Microneedle Patches-Integrated Transdermal Bioelectronics for Minimally Invasive Disease Theranostics.

Wearable epidermal electronics with non- or minimally-invasive characteristics can collect, transduce, communicate, and interact with accessible physicochemical health indicators on the skin. However, due to the stratum corneum layer, rich information about body health is buried under the skin stratum corneum layer, for example, in the skin interstitial fluid. Microneedle patches are typically designed with arrays of special microsized needles of length within 1000 µm. Such characteristics potentially enable the access and sample of biomolecules under the skin or give therapeutical treatment painlessly and transdermally. Integrating microneedle patches with various electronics allows highly efficient transdermal bioelectronics, showing their great promise for biomedical and healthcare applications. This comprehensive review summarizes and highlights the recent progress on integrated transdermal bioelectronics based on microneedle patches. The design criteria and state-of-the-art fabrication techniques for such devices are initially discussed. Next, devices with different functions, including but not limited to health monitoring, drug delivery, and therapeutical treatment, are highlighted in detail. Finally, key issues associated with current technologies and future opportunities are elaborated to sort out the state of recent research, point out potential bottlenecks, and provide future research directions.

Machine learning and bioinformatics analysis to identify autophagy-related biomarkers in peripheral blood for rheumatoid arthritis.

Background: Although rheumatoid arthritis (RA) is a common autoimmune disease, the precise pathogenesis of the disease remains unclear. Recent research has unraveled the role of autophagy in the development of RA. This research aims to explore autophagy-related diagnostic biomarkers in the peripheral blood of RA patients. Methods: The gene expression profiles of GSE17755 were retrieved from the gene expression ontology (GEO) database. Differentially expressed autophagy-related genes (DE-ARGs) were identified for the subsequent research by inserting autophagy-related genes and differentially expressed genes (DEGs). Three machine learning algorithms, including random forest, support vector machine recursive feature elimination (SVM-RFE), and least absolute shrinkage and selection operator (LASSO), were employed to identify diagnostic biomarkers. A nomogram model was constructed to assess the diagnostic value of the biomarkers. The CIBERSORT algorithm was performed to investigate the correlation of the diagnostic biomarkers with immune cells and immune factors. Finally, the diagnostic efficacy and differential expression trend of diagnostic biomarkers were validated in multiple cohorts containing different tissues and diseases. Results: In this study, 25 DE-ARGs were identified between RA and healthy individuals. In addition to "macroautophagy" and "autophagy-animal," DE-ARGs were also associated with several types of programmed cell death and immune-related pathways according to GO and KEGG analysis. Three diagnostic biomarkers, EEF2, HSP90AB1 and TNFSF10, were identified by the random forest, SVM-RFE, and LASSO. The nomogram model demonstrated excellent diagnostic value in GSE17755 (AUC = 0.995, 95% CI: 0.988-0.999). Furthermore, immune infiltration analysis showed a remarkable association between EEF2, HSP90AB1, and TNFSF10 expression with various immune cells and immune factors. The three diagnostic biomarkers also exhibited good diagnostic efficacy and demonstrated the same trend of differential expression in multiple validation cohorts. Conclusion: This study identified autophagy-related diagnostic biomarkers based on three machine learning algorithms, providing promising targets for the diagnosis and treatment of RA.

Global Trends and Hotspots on Microglia Associated with Pain from 2002 to 2022: A Bibliometric Analysis.

Background: Researchers have made significant progress in microglia associated with pain in recent years. However, more relevant bibliometric analyses are still needed on trends and directions in this field. The aim of this study is to provide a comprehensive perspective and to predict future directions of pain-related microglia research via bibliometric tools. Methods: English articles and reviews related with pain and microglia were extracted from the Web of Science core collection (WosCC) database between 2002 to 2022. Bibliometric tools such as VOSviewer, CiteSpace, and Bibliometrix R package were used to analyze publication characteristics, countries, authors, institutions, journals, research hotspots, and trend topics. Results: A total of 2761 articles were included in this analysis. Research on microglia associated with pain has increased significantly over the last two decades. China (n = 1020, 36.94%) and the United States (n = 751, 27.20%) contributed the most in terms of publications and citations, respectively. Kyushu University published the most articles in this field compared to other institutions, and Professor Inoue Kazuhide (n = 54) at this university made outstanding contributions in this field. Molecular Pain (n = 113) was the journal with the most publication, while Journal of Neuroscience had the highest number of citations. According to the authors keywords analysis, the research in this area can be summarized into 7 clusters such as "microglia activation pathways", "pain treatment research", "mental symptoms of chronic pain", and so on. Conclusion: This study provides a comprehensive analysis of pain-related microglia research in the past two decades. We identified the countries, institutions, scholars, and journals with the highest number of publications and the most influence in the field, and the research trends identified in this paper may provide new insights for future research.

