Imbalance of macrophage polarization characterized by an increase in the percentage of pro-inflammatory M1 macrophages and a decrease in anti-inflammatory M2 macrophages is considered a critical pathogenic mechanism of bisphosphonate-related osteonecrosis of the jaws (BRONJ).Because high levels of Toll-like receptor 4 (TLR4) mediates mitochondrial dyshomeostasis in Zoledronic Acid (ZA)-treated M1 macrophages, tetrahedral DNA nanomaterial (TDN)-modified with TLR4-siRNA on each vertex (TDN-TLR4-4siR) with excellent biocompatibility is synthesized. This novel TDN-TLR4-4siR nanomaterial reverses the polarization phenotype imbalance decreasing the percentage of M1 RAW264.7 macrophages. Mitochondrial dynamics analysis shows a shift from short rod-like ultrastructure to elongated shapes with more mitochondrial network continuity in ZA-primed M1 macrophages after treatment with TDN-TLR4-4siR, along with elevated expression of Mfn1 and Mfn2. TDN-TLR4-4siR further reduces intracellular ROS production and restored mitochondrial membrane potential. Furthermore, decreased sequestra formation and accelerated healing of the extraction wound are observed in the TDN-TLR4-4siR group, resulting in decreased incidence of rat BRONJ via reprogramming polarized macrophages. Consequently, this study establishes a novel strategy using TDN-TLR4-4siR nanomaterial to regulate mitochondrial homeostasis of polarized macrophages to prevent BRONJ.

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The goal of this study is to develop and validate a novel semi-automatic detection method (SADM) under nasopharyngoscopy based on the image processing technique, which can assist the evaluation of the velar closure ratio (VCR). After the development of the SADM, 72 patients were enrolled. The reliability of SADM was evaluated by repeated measurements. Velar closure ratio are given by conventional nasopharyngoscopy method and SADM were compared. Velar closure ratios given by SADM were further translated into a trichotomous classification for velopharyngeal function diagnosis, that is, velopharyngeal closure (VPC), marginal VPC (MVPC), and velopharyngeal incomplete. The 2 VCR-thresholds used for the translation were explored and validated. As results shown, SADM was proved to be reliable with an intraclass correlation coefficient of 0.996 (95% confidence interval: 0.993–0.997, P < 0.001). Intraclass correlation coefficient between conventional nasopharyngoscopy method and SADM was 0.954 (95% confidence interval: 0.927– 0.971, P < 0.001). Velar closure ratio-thresholds were set at 0.82 and 0.92 according to the ROC curve. Diagnostic sensitivity and specificity for velopharyngeal incomplete were 1.00 and 1.00. MVPC had 0.58 sensitivity and 0.96 specificities while VPC had 0.92 and 0.79, respectively. No statistically significant difference was found between the diagnosis of SADM and speech pathologists (P > 0.1). In conclusion, this study successfully developed an accurate and reliable semi-automatic method to evaluate VCR, which could help improve the efficacy of VCR evaluation and velopharyngeal function diagnosis.

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