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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.

SUBMITTER: Duvvuri M

PROVIDER: S-EPMC7197070 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Duvvuri Madhavi M Motz Kevin K Tsai Hsiu-Wen HW Lina Ioan I Ding Dacheng D Lee Andrew A Hillel Alexander T AT

Journal of visualized experiments : JoVE 20200121 155

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 ...[more]

PMID: 32065163

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Project description:Laryngotracheal stenosis is an obstructive respiratory disease that leads to voicing difficulties and dyspnea with potential life-threatening consequences. The majority of incidences are due to iatrogenic etiology from endotracheal tube intubation; however, airway scarring also has idiopathic causes. While recent evidence suggests a microbial contribution to mucosal inflammation, the microbiota associated with different types of stenosis has not been characterized. High-throughput sequencing of the V4 region of the16S rRNA gene was performed to characterize the microbial communities of 61 swab samples from 17 iatrogenic and 10 adult idiopathic stenosis patients. Nonscar swabs from stenosis patients were internal controls, and eight swabs from four patients without stenosis represented external controls. Significant differences in diversity were observed between scar and nonscar samples and among sample sites, with decreased diversity detected in scar samples and the glottis region. Permutational analysis of variance (PERMANOVA) results revealed significant differences in community composition for scar versus nonscar samples, etiology type, sample site, groups (iatrogenic, idiopathic, and internal and external controls), and individual patients. Pairwise Spearman's correlation revealed a strong inverse correlation between Prevotella and Streptococcus among all samples. Finally, bacteria in the family Moraxellaceae were found to be distinctly associated with idiopathic stenosis samples in comparison with external controls. Our findings suggest that specific microbiota and community shifts are present with laryngotracheal stenosis in adults, with members of the family Moraxellaceae, including the known pathogens Moraxella and Acinetobacter, identified in idiopathic scar. Further work is warranted to elucidate the contributing role of bacteria on the pathogenesis of laryngotracheal stenosis.IMPORTANCE The laryngotracheal region resides at the intersection between the heavily studied nasal cavity and lungs; however, examination of the microbiome in chronic inflammatory conditions of the subglottis and trachea remains scarce. To date, studies have focused on the microbiota of the vocal folds, or the glottis, for laryngeal carcinoma, as well as healthy larynges, benign vocal fold lesions, and larynges exposed to smoking and refluxate. In this study, we seek to examine the structure and composition of the microbial community in adult laryngotracheal stenosis of various etiologies. Due to the heterogeneity among the underlying pathogenesis mechanisms and clinical outcomes seen in laryngotracheal stenosis disease, we hypothesized that different microbial profiles will be detected among various stenosis etiology types. Understanding differences in the microbiota for subglottic stenosis subtypes may shed light upon etiology-specific biomarker identification and offer novel insights into management approaches for this debilitating disease.

Project description:ImportanceIn-stent restenosis (ISR) is the primary reason for stroke recurrence after intracranial stenting in patients who were treated with a standard bare-metal stent (BMS). Whether a drug-eluting stent (DES) could reduce the risk of ISR in intracranial atherosclerotic stenosis (ICAS) remains unclear.ObjectiveTo investigate whether a DES can reduce the risk of ISR and stroke recurrence in patients with symptomatic high-grade ICAS.Design, settings, and participantsA prospective, multicenter, open-label randomized clinical trial with blinded outcome assessment was conducted from April 27, 2015, to November 16, 2018, at 16 medical centers in China with a high volume of intracranial stenting. Patients with symptomatic high-grade ICAS were enrolled, randomized, and followed up for 1 year. Intention-to-treat data analysis was performed from April 1 to May 22, 2021.InterventionsPatients were randomly assigned to receive DES (NOVA intracranial sirolimus-eluting stent system) or BMS (Apollo intracranial stent system) treatment in a 1:1 ratio.Main outcomes and measuresThe primary efficacy end point was ISR within 1 year after the procedure, which was defined as stenosis that was greater than 50% of the luminal diameter within or immediately adjacent to (within 5 mm) the implanted stent. The primary safety end point was any stroke or death within 30 days after the procedure.ResultsA total of 263 participants (194 men [73.8%]; median [IQR] age, 58 [52-65] years) were included in the analysis, with 132 participants randomly assigned to the DES group and 131 to the BMS group. The 1-year ISR rate was lower in the DES group than in the BMS group (10 [9.5%] vs 32 [30.2%]; odds ratio, 0.24; 95% CI, 0.11-0.52; P < .001). The DES group also had a significantly lower ischemic stroke recurrence rate from day 31 to 1 year (1 [0.8%] vs 9 [6.9%]; hazard ratio, 0.10; 95% CI, 0.01-0.80; P = .03). No significant difference in the rate of any stroke or death within 30 days was observed between the DES and BMS groups (10 [7.6%] vs 7 [5.3%]; odds ratio, 1.45; 95% CI, 0.54-3.94; P = .46).Conclusions and relevanceThis trial found that, compared with BMSs, DESs reduced the risks of ISR and ischemic stroke recurrence in patients with symptomatic high-grade ICAS. Further investigation into the safety and efficacy of DESs is warranted.Trial registrationClinicalTrials.gov Identifier: NCT02578069.

