Engineering an immunomodulatory drug-eluting stent to treat laryngotracheal stenosis

Duvvuri, Madhavi; Motz, Kevin; Murphy, Michael; Feeley, M. M.; Ding, Dacheng; Lee, Andrew; Elisseeff, Jennifer H.; Hillel, Alexander T.

doi:10.1039/c8bm01623b

Cited by 33 publications

(31 citation statements)

References 27 publications

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“…Systemic administration of steroid drugs in high dosages slows down granulation tissue overgrowth [ 11 ] due to their pronounced anti-inflammatory effects, but in turn, leads to other long-term side effects [ 12 ]. A revolutionized systemic side effects reduction method is a drug-eluting stent that can deliver the drug directly to the diseased area [ 13 , 14 , 15 , 16 ]. Biodegradable materials [ 17 ] and 3-D printing [ 18 ] have high potential in this area, but medical-grade materials are in the development stage [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Patterned Drug-Eluting Coatings for Tracheal Stents Based on PLA, PLGA, and PCL for the Granulation Formation Reduction: In Vivo Studies

et al. 2021

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Expandable metallic stent placement is often the only way to treat airway obstructions. Such treatment with an uncoated stent causes granulation proliferation and subsequent restenosis, resulting in the procedure’s adverse complications. Systemic administration of steroids drugs in high dosages slows down granulation tissue overgrowth but leads to long-term side effects. Drug-eluting coatings have been used widely in cardiology for many years to suppress local granulation and reduce the organism’s systemic load. Still, so far, there are no available analogs for the trachea. Here, we demonstrate that PLA-, PCL- and PLGA-based films with arrays of microchambers to accommodate therapeutic substances can be used as a drug-eluting coating through securely fixing on the surface of an expandable nitinol stent. PCL and PLA were most resistant to mechanical damage associated with packing in delivery devices and making it possible to keep high-molecular-weight cargo. Low-molecular-weight methylprednisolone sodium succinate is poorly retained in PCL- and PLGA-based microchambers after immersion in deionized water (only 9.5% and 15.7% are left, respectively). In comparison, PLA-based microchambers retain 96.3% after the same procedure. In vivo studies on rabbits have shown that effective granulation tissue suppression is achieved when PLA and PLGA are used for coatings. PLGA-based microchamber coating almost completely degrades in 10 days in the trachea, while PLA-based microchamber films partially preserve their structure. The PCL-based film coating is most stable over time, which probably causes blocking the outflow of fluid from the tracheal mucosa and the aggravation of the inflammatory process against the background of low drug concentration. Combination and variability of polymers in the fabrication of films with microchambers to retain therapeutic compounds are suggested as a novel type of drug-eluting coating.

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Section: Introductionmentioning

confidence: 99%

Patterned Drug-Eluting Coatings for Tracheal Stents Based on PLA, PLGA, and PCL for the Granulation Formation Reduction: In Vivo Studies

et al. 2021

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“…Next, to determine whether the rapamycin-eluting PLLA-PCL stent was effective in mitigating scars, we previously demonstrated gene expression changes in markers of acute inflammation and fibrosis 6 . Specifically, there is a 90.3 fold reduction (SEM ± 26.0; n = 4; p < 0.01) reduction in col1a1 at day 4, as well as the acute inflammatory markers INF-γ, CD11b, Arg-1, and IL-1B 6 . Though the differences in fold change for some genes were not significant, it is possible that with a greater cohort of mice, significance could be achieved.…”

Section: Representative Resultsmentioning

confidence: 99%

“…For the management of airway stenosis or collapse, previous investigations have used drug-coated silicone and nickel-based stents 5 . A PLLA-PCL construct was chosen for this particular method because of its drug elution profile and mechanical strength in physiological conditions over a period of 3 weeks, which has been demonstrated in previous published studies 6 . PLLA-PCL is also a biocompatible and biodegradable material already approved by the FDA 4 .…”

Section: Introductionmentioning

confidence: 99%

Design of a Biocompatible Drug-Eluting Tracheal Stent in Mice with Laryngotracheal Stenosis

