Alleviation of Surgery-Induced Osteitis in Sinonasal Cavity by Dexamethasone-Loaded Poly(lactic-co-glycolic acid) (PLGA) Microparticles with Strong Calcium-Binding Affinity.

For the treatment of sinus surgery-induced osteitis in chronic rhinosinusitis (CRS), oral or intranasal administration of corticoids is generally used, although it has critical limitations and unavoidable side effects. To overcome these limitations, we designed dexamethasone (Dex)-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles with bone-specific binding affinity, which could release the encapsulated Dex in a sustained manner on the exposed bone after the surgical wound in the nasal cavity. In a previous report, we prepared poly(butyl methacrylate-co-methacryloyloxyethyl phosphate) (PBMP) with both calcium-binding phosphomonoester groups and PLGA-binding butyl groups to introduce strong calcium-binding property to PLGA particles. In this study, after successful encapsulation of Dex in the PBMP-coated PLGA particles, we applied the Dex-PLGA/PBMP to the treatment of post-operative osteitis in the sinonasal cavity. The Dex-PLGA/PBMP showed more than 5-times higher binding affinity to the hydroxyapatite (HA) surface compared to the non-coated PLGA particles, without altering the morphology and encapsulation efficiency. After establishing the neo-osteogenesis mouse model by mechanical injury of the nasal mucosa, the activity of intranasally administered Dex-PLGA/PBMP was examined to inhibit the formation of undesirable new woven bone during the wound healing process. In addition, significantly lower osteocalcin activity was observed in the group treated with Dex-PLGA/PBMP, indicating decreased activation of osteoblasts. Overall, these results demonstrate that the PLGA/PBMP microparticle strategy has great potential for the treatment of CRS-related osteitis by localized corticoid delivery on the exposed bones with minimal side effects.

Development of High-Intensity Focused Ultrasound Therapy for Inferior Turbinate Hypertrophy.

OBJECTIVES: Inferior turbinate (IT) hypertrophy is the main cause of chronic nasal obstruction. We developed a high-intensity focused ultrasound (HIFU) ablation device to treat patients with IT hypertrophy. METHODS: First, computed tomography images of patients with no evidence of sinonasal disease were evaluated to measure and compare the IT, medial mucosal thickness (MT), and space between the nasal septum and IT according to clinical characteristics such as septal deviation. A HIFU prototype was developed based on the above human anatomical studies. The experimental study was performed in five pigs; the nasal volume and histological changes at 1 and 4 weeks postoperatively were evaluated to compare the efficacy of HIFU turbinoplasty with that of radiofrequency turbinoplasty and a control group. RESULTS: The mean medial MT of the anterior, middle, and posterior portions of the IT were 4.66±1.14, 4.23±0.97, and 6.17±1.29 mm, respectively. The mean medial space was 2.65±0.79 mm. The diameter and focal depth of the prototype were 4 mm and 3 mm, respectively. HIFU showed no postoperative complications, including bleeding or scar formation. After HIFU treatment, the nasal volume increased by 196.62 mm3 (7.8%) and 193.74 mm3 (8.3%) at 1 week and 4 weeks, compared with the increase of 87.20 mm3 (3.1%) and 213.81 mm3 (9.0%), respectively, after radiofrequency therapy. A qualitative histological analysis after radiofrequency turbinoplasty showed epithelial layer disruption at 1 week and increased fibrosis, along with decreased glandular structure, at 4 weeks. The HIFU group had an intact epithelial layer at 1 week postoperatively. However, significant differences were observed at 4 weeks, including increased fibrosis and decreased glandular structure. CONCLUSION: The efficacy and safety of HIFU turbinoplasty were demonstrated in an animal study. Our. RESULTS: warrant further human clinical trials.

Endotype-related recurrence pattern of chronic rhinosinusitis in revision functional endoscopic sinus surgery.