The nucleus accumbens functional connectivity in patients with insomnia using resting-state fMRI.

Background: The aim of this study was to investigate the functional abnormalities between the nucleus accumbens (NAc) and the whole brain in individuals with Insomnia Disorder (ID) using resting-state functional magnetic resonance imaging (fMRI). Additionally, the study aimed to explore the underlying neural mechanisms of ID. Methods: We enrolled 18 participants with ID and 16 normal controls (NC). Resting-state functional connectivity (FC) between the NAc and the whole brain voxels was calculated and compared between the two groups to identify differential brain region. Receiver operating characteristic (ROC) curve analysis was employed to assess the ability of differential features to distinguish between groups. Furthermore, Pearson correlation analysis was performed to examine the relationship between neurocognitive scores and differential features. Results: The ID group exhibited significantly reduced FC values in several brain regions, including the right supplementary motor area, the bilateral middle frontal gyrus, the bilateral median cingulate and paracingulate gyri and the left precuneus. The area under the curve (AUC) of the classification model based on FC in these brain regions was 83.3%. Additionally, the abnormal functional changes observed in ID patients were positively correlated with the Fatigue Severity Scale (R = 0.650, p = 0.004). Conclusion: These findings suggest that the NAc may play a crucial role in the diagnosis of ID and could serve as a potential imaging biomarker, providing insights into the underlying neural mechanisms of the disorder.

Altered brain functional networks after Quchi (LI 11) acupuncture: An EEG analysis.

BACKGROUND: As a unique traditional Chinese medicine therapy, the central effect of acupuncture has received increasing attention. Functional brain networks can provide connectivity information among brain regions. OBJECTIVE: The study goal is to explore the regulatory effect of acupuncture on the brain functional network. METHODS: This paper analyzes the electroencephalography (EEG)-based power spectrum and brain functional network elicited by acupuncture at Quchi (LI 11). RESULTS: The power spectrum results showed that acupuncture at LI 11 decreased the energy in the alpha frequency, mainly in the central region, left parietal lobe, left temporal lobe and left frontal lobe. Moreover, functional brain networks converted from the magnitude-squared coherence matrix in the alpha band are reconstructed. The results show that acupuncture did not alter the basic properties of the brain functional connection network. During acupuncture, the average node degree, average clustering coefficient, and small-world property of the brain functional connection network decreased after acupuncture compared with that before it. However, the average characteristic path length increased after acupuncture compared with before. CONCLUSION: Acupuncture at LI 11 altered the brain's electrical activity. In the meantime, this acupuncture reduced the network's internal connectivity and information transfer efficiency.

The Efficacy of Electroacupuncture in the Treatment of Knee Osteoarthritis: A Systematic Review and Meta-Analysis.

This study aims to evaluate the comparative efficacy of electroacupuncture (EA) and analgesics in treating knee osteoarthritis (KOA) and provide evidence-based medical support for EA for the treatment of KOA. Randomized controlled trials from January 2012 to December 2021 are included in electronic databases. The Cochrane risk of bias tool for randomized trials is used to assess the risk of bias in the included studies, while the Grading of Recommendations, Assessment, Development and Evaluation is used to assess the quality of evidence. Statistical analyses are performed using Review Manager V5.4. There are 1616 patients from 20 clinical studies, including 849 patients in the treatment group and 767 patients in the control group. The effective rate in the treatment group is significantly higher than in the control group (p < 0.00001). In the treatment group, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness scores are significantly improved as compared to the control group (p < 0.0001). However, EA is similar to analgesics in improving visual analog scale scores and WOMAC subitems such as pain and joint function. EA is effective in treating KOA because it can significantly improve clinical symptoms and quality of life in KOA patients.

Manual acupuncture for neuromusculoskeletal disorders: The selection of stimulation parameters and corresponding effects.

As a minimally invasive method of physical stimulation, manual acupuncture (MA) is used globally as a sort of therapy for neuromusculoskeletal disorders. In addition to selecting appropriate acupoints, acupuncturists should also determine the stimulation parameters of needling, such as the manipulation (lifting-thrusting or twirling), needling amplitude, velocity, and stimulation time. At present, most studies focus on acupoint combination and mechanism of MA, the relationship between stimulation parameters and their therapeutic effects, as well as the influence on mechanism of action are relatively scattered, and lack of systematic summary and analysis. This paper reviewed the three types of stimulation parameters of MA, their common options and values, corresponding effects and potential mechanisms of action. The purpose of such efforts is to provide a useful reference for the dose-effect relationship of MA and the quantification and standardization of its clinical treatment of neuromusculoskeletal disorders to further promote the application of acupuncture in the world.

