Snowflake-inspired and blink-driven flexible piezoelectric contact lenses for effective corneal injury repair.

The cornea is a tissue susceptible to various injuries and traumas with a complicated cascade repair process, in which conserving its integrity and clarity is critical to restoring visual function. Enhancing the endogenous electric field is recognized as an effective method of accelerating corneal injury repair. However, current equipment limitations and implementation complexities hinder its widespread adoption. Here, we propose a snowflake-inspired, blink-driven flexible piezoelectric contact lens that can convert mechanical blink motions into a unidirectional pulsed electric field for direct application to moderate corneal injury repair. The device is validated on mouse and rabbit models with different relative corneal alkali burn ratios to modulate the microenvironment, alleviate stromal fibrosis, promote orderly epithelial arrangement and differentiation, and restore corneal clarity. Within an 8-day intervention, the corneal clarity of mice and rabbits improves by more than 50%, and the repair rate of mouse and rabbit corneas increases by over 52%. Mechanistically, the device intervention is advantageous in blocking growth factors' signaling pathways specifically involved in stromal fibrosis whilst preserving and harnessing the signaling pathways required for indispensable epithelial metabolism. This work put forward an efficient and orderly corneal therapeutic technology utilizing artificial endogenous-strengthened signals generated by spontaneous body activities.

Integrated Multiplex Sensing Clear Aligner for In Situ Monitoring of Dental Enamel Demineralization.

Clear aligners have become one of the most important tools in orthodontic treatment. However, over a lengthy period of orthodontic treatment, enamel demineralization or even dental caries could be susceptible for occurrence. Therefore, early diagnosis of enamel demineralization has been widely investigated. Nevertheless, for reasons including bulky monitoring equipment and complexity of operation, few techniques reported to date possessed clinical utility. The combination of flexible electronics and electrochemical sensing technology presented a promising strategy. Herein, an integrated multiplex sensing clear aligner (IMSCA) system, including a clear aligner with a multiplex sensor array patch, was developed for in situ monitoring of Ca2+, pH, and PO43- in the oral environment to provide a foundation for early diagnosis of enamel demineralization. The IMSCA exhibited a broad linear response range, great selectivity, temporal stability, reproducibility, and biological safety. Results of enamel demineralization simulating experiments and human permanent tooth demineralization experiments validate the capability of the IMSCA to indicate the occurrence of enamel demineralization. All results ultimately point to the promising clinical utility of the IMSCA, which facilitates the quantitative characterization of enamel demineralization in complex oral environments. This study provides a novel strategy in the early diagnosis of enamel demineralization.

Study on the Optimal Surgical Scheme for Very Severe Osteoporotic Vertebral Compression Fractures.

OBJECTIVE: Therapy of very severe osteoporotic compression fractures (VSOVCF) has been a growing challenge for spine surgeons. Opinions vary regarding the optimal surgical procedure for the treatment of VSOVCF and which internal fixation method is more effective is still under debate, and research on this topic is lacking. This retrospective study was conducted to compare the efficacy and safety of various pedicle screw fixation methods for treating VSOVCF. METHODS: This single-center retrospective comparative study was conducted between January 2015 and September 2020. Two hundred and one patients were divided into six groups according to different surgical methods: 45 patients underwent long-segment fixation (Group 1); 39 underwent short-segment fixation (Group 2); 30 received long-segment fixation with cement-reinforced screws (Group 3); 32 received short-segment fixation with cement-reinforced screws (Group 4); 29 had long-segment fixation combined with kyphoplasty (PKP) (Group 5); and 26 cases had short-segment fixation combined with PKP (Group 6). The clinical records were reviewed and the visual analogue scale (VAS) score and the Oswestry Disability Index (ODI) score were used for clinical evaluation. The vertebral height (VH), fractured vertebral body height (FVBH), and Cobb's angle were objectively calculated and analyzed on lateral plain radiographs. Student's t-tests and one-way ANOVA among groups were conducted to analyze the continuous, and the chi-squared test was used to compare the dichotomous or categorical variables. The difference was considered statistically significant when the P-value was less than 0.05. RESULTS: The six groups had similar distributions in age, gender, course of the disease, follow-up period, and injured level. In the postoperative assessment of the VAS score, the surgical intervention most likely to rank first in terms of pain relief was the short-segment fixation with cement-reinforced screws (Group 4). For the functional evaluation, the surgical intervention that is most likely to rank first in terms of ODI score was a short-segment fixation with cement-reinforced screws (Group 4), followed by long-segment fixation (Group 1). The long-segment fixation with cement-reinforced screws was the first-ranked surgical intervention for the maintenance of Cobb's angle and vertebral height, whereas the short-segment fixation performed the worst. The highest overall complication rate was in Group 6 with an incidence of 42.3% (11/26), followed by Group 2 with an incidence of 38.5% (15/39). CONCLUSION: For the treatment of VSOVCF, the short-segment fixation with cement-reinforced screws is the most effective and optimal procedure, and should be used as the preferred surgical method if surgeons are proficient in using cemented screws; otherwise, directly and unquestionably use long-segment fixation to achieve satisfactory clinical results.

