title: Controlling fibrous capsule formation through long-term down-regulation of collagen type I (COL1A1) expression by nanofiber-mediated siRNA gene silencing.
abstract: 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 ~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.
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, 637459 Singapore, Singapore.
authors.forename: Pim-on
authors.initials: PO
authors.lastname: Rujitanaroj
authors.forename: Brian
authors.initials: B
authors.lastname: Jao
authors.forename: Junghoon
authors.initials: J
authors.lastname: Yang
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: James M
authors.initials: JM
authors.lastname: Anderson
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Sing Yian
authors.initials: SY
authors.lastname: Chew
mesh_terms: D001483:Base Sequence; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D015536:Down-Regulation; D004587:Electrophoresis, Agar Gel; D020868:Gene Silencing; D007150:Immunohistochemistry; D007700:Kinetics; D008855:Microscopy, Electron, Scanning; D057139:Nanofibers; D010755:Organophosphates / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D024042:Collagen Type I; D017931:DNA Primers; D010755:Organophosphates; D011091:Polyesters; D034741:RNA, Small Interfering; C581569:poly(caprolactone-co-ethylethylene phosphate)