Thrombosis and restenosis are common problems associated with intravascular procedures such as anastomoses, balloon angioplasty, and carotid endarterectomies. Application of a molecular barrier at the site of injury to inhibit platelet deposition would be advantageous. Additional therapeutic benefit could be achieved if the modified surface provided a target for delivery of pharmaceuticals, vectors, or cells. This dissertation focuses on the development of an intravascular modification and targeted delivery system that possesses numerous potential applications in the treatment of vascular injury.
Polyethylene glycol is commonly used for modification of molecules and surfaces to increase biocompatibility, reduce immunogenicity, and provide stealth characteristics. Protein-reactive polyethylene glycols could be used to modify vascular surfaces forming a molecular barrier. In addition, the polymer could be used as a target for delivery of agents by applying a recognizable tag to the terminus. Agents could be targeted to modified vascular tissue using, for instance, the biotin/avidin recognition system.
The ability to modify vascular surfaces with protein-reactive polyethylene glycols was confirmed using quantitative flow cytometry and epi-fluorescence microscopy. Furthermore, in vitro perfusion studies with cultured cells and scrape-damaged arteries demonstrated preferential delivery of microspheres and cells to polyethylene glycol-biotin modified vascular surfaces.
An in vivo rabbit model provided a more rigorous assessment of the polymer modification and targeted delivery system. Polymer modification of balloon injured rabbit femoral arteries persisted for a minimum of 72 hours. Targeted microspheres preferentially adhered to healthy and injured arteries modified with the reactive polymer as opposed to untreated controls. Furthermore, the ability to target microspheres to the modified arteries persisted for a minimum of 72 hours.
In conclusion, it was shown that it is possible to modify vascular tissue with a protein-reactive polyethylene glycol and that this modification with signaling molecules can also provide a target for the site-specific delivery of vascular-infused agents. An intravascular targeted delivery system such as this might find numerous applications in the treatment of intravascular injury that is associated with angioplasty, stenting, and endarterectomy procedures.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07252005-130509 |
| Date | 13 October 2005 |
| Creators | Deglau, Timothy Edward |
| Contributors | Dr. Harvey S. Borovetz, Dr. Flordeliza S. Villanueva, Dr. Alan J. Russell, Dr. Eric J. Beckman, Dr. William R. Wagner |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-07252005-130509/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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