The MnO2/GelMA Composite Hydrogels Improve the ROS Microenvironment of Annulus Fibrosus Cells by Promoting the Antioxidant and Autophagy through the SIRT1/NRF2 Pathway.

Intervertebral disc degeneration (IVDD) is a worldwide disease that causes low back pain and reduces quality of life. Biotherapeutic strategies based on tissue engineering alternatives, such as intervertebral disc scaffolds, supplemented by drug-targeted therapy have brought new hope for IVDD. In this study, to explore the role and mechanism of MnO2/GelMA composite hydrogels in alleviating IVDD, we prepared composite hydrogels with MnO2 and methacrylate gelatin (GelMA) and characterized them using compression testing and transmission electron microscopy (TEM). Annulus fibrosus cells (AFCs) were cultured in the composite hydrogels to verify biocompatibility by live/dead and cytoskeleton staining. Cell viability assays and a reactive oxygen species (ROS) probe were used to analyze the protective effect of the composite hydrogels under oxidative damage. To explore the mechanism of improving the microenvironment, we detected the expression levels of antioxidant and autophagy-related genes and proteins by qPCR and Western blotting. We found that the MnO2/GelMA composite hydrogels exhibited excellent biocompatibility and a porous structure, which promoted cell proliferation. The addition of MnO2 nanoparticles to GelMA cleared ROS in AFCs and induced the expression of antioxidant and cellular autophagy through the common SIRT1/NRF2 pathway. Therefore, the MnO2/GelMA composite hydrogels, which can improve the disc microenvironment through scavenging intracellular ROS and resisting oxidative damage, have great application prospects in the treatment of IVDD.

High-Strength Smart Microneedles with "Offensive and Defensive" Effects for Intervertebral Disc Repair.

Intervertebral disc degeneration (IVDD) is a global public health issue. The injury of annulus fibrosus (AF) caused by acupuncture or discectomy can trigger IVDD again. However, there is currently no suitable method for treating AF injury. In this study, the high-strength smart microneedles (MNs) which can penetrate the AF tissue through a local and minimally invasive method, and achieve remote control of speeded-up release of the drug and hyperthermia by the Near Infrared is developed. The PDA/GelMA composite MNs loaded with diclofenac sodium are designed to extracellularly "offend" the inflammatory microenvironment and mitigate damage to cells, and intracellularly increase the level of cytoprotective heat shock proteins to enhance the defense against the hostile microenvironment, achieving "offensive and defensive" effects. In vitro experiments demonstrate that the synergistic treatment of photothermal therapy and anti-inflammation effectively reduces inflammation, inhibits cell apoptosis, and promotes the synthesis of the extracellular matrix (ECM). In vivo experiments show that the MNs mitigate the inflammatory response, promote ECM deposition, reduce the level of apoptosis, and restore the biomechanical properties of the intervertebral disc (IVD) in rats. Overall, this high-strength smart MNs display promising "offensive and defensive" effects that can provide a new strategy for IVD repair.

Engineered biomimetic micro/nano-materials for tissue regeneration.

The incidence of tissue and organ damage caused by various diseases is increasing worldwide. Tissue engineering is a promising strategy of tackling this problem because of its potential to regenerate or replace damaged tissues and organs. The biochemical and biophysical cues of biomaterials can stimulate and induce biological activities such as cell adhesion, proliferation and differentiation, and ultimately achieve tissue repair and regeneration. Micro/nano materials are a special type of biomaterial that can mimic the microstructure of tissues on a microscopic scale due to its precise construction, further providing scaffolds with specific three-dimensional structures to guide the activities of cells. The study and application of biomimetic micro/nano-materials have greatly promoted the development of tissue engineering. This review aims to provide an overview of the different types of micro/nanomaterials, their preparation methods and their application in tissue regeneration.

Hip Preservation or Total Hip Arthroplasty? A Retrospective Case-Control Study of Factors Influencing Arthroplasty Decision-Making for Patients with Osteonecrosis of the Femoral Head in China.