Establishment of basic principles and methods of acupuncture standardization in traditional Chinese medicine / 数字中医药（英文）

@#Standardization is the universal language of the world, and standardization of traditional Chinese medicine (TCM) is essential for its communication in China and globally. However, the principles and methods of TCM acupuncture standardization have been unclear and inadequate in the early stages. Based on an investigative approach to understanding the current status, identifying problems, and finding solutions, our team has established basic principles of TCM acupuncture that embody Chinese wisdom, evaluated the international strategic environment systematically, proposed the principle of “importance of harmony and exercise of impartiality”, and established basic working principles. A series of methods for TCM acupuncture standard development and evaluation have been constructed, including general standards for the revision of TCM acupuncture standards, the first TCM acupuncture clinical research management specification, a shared full chain technology platform, a data center, and an evaluation research base for TCM acupuncture clinical research. Evaluation criteria for ancient literature and expert experience, a recommendation method for the “three main and three auxiliaries” TCM guideline for prevention were established, and quantifiable assessment methods of TCM standard applicability were proposed. These findings provide methodological guidance for TCM acupuncture standardization.

Bioelectric phenomena in electroacupuncture analgesia. / 电针镇痛中的生物电现象.

Pain is a complex process of electrical signal transmission. Electroacupuncture may adjust the bioelectric state of the tissues in painful sites through electrical characteristic structural units (acupoints), thereby exerting analgesic effect. The treatment of diseases with electroacupuncture results from the interaction between the external electric field and the electrical properties of acupoint tissues. Therefore, the state of biological tissues and the parameters of electroacupuncture all affect the therapeutic effect.

Dexamethasone-Loaded Injectable In-situ Thermal Crosslinking Magnetic Responsive Hydrogel for the Physiochemical Stimulation of Acupoint to Suppress Pain in Sciatica Rats.

The physicochemical stimulation of acupoints is a widespread treatment strategy for different diseases, such as sciatica. Its efficacy is mainly based on the temporal and spatial modulation of the physicochemical properties of the acupoints. The existing therapies based on the stimulation of acupoints have certain disadvantages. Therefore, in this study, injectable dexamethasone (DXM)- and magnetic Fe3O4 nanoparticles-loaded chitosan/ß-glycerophosphate (CS/GP) thermal crosslinking hydrogels were prepared, thereby improving the performance of embedding materials. The sciatica rat models were established to compare the therapeutic effects of hydrogels and catgut. The DXM or Fe3O4-loaded CS/GP hydrogels were compared in terms of their gelation kinetics, release kinetics, magnetic responsiveness in-vitro, and biocompatibility as well as their analgesic effects on the chronic constriction injury of the sciatic nerve (CCI) rats in-vivo. The CS/GP/Fe3O4/DXM hydrogel showed comparable gelation kinetics and good magnetic responsiveness in-vitro. This hydrogel could relieve sciatica by reducing the expression levels of inflammatory factors in serum, inhibiting the p38MAPK (p38, mitogen-activated protein kinase) phosphorylation, and decreasing the expression level of the P2X4 receptor (P2X4R) in the spinal dorsal horn. In conclusion, the DXM or Fe3O4-loaded CS/GP hydrogels can be considered as a treatment option for the physiochemical stimulation therapy of acupoints to improve sciatica.

[Study on the quantitative evaluation parameter system for basic acupuncture manipulations based on 3D motion tracking technology].

OBJECTIVE: To establish a quantitative evaluation parameter system for basic acupuncture manipulations based on 3D motion tracking technology, and to further analyze the characteristics of acupuncture manipulation. METHODS: The motion tracking system Simi Motion Ver.8.5 was used to collect parameters of acupuncture manipulations, so as to establish a quantitative evaluation system mainly in spatial control parameters, time control parameters and stability parameters. Based on the evaluation parameter system, data of acupuncture manipulations (even reinforcing-reducing manipulation using lifting-thrusting technique and twirling technique) were collected from 19 teachers majored in acupuncture-moxibustion, of which the characteristics were analyzed and were compared with the results tested by traditional ATP-Ⅱ acupuncture manipulation parameter determination apparatus (ATP-Ⅱ). RESULTS: The evaluation parameter system could quantitatively analyze the basic acupuncture manipulations in 3 aspects, i.e. space, time and stability. Acupuncture manipulations were performed by shifting the needle body in a certain range along X, Y and Z axes. The amplitude and speed of thumb movement were greater than those of index finger. The time-history of lifting was similar to thrusting, while the time-history of twirling to left was similar to twirling to right in even reinforcing-reducing manipulation. The coordinate-time curve of finger movement of the evaluation system had consistent wave pattern compared with the voltage-time curve generated by ATP-Ⅱ. CONCLUSION: The quantitative evaluation parameter system based on 3D motion tracking technology can objectively evaluate basic acupuncture manipulations, and show the characteristics of different manipulations and the movement details of finger joints.