Project description:AimsIn-stent chronic total occlusion (IS-CTO) represents a unique challenge for percutaneous coronary intervention. Whether the optimal treatment for IS-CTO is angioplasty with paclitaxel-coated balloons (PCBs) or repeat stenting with drug-eluting stents (DESs) is unclear. We aimed to evaluate the long-term clinical outcome of PCB angioplasty and DES repeat stenting for DES IS-CTO.MethodsWe retrospectively included patients with DES IS-CTO who underwent successful PCB angioplasty or DES repeat stenting from January 2016 to December 2019. The primary endpoints were major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, and target lesion revascularization (TLR). Cox proportional hazards model was performed to compare the risk of MACEs between PCB angioplasty and DES repeat stenting, and to further explore the prognostic factors of patients with DES IS-CTO.ResultsA total of 214 patients with DES IS-CTO were enrolled: 78 patients (36.4%) treated with PCB and 136 patients (63.6%) treated with DES respectively. The median follow-up was 1160 days, and MACEs were observed in 28.2% of patients with PCB angioplasty versus 26.5% of patients with DES repeat stenting (P = 0.784), mainly driven by TLR (21.8% vs. 19.9%, P = 0.735). There was no significant difference in the risk of MACEs between the PCB group and the DES group (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.64-2.46, P = 0.512). Multivariate Cox analysis revealed that chronic kidney disease and ≥ 3 stent layers in the lesion were independent predictors of MACEs, while switching to another antiproliferative drug was an independent protective factor (all P < 0.05).ConclusionsPCB angioplasty was an effective alternative treatment strategy for DES IS-CTO, which had similar long-term outcomes to DES repeat stenting in contemporary practice, but both were accompanied by a high rate of long-term MACEs. Improving the poor prognosis of patients with DES IS-CTO remains a challenge.

Project description:BackgroundCurrently, drug-eluting balloon (DEB) appears to be an attractive alternative option for the treatment of in-stent restenosis (ISR). Nevertheless, the clinical outcomes of DEB have seldom been compared to those of new-generation drug-eluting stent (DES). Thus, this meta-analysis aimed to evaluate the safety and efficacy of DEB compared to those of new-generation DES in the treatment of ISR.MethodsA comprehensive search of electronic databases including PubMed, EMBASE, and Cochrane Library up to November 2, 2017 was performed to identify pertinent articles comparing DEB to new-generation DES for the treatment of ISR. In addition, conference proceedings for the scientific sessions of the American College of Cardiology, American Heart Association, European Society of Cardiology, Transcatheter Cardiovascular Therapeutics, and EuroPCR were also searched. The primary endpoint was target lesion revascularization (TLR) at the longest follow-up. Dichotomous variables were presented as risk ratios (RR s) with 95% confidence intervals (CI s), while the overall RR s were estimated using the Mantel-Haenszel random-effects model.ResultsFive randomized controlled trials (RCTs) and eight observational studies involving 2743 patients were included in the present meta-analysis. Overall, DEB was comparable to new-generation DES in terms of TLR (RR = 1.24, 95% CI: 0.89-1.72, P = 0.21), cardiac death (RR = 1.55, 95% CI: 0.89-2.71, P = 0.12), major adverse cardiovascular event (RR = 1.21, 95% CI: 0.98-1.48, P = 0.07), myocardial infarction (RR = 1.12, 95% CI: 0.72-1.76, P = 0.62), and stent thrombosis (RR = 0.95, 95% CI: 0.38-2.42, P = 0.92). However, DEB was associated with higher risk of all-cause mortality than new-generation DES (RR = 1.65, 95% CI: 1.09-2.50, P = 0.02). This was especially true in the real-world observational studies (RR = 1.79, 95% CI: 1.12-2.88, P = 0.02). In RCTs, however, no significant difference was found between the two treatment strategies in the risk of all-cause mortality.ConclusionsThe current meta-analysis showed that DEB and new-generation DES had comparable safety and efficacy for the treatment of ISR in RCTs. However, treatment with DEB was associated with higher risk of all-cause mortality in the real-world nonrandomized studies.

Dataset Information

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

Publications

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

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