Journal
ACTA BIOMATERIALIA
Volume 9, Issue 1, Pages 4513-4524Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2012.09.029
Keywords
RNA interference; Gene knockdown; Scaffold-mediated transfection; Cell penetrating peptides; Electrospinning
Funding
- AStar BMRC SSCC Grant [09/016]
- MOE [RG75/10]
- NIH [NIBIB EB006365-07-A2]
- National Basic Research Program of China (973 Program) [2010CB934000]
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [R01EB000282, R01EB006365] Funding Source: NIH RePORTER
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The foreign body reaction often interferes with the long-term functionality and performance of implanted biomedical devices through fibrous capsule formation. While many implant modification techniques have been adopted in attempts to control fibrous encapsulation, the outcomes remained sub-optimal. Nanofiber scaffold-mediated RNA interference may serve as an alternative approach through the localized and sustained delivery of siRNA at implant sites. In this study, we investigated the efficacy of siRNA-poly(caprolactone-co-ethylethylene phosphate) nanofibers in controlling fibrous capsule formation through the down-regulation of collagen type I (COL1A1) in vitro and in vivo. By encapsulating complexes of COL1A1 siRNA with a transfection reagent (Transit TKO) or the cell penetrating peptides CADY or MPG within the nanofibers (550-650 nm in diameter), a sustained release of siRNA was obtained for at least 28 days (loading efficiency similar to 60-67%). Scaffold-mediated transfection significantly enhanced cellular uptake of oligonucleotides and prolonged in vitro gene silencing duration by at least 2-3 times as compared to conventional bolus delivery of siRNA (14 days vs. 5-7 days by bolus delivery). In vivo subcutaneous implantation of siRNA scaffolds revealed a significant decrease in fibrous capsule thickness at weeks 2 and 4 as compared to plain nanofibers (p < 0.05). Taken together, the results demonstrated the efficacy of scaffold-mediated siRNA gene-silencing in providing effective long-term control of fibrous capsule formation. (C) 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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