New Proposals for Application of Terahertz Imaging Technique in Chinese Medicine.

The rapid development of terahertz technology promotes the realization of various terahertz imaging systems. Terahertz technology features terahertz waves as good non-invasive illumination sources due to their high spectral resolution, penetration and safety. The terahertz imaging technique (TIT) has gradually been extended from the biomedical field to the field of Chinese medicine (CM), and it has become a powerful tool for seeking scientific evidence for CM theories with the use of modern science and technology. This paper reviews the current application of TITs in the field of CM research, and most importantly offers novel proposals for the application of TITs in CM research from the perspective of CM syndrome objectification and acupuncture research and cites existing reports as reference to the feasibility of these new proposals.

Three-dimensional Finger Motion Tracking during Needling: A Solution for the Kinematic Analysis of Acupuncture Manipulation.

Three-dimensional (3D) motion tracking has been used in many fields, such as the researches of sport and medical skills. This experiment aimed to use 3D motion tracking technology to measure the kinematic parameters of the joints of fingers during acupuncture manipulation (AM) and establish three technical indicators "amplitude, velocity and time". This method can reflect the operation characteristics of AM and provide quantitative parameters along three axes of multiple finger joints. The current evidence shows that the method has great potential for future applications such as the study of the dose-effect relationship of acupuncture, teaching, and learning of AM, and the measurement and preservation of famous acupuncturists' AM.

[Development of handshape tuina-cupping instrument based on pulsating airflow technology].

A new type of handshape tuina-cupping instrument is developed to overcome the shortcomings of traditional cupping therapy, such as indentation and pain, and simulates the tuina manipulation, so as to realize the combination of cupping therapy and tuina manipulation. The handshape tuina-cupping instrument has a trumpet-shaped, silica gel edge. At the same time, the finger-belly shape is added at the cupping edge to simulate the shape of fingers during tuina. Under the action of air suction and deflation of pulsating airflow, the purpose of simulating tuina manipulation is achieved, and the indentation and pain caused by the handshape tuina-cupping instrument is significantly less than that of the traditional cupping instrument.

[Conduction pathway and function of physical signals of moxibustion stimulus].

By reviewing the relevant literature in recent years, this paper analyzes the transformation and conduction of moxibustion physical signals, and explores the action mechanism of moxibustion. It is found that the different molecular targets activated by moxibustion photothermal signal are the keys to transform stimulation signal into biological signal. Photothermal signal transmits signal through neuroendocrine immune system and produces a series of biological reactions, thus regulating the functions of various systems of the body.

Increased Level of Systolic Blood Pressure in Hepatocellular Carcinoma Patients with Diabetes Mellitus.

BACKGROUND: More than 50% of patients with type 2 diabetes mellitus (DM) also have hypertension. Moreover, hypertension has been regarded as one paraneoplastic phenomenon of hepatocellular carcinoma (HCC). Our study was designed to determine the relationship between blood pressure and DM in HCC patients. PATIENTS AND METHODS: A total of 879 HCC patients were included and 151 (17.2%) were diagnosed with DM. Multivariable logistic regression analysis was used to determine the relationship and the results were expressed as adjusted odds ratios (AORs) and their 95% confidence intervals (CIs). Considering the effect of potential confounders, sub-group analysis was performed. We would further study the association of systolic blood pressure (SBP) with fasting glucose, and the association between DM duration/treatment and SBP level. RESULTS: Compared with non-diabetic patients, the diabetic patients had increased levels of SBP (133.7±18.5 mmHg vs 128.3±15.2 mmHg, P=0.001) and fasting blood glucose (9.13±3.04 mmol/L vs 5.18±1.08 mmol/L, P<0.001), an elder age (58.5±10.2 years vs 55.3±11.2 years, P=0.001), a higher percentage of cirrhosis diagnosis (60.9% vs 48.2%, P=0.004), lower percentages of drinking (18.5% vs 30.8%, P=0.002) and smoking (30.5% vs 43.7%, P=0.003), and decreased levels of GGT (median/interquartile-range 88/53-177 U/L vs 117/58-248 U/L, P=0.037), platelet count (121.4±76.6 ×109/L vs 151.2±82.8 ×109/L, P<0.001) and hemoglobin (124.3±25.5 g/L vs 133.6±24.2 g/L, P<0.001). Multivariable analysis showed that, statistically significant differences were found for SBP ≥140 mmHg (AOR=2.101; 95% CI, 1.424-3.100; P<0.001), smoking (AOR=0.637; 95% CI, 0.415-0.979; P=0.040), hemoglobin (AOR=0.990; 95% CI, 0.983-0.998; P=0.010) and platelet count (AOR=0.996; 95% CI, 0.994-0.999; P=0.009). For the relationship between SBP and DM, the positive result was supported by most (10/14) of the subgroup analyses. CONCLUSION: SBP level was increased in HCC patients with diabetes mellitus.