Bone-Metabolism-Related Serum microRNAs to Diagnose Osteoporosis in Middle-Aged and Elderly Women.

Objective: Postmenopausal osteoporosis (PMOP), a chronic systemic metabolic disease prevalent in middle-aged and elderly women, heavily relies on bone mineral density (BMD) measurement as the diagnostic indicator. In this study, we investigated serum microRNAs (miRNAs) as a possible screening tool for PMOP. Methods: This investigation recruited 83 eligible participants from 795 community-dwelling postmenopausal women between June 2020 and August 2021. The miRNA expression profiles in the serum of PMOP patients were evaluated via miRNA microarray (six PMOP patients and four postmenopausal women without osteoporosis (n-PMOP) as controls). Subsequently, results were verified in independent sample sets (47 PMOP patients and 26 n-PMOP controls) using quantitative real-time PCR. In addition, the target genes and main functions of the differentially expressed miRNAs were explored by bioinformatics analysis. Results: Four highly expressed miRNAs in the serum of patients (hsa-miR-144-5p, hsa-miR-506-3p, hsa-miR-8068, and hsa-miR-6851-3p) showed acceptable disease-independent discrimination performance (area under the curve range: 0.747-0.902) in the training set and verification set, outperforming traditional bone turnover markers. Among four key miRNAs, hsa-miR-144-5p is the only one that can simultaneously predict changes in BMD in lumbar spine 1-4, total hip, and femoral neck (ß = -0.265, p = 0.022; ß = -0.301, p = 0.005; and ß = -0.324, p = 0.003, respectively). Bioinformatics analysis suggested that the differentially expressed miRNAs were targeted mainly to YY1, VIM, and YWHAE genes, which are extensively involved in bone metabolism processes. Conclusions: Bone-metabolism-related serum miRNAs, such as hsa-miR-144-5p, hsa-miR-506-3p, hsa-miR-8068, and hsa-miR-6851-3p, can be used as novel biomarkers for PMOP diagnosis independent of radiological findings and traditional bone turnover markers. Further study of these miRNAs and their target genes may provide new insights into the epigenetic regulatory mechanisms of the onset and progression of the disease.

Study on Risk Factors of Primary Non-traumatic OVCF in Chinese Elderly and a Novel Prediction Model.

OBJECTIVE: Prevention of fragility fractures is one of the public health priorities worldwide, whilst the incidence of osteoporotic vertebral compression fractures (OVCF) continues to rise and lacks the corresponding accurate prediction model. This study aimed to screen potential causes and risk factors for primary non-traumatic osteoporotic vertebral compression fractures (NTOVCF) in the elderly by characterizing a patient population with NTOVCF and comparing it with a population of osteoporotic patients. METHODS: Between January 2013 and January 2022, 208 elderly patients with unequivocal evidence of bone fragility manifested as painful NTOVCF were enrolled, and compared with 220 patients with osteoporosis and no fractures. The demographic data, bone turnover markers, blood routine, serum biochemical values, and radiological findings were investigated. Differences between the fracture and non-fracture groups were analyzed, and variables significant in univariate analysis and correlation analysis were included in the logistic analysis to build the risk prediction model for osteoporotic vertebral fractures. Univariate analysis using student's t-tests for continuous variables or a chi-squared test for categorical variables was conducted to identify risk factors. RESULTS: No significant differences were revealed regarding age, gender, BMI, smoking, alcohol consumption, blood glucose, propeptide of type I procollagen (P1NP), and N-terminal middle segment osteocalcin (N-MID) (P > 0.05). Parathyroid Hormone (PTH), 25(OH)D, serum albumin (ALB), hemoglobin (HB), bone mineral density (BMD), and cross-sectional area (CSA) of the paraspinal muscle in the fracture group were significantly lower than those in the control group; however, b-C-terminal telopeptide of type I collagen (ß-CTX), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-prostatic acid phosphatase (NACP), and fatty degeneration ratio (FDR) were significantly higher than those in the control group (P < 0.05). Logistic regression analysis showed that ALB, HB, CSA, and BMD were negatively correlated with NTOVCF, while ß-CTX, HDL-C, NACP, and FDR were positively correlated with NTOVCF. CONCLUSION: Decreased physical activity, anemia, hypoproteinemia, imbalances in bone metabolism, abnormal lipid metabolism, and degenerative and decreased muscle mass, were all risk factors for OVCF in the elderly, spontaneous fractures may be the consequence of cumulative declines in multiple physiological systems over the lifespan. Based on this risk model, timely detection of patients with high OVCF risk and implementation of targeted preventive measures is expected to improve the effect of fracture prevention.

