keskin, Dilek |
| Publisher | METU |
| Source Sets | Middle East Technical Univ. |
| Language | English |
| Detected Language | English |
| Type | Ph.D. Thesis |
| Format | text/pdf |
| Rights | Access forbidden for 1 year |
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