In vitro evaluation of a novel oxygen-generating biomaterial for chronic rhinosinusitis therapy.

BACKGROUND: Hypoxia due to closure at the ostiomeatal complex is widely considered one of the major pathogenic mechanisms leading to chronic inflammation in chronic rhinosinusitis (CRS). The objective of this study was to develop and characterize an oxygen-generating biomaterial (OGB) as an innovative treatment strategy for CRS. METHODS: An OGB was fabricated by coating hydrophobic beeswax (BW, 15mg or 30mg) on the surface of calcium peroxide - catalase complex (CPO-CA, 30mg) and characterized using scanning electron microscopy (SEM). In vitro releases of both oxygen and hydrogen peroxide (H2 O2 ) were spectrophotometrically quantified, and cytotoxicity in human sinonasal epithelial cells (HSNECs) was evaluated. The influence of OGB on transepithelial Cl- secretion was also determined by pharmacologically manipulating HSNECs, cultured under hypoxic conditions, in Ussing chambers. RESULTS: Three groups of OGBs: (1) CPO only; (2) CPO coated with CA and BW (1:1 ratio, CPO-CA(1)-BW(1)); and (3) CPO coated with CA and BW (1:0.5 ratio, CPO-CA(1)-BW(0.5) were analyzed for accumulated oxygen release over 7 days: highest release (mmol/mg) was observed in CPO-CA(1)-BW(1) = 0.11 ± 0.003, followed by CPO-CA(1)-BW(0.5) = 0.08 ± 0.010, and CPO = 0.05 ± 0.004 (p < 0.0001). H2 O2 production (mM) was significantly higher in CPO (1.87 ± 0.50) compared to CPO-CA (1)-BW(1) (0.00 ± 0.00) (p < 0.001) after 24 h. CPO-CA(1)-BW(1) showed significantly reduced cytotoxicity and increased Cl- transport compared to the CPO group. CONCLUSION: A novel OGB (CPO-CA-BW complex) exhibited sustained oxygen release over 7 days without significant cytotoxicity after 24 h in vitro. Preclinical studies evaluating the efficacy of OGB in CRS are warranted, especially for potential therapy in an obstruction-based CRS model.

Azithromycin and ciprofloxacin inhibit interleukin-8 secretion without disrupting human sinonasal epithelial integrity in vitro.

BACKGROUND: We recently developed a ciprofloxacin and azithromycin sinus stent (CASS) to target recalcitrant infections in chronic rhinosinusitis (CRS). The objective of this study was to evaluate the anti-inflammatory activity of azithromycin released from the CASS and assess the impact on the integrity and function of primary human sinonasal epithelial cells (HSNECs). METHODS: Pseudomonas aeruginosa lipopolysaccharide (LPS)-stimulated HSNECs were treated with azithromycin and/or ciprofloxacin at concentrations attainable from CASS release. Interleukin-8 (IL-8) secretion was quantified by enzyme-linked immunosorbent assay (ELISA). Epithelial integrity (transepithelial resistance [TEER], paracellular permeability [fluorescein isothiocyanate-labeled dextran], lactate dehydrogenase [LDH] assays) and function (ciliary beat frequency [CBF]) were also evaluated. RESULTS: Azithromycin significantly reduced secreted IL-8 from P. aeruginosa LPS-stimulated HSNECs at all concentrations tested (mean ± standard deviation; control = 5.77 ± 0.39 ng/mL, azithromycin [6 µg/mL] = 4.58 ± 0.40 ng/mL, azithromycin [60 µg/mL] = 4.31 ± 0.06, azithromycin [180 µg/mL] = 4.27 ± 0.26 ng/mL, p < 0.05). Co-incubation with azithromycin (6 µg/mL) and ciprofloxacin (2.4 µg/mL) in LPS-stimulated HSNECs also displayed a significant reduction in secreted IL-8 when compared to P. aeruginosa LPS alone (co-treatment = 4.61 ± 0.29 ng/mL, P. aeruginosa LPS = 7.35 ± 0.89 ng/mL, p < 0.01). The drugs did not negatively impact TEER, paracellular permeability, LDH release, or CBF, indicating retention of cell integrity and function. CONCLUSION: Azithromycin decreased P. aeruginosa LPS IL-8 production in HSNECs at drug concentrations attainable with sustained release of azithromycin from the CASS. In addition to antibacterial activity, anti-inflammatory properties of the CASS should provide further benefit for patients with recalcitrant CRS.

Antibiotic eluting sinus stents.

OBJECTIVES: Chronic rhinosinusitis (CRS) is a multifactorial disease affecting up to 16% of the United States population and disproportionately affecting the cystic fibrosis (CF) patient population. Despite treating the underlying infection, the use of systemic antibiotics has shown little efficacy in alleviation of symptom burden. This review seeks to discuss recent research on novel antibiotic eluting stent therapy in vitro and within animal models as well as the factors that contribute to its efficacy. DATA SOURCES: PubMed literature review. REVIEW METHODS: A review of all published literature related to antibiotic eluting sinus stents was conducted to integrate and summarize this innovative approach to chronic sinus infections. RESULTS: Placement of the ciprofloxacin sinus stent (CSS) and ciprofloxacin-ivacaftor sinus stent (CISS) exhibited improvement in endoscopic and radiographic findings in rabbit CRS models. While the CSS showed an overall trend toward improvement in microscopic findings and a reduction in biofilm mass, there remained a significant quantity of planktonic bacteria due to antibiotic depletion from an initial burst release in the first 48 hours of stent placement. The CISS and ciprofloxacin-azithromycin sinus stents (CASSs) exhibited controlled antibiotic release over the study period leading to greatly reduced planktonic bacterial load and biofilm mass. In vitro studies indicate that CASS may be just as efficacious at reducing biofilm mass. CONCLUSION: Antibiotic eluting sinus stents show significant promise as a novel therapeutic strategy for CRS. The CISS may have particular promise for the CF patient population by addressing both the infectious and genetic components of disease. Animal studies demonstrate significant promise for translation into human studies. Human clinical trials are warranted to determine the efficacy of antibiotic sinus stents in human patients. LEVEL OF EVIDENCE: NA.