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

Abstract

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.

Sirolimus-eluting airway stent reduces profibrotic Th17 cells and inhibits laryngotracheal stenosis

“…Given the potential for systemic side effects with systemic sirolimus, there is an advantage for local delivery of sirolimus. Previously, we designed and demonstrated proof of concept for a SEAS with a reliable drug release profile and mechanical stability ( 22 , 51 ). In the current study, we rigorously tested the efficacy of the SEAS in LTS-induced mice and demonstrated a reduction in pathologic fibrosis equivalent to the observed effects of systemic sirolimus.…”

Glutamine Inhibition Reduces Iatrogenic Laryngotracheal Stenosis

“…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 …”

Stents for small airways: current practice

“…Regarding custom made stents, now we have novel technology with 3D printing and 3D software animation [16,17]. Novel materials that have been used for drug eluting stents are: biodegradable polydioxanone [18], biocompatible [19], and flexible filaments [20]. Silicon stents can be modified in order to fit more efficiently in some cases.…”