Engineering an immunomodulatory drug-eluting stent to treat laryngotracheal stenosis

Madhavi Duvvuri, Kevin Motz, Michael Murphy, Michael Feeley, Dacheng Ding, Andrew Lee, Jennifer Hartt Elisseeff, Alexander Tell Hillel

Research output: Contribution to journalArticle

Abstract

Objective: Develop a drug-eluting stent construct with a reliable drug-release profile and adequate mechanically stability for a trial in a small animal model of laryngotracheal stenosis (LTS), a debilitating pathologic narrowing of the airway leading to significant shortness of breath. Methods: Biodegradable, biocompatible stents containing 1.0% rapamycin made of PLLA-PCL (70% Poly-l-Lactide and 30% Polycaprolactone blend) and 50:50 PDLGA (Poly(dl-lactide-co-glycolide)) were compared. Mechanical strength testing and drug elution rates using high performance liquid chromatography analysis (HPLC) was assessed. Next, efficacy of stent elution on LTS derived scar fibroblasts. Finally, stents were placed in situ in an LTS mouse model. Results: The PLLA-PCL stent construct exhibited greater mechanical strength compared to the PDLGA stent over a 4-week period (Young's Modulus (PLLA-PCL) = 13.82; Young's Modulus (PDLGA) = 4.015). Moreover, the PLLA-PCL stent showed a reliable rapamycin release profile for 6 weeks (30% elution for PLLA-PCL stents compared to <1% elution for PDLGA). Collagen 1 (p < 0.05) and fibroblast cell proliferation were decreased in vitro when treated with the rapamycin stent. In vivo, the rapamycin stent reduced lamina propria thickness (p < 0.05) and collagen 1(p < 0.05), collagen 3, TGF-B (p < 0.05) and a-SMA (p < 0.05). Conclusions: The PLLA-PCL construct demonstrated superior mechanical strength and greater drug elution compared to PDLGA stents. We demonstrated the feasibility of testing this drug-eluting stent in vivo, showing that the rapamycin-eluting stent treats fibrosis. To our knowledge this is the first study to deploy a drug-eluting stent to treat tracheal pathology in an animal model. Optimization of a rapamycin-eluting PLLA-PCL stent for translational investigation will lead to improved treatment strategies of LTS.

Original languageEnglish (US)
Pages (from-to)1863-1874
Number of pages12
JournalBiomaterials science
Volume7
Issue number5
DOIs
StatePublished - May 1 2019

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Stents
Polycaprolactone
Pharmaceutical Preparations
Sirolimus
Collagen
Strength of materials
Fibroblasts
Animals
Elastic moduli
dilactide
Cell proliferation
High performance liquid chromatography
Testing
Pathology
polycaprolactone

ASJC Scopus subject areas

  • Biomedical Engineering
  • Materials Science(all)

Cite this

Engineering an immunomodulatory drug-eluting stent to treat laryngotracheal stenosis. / Duvvuri, Madhavi; Motz, Kevin; Murphy, Michael; Feeley, Michael; Ding, Dacheng; Lee, Andrew; Elisseeff, Jennifer Hartt; Hillel, Alexander Tell.

In: Biomaterials science, Vol. 7, No. 5, 01.05.2019, p. 1863-1874.

Research output: Contribution to journalArticle

Duvvuri, Madhavi ; Motz, Kevin ; Murphy, Michael ; Feeley, Michael ; Ding, Dacheng ; Lee, Andrew ; Elisseeff, Jennifer Hartt ; Hillel, Alexander Tell. / Engineering an immunomodulatory drug-eluting stent to treat laryngotracheal stenosis. In: Biomaterials science. 2019 ; Vol. 7, No. 5. pp. 1863-1874.
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abstract = "Objective: Develop a drug-eluting stent construct with a reliable drug-release profile and adequate mechanically stability for a trial in a small animal model of laryngotracheal stenosis (LTS), a debilitating pathologic narrowing of the airway leading to significant shortness of breath. Methods: Biodegradable, biocompatible stents containing 1.0{\%} rapamycin made of PLLA-PCL (70{\%} Poly-l-Lactide and 30{\%} Polycaprolactone blend) and 50:50 PDLGA (Poly(dl-lactide-co-glycolide)) were compared. Mechanical strength testing and drug elution rates using high performance liquid chromatography analysis (HPLC) was assessed. Next, efficacy of stent elution on LTS derived scar fibroblasts. Finally, stents were placed in situ in an LTS mouse model. Results: The PLLA-PCL stent construct exhibited greater mechanical strength compared to the PDLGA stent over a 4-week period (Young's Modulus (PLLA-PCL) = 13.82; Young's Modulus (PDLGA) = 4.015). Moreover, the PLLA-PCL stent showed a reliable rapamycin release profile for 6 weeks (30{\%} elution for PLLA-PCL stents compared to <1{\%} elution for PDLGA). Collagen 1 (p < 0.05) and fibroblast cell proliferation were decreased in vitro when treated with the rapamycin stent. In vivo, the rapamycin stent reduced lamina propria thickness (p < 0.05) and collagen 1(p < 0.05), collagen 3, TGF-B (p < 0.05) and a-SMA (p < 0.05). Conclusions: The PLLA-PCL construct demonstrated superior mechanical strength and greater drug elution compared to PDLGA stents. We demonstrated the feasibility of testing this drug-eluting stent in vivo, showing that the rapamycin-eluting stent treats fibrosis. To our knowledge this is the first study to deploy a drug-eluting stent to treat tracheal pathology in an animal model. Optimization of a rapamycin-eluting PLLA-PCL stent for translational investigation will lead to improved treatment strategies of LTS.",
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AU - Murphy, Michael

AU - Feeley, Michael

AU - Ding, Dacheng

AU - Lee, Andrew

AU - Elisseeff, Jennifer Hartt

AU - Hillel, Alexander Tell

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