A Hydrogel Microneedle Patch for Point-of-Care Testing Based on Skin Interstitial Fluid.

Skin interstitial fluid (ISF) holds great potential as a highly desirable sample resource for point-of-care testing (POCT), where the key is to effectively collect target biomarkers from ISF. Hydrogel microneedle patch has great promise for ISF extraction. However, it is challenging to recover target biomarkers from the extracted skin ISF in hydrogel microneedle patches in an easy-administrated, fast, and bulky instrument-free manner. Herein, a hydrogel microneedle patch made of polyvinyl alcohol (PVA) and chitosan (CS) for POCT based on the ISF is developed. The phase transition property of PVA/CS hydrogel makes the microneedles stiff when dry, which is beneficial to easily penetrate into skin. Meanwhile, the highly porous microstructure of hydrogel offers good swelling ability for extraction of ISF and the thermal degradation property of PVA makes it convenient to quickly and efficiently recover target biomarkers from microneedle patch. The capability of this platform for POCT applications is further demonstrated by successful detections of typical biomarkers collected from the mimetic skin and monitoring the glucose level in rabbit skins during a day. The developed hydrogel microneedle patch holds the advantages of extraction of skin ISF and recovery of biomarkers, thus presenting as a powerful platform for skin ISF-based POCT applications.

Paper-based point-of-care immunoassays: Recent advances and emerging trends.

Immunoassay has been routinely used in hospitals and central labs. Nowadays, to further meet the requirement of widespread applications of immunoassays, it is urgently needed to produce a simplified, rapid and low-cost immunoassay to perform tests on site. To this end, paper-based point-of-care (POC) immunoassays have attracted intensive interests in recent years. In this paper, we present a comprehensive review of the recent advances and emerging trends of paper-based POC immunoassays, including the fundamental components and work principles, various detection mechanisms and applications, and existing commercialized devices/products. At last, we envision three promising development directions for paper-based POC immunoassays.

Stimulation Parameters of Manual Acupuncture and Their Measurement.

The therapeutic effect of manual acupuncture (MA) is closely related to the stimulation amount. In the clinical studies, the stimulation amount is often difficult to be determined. The reason is that there are many parameters affecting the stimulation amount, including manipulation selection, treatment time, needling velocity, and force, and no complete and reasonable scheme is available for the measurement of stimulation parameters. This paper reviewed the theoretical and laboratory measurement studies on MA stimulation, summarized 4 types of available parameters according to the theory of physics, and compared the advantages and disadvantages of the existing methods of parameter measurement. Such efforts are hoped for providing reference for the establishment of the stimulation parameter system of MA and possible technical solutions for future measurement experiments.

[Design and implementation of a method for temperature parameter collection inside acupoint].

OBJECTIVE: To realize real-time measurement and recording of temperature parameters inside acupoints during acupuncture treatment. METHODS: The fine wire thermocouple was embedded in hollow needle body as acupoint detection probe. According to the structure of acupoint temperature signal processing circuit, the Agilent 34420A nanovolt/micro-eurometer was used to design the technology method of acupoint temperature data acquisition, and an acupoint temperature collection platform was established. In addition, a verification experiment was conducted to verify the feasibility and stability of the system. RESULTS: The contrast experiment with mercury thermometer measurement showed that the temperature measurement curve of the designed acupoint temperature data collection platform was highly consistent with that of the standard thermometer, which verified the stability and reliability of the designed temperature measurement platform. The experiment of animal in-vivo measurement showed that the acupoint temperature probe had good feasibility for in-vivo acupoint temperature measurement. CONCLUSION: Acupoint temperature probe and acupoint temperature data collection technology can measure the temperature inside acupoints, and ensured the accuracy and veracity of the results. As an experimental method of acupoints temperature parameter collection, it can quantitatively record the temperature changes during the acupuncture treatment.