Device-based local delivery of siRNA against mammalian target of rapamycin (mTOR) in a murine subcutaneous implant model to inhibit fibrous encapsulation
Open accessAbstract
Fibrous encapsulation of surgically implanted devices is associated with elevated proliferation and activation of fibroblasts in tissues surrounding these implants, frequently causing foreign body complications. Here we test the hypothesis that inhibition of the expression of mammalian target of rapamycin (mTOR) in fibroblasts can mitigate the soft tissue implant foreign body response by suppressing fibrotic responses around implants. In this study, mTOR was knocked down using small interfering RNA (siRNA) conjugated with branched polyethylenimine (bPEI) in fibroblastic lineage cells in serum-based cell culture as shown by both gene and protein analysis. This mTOR knock-down led to an inhibition in fibroblast proliferation by 70% and simultaneous down-regulation in the expression of type I collagen in fibroblasts in vitro. These siRNA/bPEI complexes were released from poly(ethylene glycol) (PEG)-based hydrogel coatings surrounding model polymer implants in a subcutaneous rodent model in vivo. No significant reduction in fibrous capsule thickness and mTOR expression in the foreign body capsules were observed. The siRNA inefficacy in this in vivo implant model was attributed to siRNA dosing limitations in the gel delivery system, and lack of targeting ability of the siRNA complex specifically to fibroblasts. While in vitro data supported mTOR knock-down in fibroblast cultures, in vivo siRNA delivery must be further improved to produce clinically relevant effects on fibrotic encapsulation around implants.
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Other general anti-inflammatory drugs such as aspirin and rapamycin have been shown effective for reduction of FBR.
“Similar to dexamethasone, other general anti-inflammatory drugs such as aspirin (Malik et al., 2011) and rapamycin (Takahashi et al., 2010) have also been shown effective for the reduction of FBR.”
From Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics (2021) · cites this paper as Takahashi et al., 2010
The Introduction (page unavailable) reports that rapamycin and its analogues prevent cardiac and pulmonary fibrosis, but presents their potential to prevent implant-induced fibrosis as a hypothesis. The Results (page unavailable) report no significant reduction in foreign-body capsule thickness with mTOR-targeted siRNA; the paper does not show that rapamycin reduces FBR. (LLM, conf=0.86)
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Biodegradable Stent with mTOR Inhibitor-Eluting Reduces Progression of Ureteral Stricture
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- Authors
- Takahashi, H., Wang, Y., & Grainger, D. W.
- Affiliations
- University of Utah (US)
- Corresponding author
- Grainger, David W.
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 147
- Issue
- 3
- Pages
- 400-407
- ISSN
- 0168-3659 (ISSN-L)
- PMC
- PMC2975752
- OpenAlex
- W2014998173
- Cited by
- 58
- References
- 62
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 5 · 2015: 5 · 2014: 5 · 2013: 5 · 2012: 6
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Utah
- National Institutes of Health
- National Institute of Biomedical Imaging and Bioengineering (EB000894, R01EB000894)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Keywords
- mTOR, siRNA delivery, fibrous encapsulation, foreign body reaction, fibroblast proliferation, type I collagen, branched polyethylenimine
- MeSH terms
- Animals, Drug Implants, Female, Fibroblasts, Fibrosis, Foreign-Body Reaction, Kinetics, Mice, Inbred C57BL, Polyethylene Glycols, Polyethyleneimine, Solubility, Down-Regulation, Hydrogels, Collagen Type I, RNA Interference, RNA, Small Interfering, NIH 3T3 Cells, Cell Proliferation, Mice, TOR Serine-Threonine Kinases
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