Tyrosine phosphorylation tunes chemical and thermal sensitivity of TRPV2 ion channel.

Transient receptor potential vanilloid 2 (TRPV2) is a multimodal ion channel implicated in diverse physiopathological processes. Its important involvement in immune responses has been suggested such as in the macrophages' phagocytosis process. However, the endogenous signaling cascades controlling the gating of TRPV2 remain to be understood. Here, we report that enhancing tyrosine phosphorylation remarkably alters the chemical and thermal sensitivities of TRPV2 endogenously expressed in rat bone marrow-derived macrophages and dorsal root ganglia (DRG) neurons. We identify that the protein tyrosine kinase JAK1 mediates TRPV2 phosphorylation at the molecular sites Tyr(335), Tyr(471), and Tyr(525). JAK1 phosphorylation is required for maintaining TRPV2 activity and the phagocytic ability of macrophages. We further show that TRPV2 phosphorylation is dynamically balanced by protein tyrosine phosphatase non-receptor type 1 (PTPN1). PTPN1 inhibition increases TRPV2 phosphorylation, further reducing the activation temperature threshold. Our data thus unveil an intrinsic mechanism where the phosphorylation/dephosphorylation dynamic balance sets the basal chemical and thermal sensitivity of TRPV2. Targeting this pathway will aid therapeutic interventions in physiopathological contexts.

All the cells in our body have a membrane that separates their interior from the outside environment. However, studded across this barrier are numerous ion channels which allow the cell to sense and react to changes in its surroundings. This includes the ion channel TRPV2, which opens in response to mechanical pressure, certain chemical signals, or rising temperature levels. Many types of cell express TRPV2, including cells in the nervous system, muscle, and the immune system. However, despite being extensively studied, it is still not clear how TRPV2 opens and closes upon encountering high temperatures. In particular, previous work suggested that TRPV2 only responds when a cell's surroundings reach around 52°C, which is a much higher temperature than cells inside our body normally encounter, even during a fever. To help resolve this mystery, Mo, Pang et al. studied TRPV2 in neurons responsible for sending sensory information and in immune cells called macrophages which had been extracted from rodents and grown in the laboratory. They found that when the cells were bathed in solutions containing magnesium ions, their TRPV2 channels were more sensitive to a number of different cues, including temperature. Further biochemical experiments showed that magnesium ions do not directly affect TRPV2, but increase the activity of another protein called JAK1. The magnesium ions caused JAK1 to attach specialized structures called phosphorylation tags to TRPV2. This modification (known as phosphorylation) made the channel more sensitive, allowing it to open in response to temperatures as low as 40°C. Mo, Pang et al. found that inhibiting JAK1 reduced the activity of TRPV2. Conversely, inhibiting the enzyme that removes the phosphorylation tags, called PTPN1, increased the channel's activity. They also discovered that when JAK1 was blocked, macrophages were less able to 'eat up' bacteria, which is one of their main roles in the immune system. Taken together these experiments advance our understanding of how TRPV2 becomes active. The balance between the phosphorylation by JAK1 and the dephosphorylation by PTPN1 controls the temperature at which TRPV2 opens. Since TRPV2 contributes to several biological functions, including the development of the nervous system, the maintenance of heart muscles, and inflammation, these findings will be important to scientists in a broad range of fields.

Multifunctional flexible contact lens for eye health monitoring using inorganic magnetic oxide nanosheets.

As a non-invasive innovative diagnosis platform, advanced flexible contact lenses can dynamically monitor vital ocular indicators, spot abnormalities and provide biofeedback guidance for real-time diagnosis and rehabilitation tracking of chronic eye diseases. However, most of the state-of-the-art reported contact lenses either can only monitor a single indicator at a time or realize multifunctional integration based on multiple materials. Herein, we developed a flexible multifunctional contact lens based on inorganic γ-Fe2O3@NiO magnetic oxide nanosheets, which can be attached conformally and seamlessly to the eyeball to simultaneously monitor glucose level in tears, eyeball movement, and intraocular pressure. The optimized contact lens has a reliable glucose detection limit (0.43 µmol), superior eye movement measurement accuracy (95.27%) and high intraocular pressure sensitivity (0.17 MHz mmHg- 1). This work presents a concept in the biochemical and biophysical integrated sensing of ocular signals using contact lens via an innovative material, and provides a personalized and efficient way for health management.