OBJECTIVE: The recurrence of chronic rhinosinusitis (CRS) after functional endoscopic sinus surgery (FESS) is influenced by various factors, potentially including the endotype based on the molecular pathophysiology of CRS. This study investigated differences in the recurrence pattern of CRS by endotype after primary FESS. METHODS: This retrospective study enrolled patients who had undergone revision FESS for recurrent CRS. Based on their clinical diagnosis, the patients were divided into two endotype groups: recurrent eosinophilic CRS (rECRS) and recurrent non-eosinophilic CRS (rNECRS). We compared and analyzed preoperative computed tomography (CT) findings, including typical anatomical findings of recurred CRS such as lateralized middle turbinate and retained uncinate process, the sinus where recurrence took place, and previous surgical completeness of the sinuses, between the rECRS and rNECRS groups. RESULTS: In total, 142 patients were enrolled (48 rECRS, 94 rNECRS). No significant difference was found in the typical anatomic findings of recurrent CRS between the rECRS and rNECRS groups. The rates of the completeness of previous surgeries was significantly higher in rECRS than in rNECRS(P=.031). Despite the completeness of previous surgeries, the recurrence rate of frontal and ethmoidal sinuses was higher in the rECRS than rNECRS(P=.012, P<.001, respectively). In subgroup analysis according to the severity of ECRS, the number of involved sinuses and the rates of CRS recurrence and surgical completeness in frontal and anterior ethmoidal sinuses increased with ECRS severity. CONCLUSIONS: CT findings of revision FESS cases differed by CRS endotype. The rECRS group showed higher recurrence in the frontal and ethmoidal sinuses despite a higher surgical completeness rate. Incomplete surgery was more often found in the rNECRS group.

Clinical characteristics of asymptomatic allergen sensitization with nasal septal deviation, often misdiagnosed as allergic rhinitis.

PURPOSE: Allergic rhinitis (AR) is often defined based on symptoms accompanied by a positive allergen sensitivity test result. However, a positive skin prick test (SPT) does not always imply the occurrence of clinical symptoms. If an asymptomatic allergen-sensitized patient has nasal septal deviation (DSN) that could cause nasal obstruction, the condition could easily be confused with typical symptomatic AR. This study investigated the clinical and laboratory characteristics of asymptomatic allergen-sensitization with septal deviation (ASSD). METHODS: Patients from a nationwide AR cohort study, conducted in 8 university hospitals, were investigated. AR was diagnosed when there were at least 1 rhinitis symptom with a positive SPT result. The ASSD group included patients who had severe nasal obstruction with few other symptoms and a positive SPT, along with septal deviation. Clinical and laboratory characteristics were compared between the ASSD group and the true AR group. RESULTS: In total, 728 patients were included. The average age was 32.2 ± 12.7 and 66% of the patients had DSN. SPT indicated that ASSD patients were less sensitized to house dust mite (p = 0.019 for Dp and p = 0.021 for Df). There was a significant sex difference: the male-to-female ratio was higher in the ASSD than in the AR group (3.59 vs. 1.77, p = 0.012). However, no statistically significant differences in age, family history, and body mass index were found. CONCLUSION: ASSD can mimic AR. When dealing with allergen-sensitized patients with a predominant symptom of nasal obstruction, DSN might also be considered before confirming a diagnosis of AR.

Bone morphogenetic protein-2 as a novel biomarker for refractory chronic rhinosinusitis with nasal polyps.

