Tissue engineering is a promising alternative strategy to produce artificial bone substitutes / however, the control of the cell organization and cell behavior to create fully functional 3-D constructs has not yet been achieved. To overcome these, activities have been concentrated on the development of multi-functional tissue engineering scaffolds capable of delivering the required bioactive agents to initiate and control cellular activities. The aim of this study was to prepare tissue engineered constructs composed of polymeric scaffolds seeded with mesenchymal stem cells (MSCs) carrying a nanoparticulate growth factor delivery system that would sequentially deliver the growth factors in order to mimic the natural bone healing process. To achieve this, BMP-2 and BMP-7, the osteogenic growth factors, were encapsulated in different polymeric nanocapsules (poly(lactic acid-co-glycolic acid) (PLGA) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)) with different properties (degradation rates, crystallinity) and, therefore, different release rates to achieve the early release of BMP-2 followed by the release of BMP-7, as it is in nature. Initially, these nanoparticulate delivery systems were characterized and then the effect of single, simultaneous and sequential delivery of BMP-2 and BMP-7 from these delivery systems was studied in vitro using rat bone marrow MSCs. The effect of using these two growth factors in a sequential manner by mimicking their natural bioavailability timing was shown with maximized osteogenic activity results. BMP-2 loaded PLGA nanocapsules were subcutaneously implanted into Wistar rats and according to initial results, their biocompatibility as well as the positive effect of BMP-2 release on the formation of osteoclast-like cells was shown. To complete the construction of the bioactive scaffold, this nanoparticulate sequential delivery system was incorporated into two different types of polymeric systems / natural (chitosan) and synthetic (poly(& / #949 / -caprolactone) (PCL)). 3-D fibrous scaffolds were produced using these materials by wet spinning and 3-D plotting. Incorporation of nanocapsules into 3-D chitosan scaffolds was studied by two different methods: incorporation within and onto chitosan fibers. Incorporation into 3-D PCL scaffolds was achieved by coating the nanocapsules onto the fibers of the scaffolds in an alginate layer. With both scaffold systems, incorporation of nanocapsule populations capable of delivering BMP-2 and BMP-7 in single, simultaneous and sequential fashion was achieved. As with free nanocapsules, the positive effect of sequential delivery on the osteogenic differentiation of MSCs was shown with both scaffold systems, creating multi-functional scaffolds capable of inducing bone healing.
| Identifer | oai:union.ndltd.org:METU/oai:etd.lib.metu.edu.tr:http://etd.lib.metu.edu.tr/upload/3/12611188/index.pdf |
| Date | 01 September 2009 |
| Creators | Yilgor, Pinar |
| Contributors | Hasirci, Nesrin |
| 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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