Clinical translation of RNA interference has been impeded by the lack of safe and effective technologies for cytoplasmic delivery to target cells. Regenerative medicine is a potentially high impact but relatively underexplored application area for short interfering RNA (siRNA) therapies. We have developed a versatile, biodegradable, and injectable polyester urethane (PEUR) tissue scaffold-based approach for sustained and tunable gene silencing at local tissue sites. Tissue regenerative PEUR scaffold-based delivery of endosomolytic nanoparticles (si-NPs) achieved over 90% in vivo gene silencing sustained for 35 days at a low dose of 200 µg/kg siRNA/mouse. Addition of the excipient trehalose was used to control the rate of si-NP release, which enabled modulation of the temporal gene silencing profile in vivo. Finally, prolyl hydroxylase domain 2 (PHD2) silencing studies demonstrated that this platform can promote functional tissue regenerative responses in vivo by increasing vascular volume 3-fold. This versatile system provides an efficient platform to investigate loss of function phenotypes in basic tissue engineering studies and can be therapeutically applied to silence genes that are deleterious to tissue regeneration.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03242014-182641 |
| Date | 16 April 2014 |
| Creators | Nelson, Christopher Edward |
| Contributors | Craig L. Duvall, Todd D. Giorgio, Hak-Joon Sung, Scott A. Gulecher, Jeffrey M. Davidson |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03242014-182641/ |
| Rights | restricted, 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 Vanderbilt University 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. |
Page generated in 0.013 seconds