BACKGROUND: Bone morphogenetic proteins (BMPs), which are members of the TGF-ß superfamily, regulate bone remodeling by stimulating osteoblasts and osteoclasts. Although the association between osteitis and poor surgical outcomes is well known in patients with chronic rhinosinusitis (CRS), BMPs have not been fully investigated as potential biomarkers for the prognosis of CRS. OBJECTIVE: Our aim was to investigate the role of BMPs in osteitis in patients with CRS with nasal polyps (NPs) (CRSwNPs), as well as associations between BMPs and inflammatory markers in sinonasal tissues from patients with CRSwNP. METHODS: We investigated the expression of 6 BMPs (BMP-2, BMP-4, BMP-6, BMP-7, BMP-9, and BMP-10) and their cellular origins in NPs of human subjects by using immunohistochemistry and ELISA of NP tissues. Exploratory factor analysis was performed to identify associations between BMPs and inflammatory markers. Air-liquid interface cell culture of human nasal epithelial cells was performed to evaluate the induction of the epithelial-mesenchymal transition by BMPs. RESULTS: Of the 6 BMPs studied, BMP-2 and BMP-7 were associated with refractoriness. Only BMP-2 concentrations were higher in patients with severe osteitis and advanced disease extent according to the computed tomography findings. Eosinophils and some macrophages were identified as cellular sources of BMP-2 in immunofluorescence analysis. An in vitro experiment revealed that BMP-2 induced epithelial-mesenchymal transition in air-liquid interface-cultured human nasal epithelial cells, particularly in a TH2 milieu. CONCLUSION: BMP-2 could reflect the pathophysiology of mucosa and bone remodeling and may be a novel biomarker for refractory CRSwNP.

The Impact of Socioeconomic Status on Hospital Accessibility in Otorhinolaryngological Disease in Korea.

This study aimed to investigate the impact of socioeconomic status (SES) on otorhinolaryngology disease severity status diagnosed at the first hospital visit. We conducted a retrospective study over 20 years (2000-2019). Otorhinolaryngological diseases included chronic rhinosinusitis (CRS), sensorineural hearing loss (SNHL), oral ulcer, and malignant neoplasms. A logistic regression model was employed to assess the effect of SES on the severity of each disease at the first hospital visit. The severity of CRS increased in patients with lower SES (P = .028). The severities of SNHL (P = .032) and oral ulcer (P < .001) also associated with SES. In contrast, between the low- and high-SES groups observed no differences in cancer stage (P = .845). Patients with SNHL, oral ulcer, and CRS had a more severe disease status in the low-SES group than in the high-SES group at the first hospital visit. Efforts to increase hospital accessibility for low-SES otorhinolaryngological patients should be made.

Enhanced Type 2 Immune Reactions by Increased IL-22/IL-22Ra1 Signaling in Chronic Rhinosinusitis With Nasal Polyps.

PURPOSE: Recent studies have revealed the pathogenic role of interleukin (IL)-22 in atopic dermatitis and asthma. However, little is known about the role of IL-22 in the pathophysiology of chronic rhinosinusitis with nasal polyps. We aimed to investigate the expression of IL-22 and its pathogenic function in type 2 immune reactions of nasal polyps (NP). METHODS: Protein levels of inflammatory mediators were determined by multiplex immunoassay, and principal component analysis (PCA) was performed. Immunofluorescence analysis and mast cell culture were used to determine the cellular sources of IL-22. Normal human bronchial epithelial (NHBE) cells were stimulated using IL-22 in combination with diverse cytokines, and thymic stromal lymphopoietin (TSLP) was measured. RESULTS: IL-22 expression was not up-regulated in NP compared with control tissues, but IL-22-high NP revealed distinct features characterized by type 2 inflammatory cytokines such as chemokine (C-C motif) ligand (CCL)-11, CCL-24, and IL-5 on the PCA. Additionally, IL-22 positively correlated with type 2 immune mediators and the disease severity in NP. For the localization of the cellular sources of IL-22 in eosinophilic NP, it was expressed in cells mostly composed of eosinophil peroxidase-positive cells and partially of tryptase-positive cells. The human mast cell line, LAD2 cells, released IL-22 mediated by immunoglobulin E. Moreover, IL-22 receptor subunit alpha-1 (IL-22Ra1) expression was significantly increased in NP. IL-22Ra1 was up-regulated with poly(I:C) stimulation in NHBE cells. Furthermore, TSLP production was enhanced when stimulated with a combination of IL-13, poly(I:C), and IL-22. Treatment with anti-IL-22Ra1 also inhibited IL-22-induced enhancement of TSLP production. CONCLUSION: IL-22 was associated with type 2 inflammatory reactions in NP. The IL-22/IL-22Ra1 axis was enhanced and might be involved in type 2 inflammatory reactions via TSLP production in NP.