Identification of circRNA Expression Profiles in BMSCs from Glucocorticoid-Induced Osteoporosis Model.

BACKGROUND: Circular RNAs (circRNAs) contribute to the regulation of many diseases. However, little is known about the role of circRNAs in the development of glucocorticoid-induced osteoporosis (GIOP). The present study is aimed at systematically characterizing the circRNA expression profiles in GIOP and predict the potential functions of the associated regulatory networks. METHODS: A small animal GIOP model was developed in Sprague-Dawley rats given daily intraperitoneal doses of the synthetic glucocorticoid dexamethasone. Micro-CT and bone histomorphometry were performed to characterize the bone loss. Alizarin red S (ARS) staining and alkaline phosphatase (ALP) activity were assessed to determine the osteogenic differentiation potential of BMSCs. RNA sequencing was performed to identify differentially expressed circRNAs in BMSCs between the GIOP and normal groups, which were validated by qRT-PCR. siRNA interference experiments were used to demonstrate their function. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the functions of differentially expressed circRNAs. The microRNA (miRNA) targets of the circRNAs and circRNA-miRNA interactions were predicted. RESULTS: Micro-CT and bone histomorphometry confirmed the rat GIOP model. Both ARS intensity and ALP activity were decreased in GIOP BMSCs. Seventeen circRNAs were identified by fold change = 2.0, p < 0.05, and false discovery rate < 0.05, of which 7 were upregulated and 10 were downregulated. The qRT-PCR results of the selected circRNAs were consistent with the RNA-seq results and showed that circARSB and circAKT3 were significantly upregulated, while circPTEN and circTRPM7 were downregulated in the GIOP group. Further functional experiments found that downregulation of circARSB and circPTEN expression resulted in a corresponding change in osteogenic differentiation, suggesting that circARSB negatively, while circPTEN positively, regulates BMSC osteogenic differentiation. Analysis of circRNA-targeted miRNAs predicted that miR-135a-5p was associated with circARSB and circAKT3, and miR-881-3p was associated with circPTEN and circTRPM7. Furthermore, the signalling pathways associated with these differentially expressed circRNAs were predicted. CONCLUSIONS: The present study identified circARSB, circAKT3, circPTEN, and circTRPM7 as being associated with osteogenic differentiation during GIOP through a circRNA-targeted miRNA-mRNA axis, which might provide insight into the pathophysiological mechanism of GIOP.

Declining serum bone turnover markers are associated with the short-term positive change of lumbar spine bone mineral density in postmenopausal women.

OBJECTIVE: While serum bone turnover markers (BTMs) and bone mineral density (BMD) have been confirmed as useable risk assessment tools for postmenopausal osteoporosis, the associations between BTMs and BMD changes are still ambiguous. The aim of this study was to explore the underlying associations between BTMs and BMD changes in postmenopausal women. METHODS: Between January 2015 and October 2020, 135 postmenopausal women were retrospectively enrolled. They were divided into two groups according to lumbar spine (LS) 1-4 BMD change (1 y T-score minus baseline T-score, Group 1 [n = 36] < 0 and Group 2 [n = 99] ≥ 0). The changes of BTMs (N-terminal middle segment osteocalcin [N-MID], propeptide of type I procollagen [P1NP], and ß-C-terminal telopeptide of type I collagen [ß-CTX]) and their associations with LS 1-4 BMD change were analyzed. The biochemical indices and clinical parameters related with LS 1-4 BMD change were also evaluated. RESULTS: The 1 year N-MID, P1NP, ß-CTX and Phosphorus in Group 2 were lower than those in Group 1 (P < 0.05), their changes within 1 year were significantly negatively correlated with LS 1-4 BMD change (R2 = -0.200, P < 0.001; R2 = -0.230, P < 0.001; R2 = -0.186, P < 0.001; R2 = -0.044, P = 0.015; respectively). Except for the Phosphorus change (area under the curve [AUC] = 0.623), the changes of N-MID, P1NP, and ß-CTX and their 1 year levels had similar AUC to diagnose the short-term LS 1-4 BMD change (AUC > 0.7 for all, with the AUC of 1 y P1NP being the largest at 0.803). Binary logistic regression analysis showed that the physical activity and drug intervention were the determinant factors for the LS 1-4 BMD change (odds ratio = 6.856, 95% confidence interval: 2.058-22.839, P = 0.002; odds ratio  = 5.114, 95% confidence interval: 1.551-16.864, P = 0.007; respectively). CONCLUSIONS: Declining N-MID, P1NP, ß-CTX, and Phosphorus are associated with the short-term increase of LS 1-4 BMD within 1 year. Physical activity and drug intervention are factors significantly influencing the change of LS 1-4 BMD in postmenopausal women.