OBJECTIVE: At present, there is no consensus or guidance on indications for osteonecrosis of the femoral head (ONFH) patients to receive hip arthroplasty (THA) treatment. This study aims to explore the factors that influence the decision-making for THA in patients with ONFH, and to provide references for clinical decision for ONFH patients to be indicated for THA or hip preservation. METHODS: This retrospective case-control study involved data for ONFH patients from July 2016 to October 2021 from the China Osteonecrosis of the Femoral Head Database (CONFHD). The patients with ONFH, and unilateral hip affected at the first visit were divided into THA group and non-THA group according to if they had undergone THA treatment. The differences between the two groups of patients in terms of gender, age at the time of consultation, body mass index (BMI), etiology, onset side, association research circulation osseous (ARCO) stage, hip joint function, visual analog scale (VAS), etc. were analyzed. Multivariate binomial logistic regression analysis was then applied to evaluate the risk factors of ONFH patients who underwent THA during the first visit. RESULTS: A total of 640 patients were recruited for analysis, including 209 cases from the THA group and 431 cases from the non-THA group. The results of univariate analysis showed that the two groups of patients were significantly different in the following six indicators: age (59 vs. 46, Z = -9.58, p < 0.001), duration of disease (78 vs. 17, Z = -16.14, p < 0.001), gender composition (χ2  = 8.09, p = 0.004), disease etiology (χ2  = 33.04, p < 0.001), ARCO stage (χ2  = 334.86, p < 0.001), flexion of hip joint (χ2  = 172.33, p < 0.001). However, the comparison between the two groups on VAS (Z = -0.82, p = 0.41), BMI (Z = -1.35, p = 0.18), and onset side (χ2  = 1.53, p = 0.22) did not obviously differ. The results regression analysis showed that the age at the time of consultation, duration of disease, ARCO stage, and the hip joint function affected the decision making if the patients should undergo THA. The results of receiver operating characteristic curve (ROC) analysis showed that aforementioned indicators were satisfactory in predicting whether patients with ONFH would be treated with THA. The regression model using the above four indicators as comprehensive indicators has satisfactory performance in predicting whether to perform THA, and the area under the curve (AUC) is 93.94%. CONCLUSION: These factors such as age, duration of disease, ARCO stage, and hip flexion function should be considered comprehensively before making decisions to perform THA or not in our clinical practice.

Exercise vs Conventional Treatment for Treatment of Primary Osteoporosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Physical exercise has obvious effects on bone loss, pain relief, and improvement of bone metabolism indexes in patients with osteoporosis, but currently lacks sufficient evidence. The aim of this systematic review and meta-analysis was to synthesize and present the best available evidence on the effectiveness and safety of exercises in the treatment of primary osteoporosis. METHODS: Publications pertaining to the effectiveness of exercise on bone mineral density (BMD), visual analog scores (VAS), and biochemical markers of bone metabolism in primary osteoporosis (POP) from PubMed, Cochrane Library, Embase, VIP, CNKI, and Wanfang Database were retrieved from their inception to April 2020. RESULTS: A total of 20 studies with 1824 participants were included. The results of the meta-analysis revealed that exercise therapy for lumbar spine and femoral neck BMD is statistically different from conventional therapy (lumbar spine BMD: SMD = 0.78, 95%CI: 0.46, 1.10, P < 0.00001, I2  = 85%; femoral neck BMD (SMD = 0.80, 95%CI: 0.34, 1.27, P = 0.0007, I2  = 88%), exercise therapy can significantly increase the lumbar spine BMD of patients with OP, especially in lumbar spine2-4 BMD (SMD = 0.47; 95%CI: 0.20, 0.75; P = 0.0008; I2  = 69%). Compared with conventional treatment, kinesitherapy also has significant differences in alleviating the pain of POP patients (SMD = -1.39, 95%CI: -2.47,-0.31, P = 0.01, I2  = 97%). Compared with conventional therapy, kinesitherapy has no significant difference in improving biochemical markers of bone metabolism such as bone glaprotein (BGP) (SMD = 2.59, 95%CI:0.90, 4.28, P = 0.003, I2  = 98%), N-terminal pro peptide of type I procollagen (PINP) (SMD = 0.77, 95%CI: -0.44 to 1.98, P = 0.21, I2  = 95%), serum phosphorus (SMD = 0.04, 95%CI: -0.13, 0.22, P = 0.61, I2  = 30%), alkaline phosphatase (ALP) (SMD = -0.08, 95%CI: -0.44, 0.27, P = 0.64, I2  = 76%), and serum calcium (SMD = 0.12, 95%CI: -0.18, 0.43, P = 0.42, I2  = 63%) in POP patients. CONCLUSIONS: Kinesitherapy significantly improved lumbar spine and femoral neck BMD, and relieve the pain of patients in the current low-quality evidence. Additional high-quality evidence is required to confirm the effect of exercise therapy on the biochemical markers of bone metabolism in POP patients.