Duvvuri

Motz²,

Tsai³

et al. 2020

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Laryngotracheal stenosis (LTS) is a pathologic narrowing of the subglottis and trachea leading to extrathoracic obstruction and significant shortness of breath. LTS results from mucosal injury from a foreign body in the trachea, leading to tissue damage and a local inflammatory response that goes awry, leading to the deposition of pathologic scar tissue. Treatment for LTS is surgical due to the lack of effective medical therapies. The purpose of this method is to construct a biocompatible stent that can be miniaturized to place into mice with LTS. We demonstrated that a PLLA-PCL (70% poly-L-lactide and 30% polycaprolactone) construct had optimal biomechanical strength, was biocompatible, practicable for an in vivo placement stent, and capable of eluting drug. This method provides a drug delivery system for testing various immunomodulatory agents to locally inhibit inflammation and reduce airway fibrosis. Manufacturing the stents takes 28-30 h and can be reproduced easily, allowing for experiments with large cohorts. Here we incorporated the drug rapamycin within the stent to test its effectiveness in reducing fibrosis and collagen deposition. Results revealed that PLLA-PCL tents showed reliable rapamycin release, were mechanically stable in physiological conditions, and were biocompatible, inducing little inflammatory response in the trachea. Further, the rapamycin-eluting PLLA-PCL stents reduced scar formation in the trachea in vivo.

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“…Therefore, it is important to identify strategies to deliver DON to the site of disease while avoiding systemic side effects. One option would be topical treatments, such as intralesional injection or a drug‐eluting stent, to effectively deliver glutamine inhibition to scar tissue in iLTS patients 28,29 . Alternatively, systemic administration of selective glutaminase inhibitor, CB‐839, has potential in iLTS as it showed a robust anti‐tumor effect in preclinical trials without significant toxicity 30 …”

Section: Discussionmentioning

confidence: 99%

Glutamine Inhibition Reduces Iatrogenic Laryngotracheal Stenosis

et al. 2021

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Objective/Hypothesis Glutamine inhibition has been demonstrated an antifibrotic effect in iatrogenic laryngotracheal stenosis (iLTS) scar fibroblasts in vitro. We hypothesize that broadly active glutamine antagonist, DON will reduce collagen formation and fibrosis‐associated gene expression in iLTS mice. Study Design Prospective controlled animal study. Methods iLTS in mice were induced by chemomechanical injury of the trachea using a bleomycin‐coated wire brush. PBS or DON (1.3 mg/kg) were administered by intraperitoneal injection (i.p.) every other day. Laryngotracheal complexes were harvested at days 7 and 14 after the initiation of DON treatment for the measurement of lamina propria thickness, trichrome stain, immunofluorescence staining of collagen 1, and fibrosis‐associated gene expression. Results The study demonstrated that DON treatment reduced lamina propria thickness (P = .025) and collagen formation in trichrome stain and immunofluorescence staining of collagen 1. In addition, DON decreased fibrosis‐associated gene expression in iLTS mice. At day 7, DON inhibited Col1a1 (P < .0001), Col3a1 (P = .0046), Col5a1 (P < .0001), and Tgfβ (P = .023) expression. At day 14, DON reduced Co1a1 (P = .0076) and Tgfβ (P = .023) expression. Conclusions Broadly active glutamine antagonist, DON, significantly reduces fibrosis in iLTS mice. These results suggest that the concept of glutamine inhibition may be a therapeutic option to reduce fibrosis in the laryngotracheal stenosis. Level of Evidence N/A Laryngoscope, 131:E2125–E2130, 2021

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Engineering an immunomodulatory drug-eluting stent to treat laryngotracheal stenosis

Abstract: A rapamycin-eluting PLLA-PCL stent is deployed into a diseased mouse trachea to treat laryngotracheal stenosis.

Cited by 33 publications

References 27 publications

Patterned Drug-Eluting Coatings for Tracheal Stents Based on PLA, PLGA, and PCL for the Granulation Formation Reduction: In Vivo Studies

Patterned Drug-Eluting Coatings for Tracheal Stents Based on PLA, PLGA, and PCL for the Granulation Formation Reduction: In Vivo Studies

Design of a Biocompatible Drug-Eluting Tracheal Stent in Mice with Laryngotracheal Stenosis

Glutamine Inhibition Reduces Iatrogenic Laryngotracheal Stenosis

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