Elastase-Positive Neutrophils Are Associated With Refractoriness of Chronic Rhinosinusitis With Nasal Polyps in an Asian Population.

PURPOSE: Various immune cells, including eosinophils and neutrophils, are known to contribute to the development of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the current understanding of the role of neutrophils in the development of CRSwNP still remains unclear. Therefore, we investigated risk factors for refractoriness of CRSwNP in an Asian population. METHODS: Protein levels of 17 neutrophil-related mediators in nasal polyps (NPs) were determined by multiplex immunoassay, and exploratory factor analysis using principal component analysis was performed. Immunofluorescence analysis was conducted to detect human neutrophil elastase (HNE) or myeloperoxidase (MPO)-positive cells. Tissue eosinophilic nasal polyp (ENP) and tissue neutrophilia (Neuhigh) were defined as greater than 70 eosinophils and 20 HNE-positive cells, otherwise was classified into non-eosinophilic nasal polyp (NENP) and absence of tissue neutrophilia (Neulow). RESULTS: In terms of disease control status, NENP-Neulow patients showed the higher rate of disease control than NENP-Neuhigh and ENP-Neuhigh patients. Linear by linear association demonstrated the trend in refractoriness from NENP-Neulow to NENP-Neuhigh or ENP-Neulow to ENP-Neuhigh. When multiple logistic regression was performed, tissue neutrophilia (hazard ratio, 4.38; 95% confidence interval, 1.76-10.85) was found as the strongest risk factor for CRSwNP refractoriness. Additionally, exploratory factor analysis revealed that interleukin (IL)-18, interferon-γ, IL-1Ra, tumor necrosis factor-α, oncostatin M, and MPO were associated with good disease control status, whereas IL-36α and IL-1α were associated with refractory disease control status. In subgroup analysis, HNE-positive cells and IL-36α were significantly upregulated in the refractory group (P = 0.0132 and P = 0.0395, respectively), whereas MPO and IL-18 showed higher expression in the controlled group (P = 0.0002 and P = 0.0009, respectively). Moreover, immunofluorescence analysis revealed that IL-36R⁺HNE⁺-double positive cells were significantly increased in the refractory group compared to the control group. We also found that the ratio of HNE-positive cells to α1 anti-trypsin was increased in the refractory group. CONCLUSIONS: Tissue neutrophilia had an influence on treatment outcomes in the Asian CRSwNP patients. HNE-positive cells and IL-36α may be biomarkers for predicting refractoriness in Asians with CRSwNP. Additionally, imbalances in HNE and α1 anti-trypsin may be associated with pathophysiology of neutrophilic chronic rhinosinusitis.

Silicon nanodisk array design for effective light trapping in ultrathin c-Si.

The use of ultrathin c-Si (crystalline silicon) wafers thinner than 20 µm for solar cells is a very promising approach to realize dramatic reduction in cell cost. However, the ultrathin c-Si requires highly effective light trapping to compensate optical absorption reduction. Conventional texturing in micron scale is hardly applicable to the ultrathin c-Si wafers; thus, nano scale texturing is demanded. In general, nanotexturing is inevitably accompanied by surface area enlargements, which must be minimized in order to suppress surface recombination of minority carriers. In this study, we demonstrate using optical simulations that periodic c-Si nanodisk arrays of short heights less than 200 nm and optimal periods are very useful in terms of light trapping in the ultrathin c-Si wafers while low surface area enlargements are maintained. Double side texturing with the nanodisk arrays leads to over 90% of the Lambertian absorption limit while the surface area enlargement is kept below 1.5.