Acupotomy Therapy for Knee Osteoarthritis Pain: Systematic Review and Meta-Analysis.

METHODS: We performed a comprehensive search on PubMed, the Cochrane Library, EMBASE, and four Chinese databases for articles published prior to June 2020. We included only randomized controlled trials (RCTs) that used acupotomy therapy as the major intervention in adults with knee OA, were published in either Chinese and English, included more than 20 subjects in each group, and included pain and function in the outcome measures. Knee OA was defined by the American College of Rheumatology or Chinese Orthopedic Association criteria in all studies. We extracted the visual analogue scale (VAS) pain score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, the total effectiveness rate, the modified Japanese Orthopedic Association (JOA) activities of daily living score, and Lysholm's score. We calculated the mean difference (MD) or risk ratio (RR) for all relevant outcomes. Meta-analyses were conducted using random-effects models when appropriate. RESULTS: We identified 1317 potentially relevant studies, thirty-two of which met the eligibility criteria and were conducted in China between 2007 and 2020. A total of 3021 knee OA patients (62.96% female, median age: 57 years, and median disease duration: 33 months) were included. The treatment duration ranged from 1 week to 5 weeks (median: 3 weeks). The typical acupotomy treatment involved releasing soft tissue adhesions and was performed once a week for 1-5 weeks until the pain was relieved. The control group treatments included acupuncture (8 studies), electroacupuncture (10 studies), sodium hyaluronate (8 studies), radiofrequency electrotherapy (1 study), and nonsteroidal anti-inflammatory drugs (NSAIDs, 5 studies). The results from the meta-analysis showed that acupotomy led to superior improvements in the VAS pain score (MD = -1.11; 95% confidence interval (CI), -1.51 to -0.71; p < 0.00001) and WOMAC pain score (MD = -2.32; 95% CI, -2.94 to -1.69; p < 0.00001), a higher total effectiveness rate (RR = 1.15; 95% CI, 1.09-1.21; p < 0.00001), and superior improvements in the JOA score (MD = 6.39; 95% CI, 4.11-9.76; p < 0.00001) and Lysholm's score (MD = 12.75; 95% CI, 2.61-22.89; p = 0.01) for overall pain and function. No serious adverse events were reported. CONCLUSION: Chinese acupotomy therapy may relieve pain and improve function in patients with knee OA. Furthermore, rigorously designed and well-controlled RCTs are warranted.

Comparative Effectiveness of Different Combinations of Treatment Interventions in Patients with Stroke at the Convalescence Stage Based on the Markov Decision Process.

OBJECTIVE: The objective of this study was to compare the effectiveness of different combinations of interventions in patients with stroke at the convalescence stage based on the electronic health records (EHRs) by using the Markov decision process (MDP) theory and explore the feasibility of the Markov model in the real-world study (RWS). METHODS: Screening was conducted for patients with stroke at the convalescence stage who were admitted to the Third Affiliated Hospital of Zhejiang Chinese Medical University from January 2012 to January 2017 based on the EHRs. The relevant clinical data were extracted, and the appropriate conversion was made (state-action-reward) according to the Markov model. The transformed data were analysed and solved by the MDP to obtain the best interventions for patients with various stroke recovery periods. RESULTS: 926 patients with stroke at the convalescence stage were initially selected. And according to the inclusion exclusion criteria, 854 patients were screened. Through the MDP, we obtained the following results: (1)when the patients with stroke at the convalescence stage have a medical history, but no complications, and mild neurological impairment, ≥66-year- and 18-45-year-old patients are advised to choose acupuncture treatment. 46-65-year-old patients are advised to choose rehabilitation treatment. When patients with moderate to severe neurological impairment, patients are advised to choose rehabilitation, Chinese herbal decoction, and acupuncture combined therapy. (2) Without complications or medical history, patients who are ≥ 66 years old are recommended to choose rehabilitation treatment when the nerve function impairment is mild; rehabilitation and acupuncture treatment are recommended when moderate and severe injuries are caused. (3) The combination of rehabilitation, Chinese herbal decoction, and acupuncture treatment is recommended for patients with phlegm and blood stasis. Acupuncture treatment is recommended for patients with mild impairment of nerve function in qi deficiency and blood stasis type. Rehabilitation, Chinese herbal decoction, and acupuncture treatment are recommended for moderate-severe injuries. CONCLUSIONS: The MDP makes it possible to study the effectiveness of various treatment methods in stroke patients who are at the convalescence stage. Further exploratory studies using MDP theory in other areas in which complex interventions are common would be worthwhile.