The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity.

Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.

A Versatile Nanoplatform for Broad-Spectrum Immunotherapy by Reversing the Tumor Microenvironment.

Immunotherapy is currently an important adjuvant therapy for malignant tumors besides surgical treatment. However, the heterogeneity and low immunogenicity of the tumor are two main challenges of the immunotherapy. Here, we have constructed a nanoplatform (CP@mRBC-PpIX) to realize reversion of the tumor acidosis and hypoxia through alkali and oxygen generation triggered by tumor acidosis. By targeting tumor universal features other than endogenous biomarkers, it was found that CP@mRBC-PpIX could polarize tumor-associated macrophages to anti-tumor M1 phenotype macrophages to enhance tumor immune response. Furthermore, under regional light irradiation, the reactive oxygen species produced by photosensitizers located in CP@mRBC-PpIX could increase the immunogenicity of tumors, so that tumor changes from an immunosuppressive "cold tumor" to an immunogenic "hot tumor," thereby increasing the infiltration and response of T cells, further amplifying the effect of immunotherapy. This strategy circumvented the problem of tumor heterogeneity to realize a kind of broad-spectrum immunotherapy, which could effectively prevent tumor metastasis and recurrence.

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis.

BACKGROUND Rheumatoid arthritis (RA) has a high prevalence in the elderly population. The genes and pathways in the inflamed synovium in patients with RA are poorly understood. This study aimed to identify differentially expressed genes (DEGs) linked to the progression of synovial inflammation in RA using bioinformatics analysis. MATERIAL AND METHODS Gene expression profiles of datasets GSE55235 and GSE55457 were acquired from the Gene Expression Omnibus (GEO) database. DEGs were identified using Morpheus software, and co-expressed DEGs were identified with Venn diagrams. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into subnetworks using the Molecular Complex Detection (MCODE) algorithm. The functions of the top module were assessed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. RESULTS DEGs that were upregulated were significantly enhanced in protein binding, the cell cytosol, organization of the extracellular matrix (ECM), regulation of RNA transcription, and cell adhesion. DEGs that were downregulated were associated with control of the immune response, B-cell and T-cell receptor signaling pathway regulation. KEGG pathway analysis showed that upregulated DEGs enhanced pathways associated with the cell adherens junction, osteoclast differentiation, and hereditary cardiomyopathies. Downregulated DEGs were enriched in primary immunodeficiency, cell adhesion molecules (CAMs), cytokine-cytokine receptor interaction, and hematopoietic cell lineages. CONCLUSIONS The findings from this bioinformatics network analysis study identified molecular mechanisms and the key hub genes that may contribute to synovial inflammation in patients with RA.

Treatment of Anterior Sternoclavicular Joint Dislocation with Acromioclavicular Joint Hook Plate.

OBJECTIVE: To evaluate the safety and efficacy of using acromioclavicular joint hook plates for the treatment of anterior sternoclavicular joint dislocation. METHODS: Ten patients who suffered anterior sternoclavicular joint dislocation were retrospectively analyzed, and underwent acromioclavicular joint hook plate surgeries from January 2015 to May 2017. There were 7 male and 3 female patients, with a mean age of 43.6 years. According to the American Shoulder and Elbow Society (ASES) scoring system, the preoperative physical function had a mean of 83.5. RESULTS: Reduction and fixation were performed with hook plates in all 10 patients. All patients were followed up, with a mean duration of 16.9 months. There were no complications, no wound infections, and no plate or screw breakages. Movement of the shoulder girdle was improved in all patients. According to the ASES scoring system, the postoperative physical function had a mean of 94.8. CONCLUSION: The acromioclavicular joint hook plate demonstrates safety and efficacy for the treatment of anterior sternoclavicular joint dislocation. However, there are still some deficiencies that need to be improved.

Application of the Guiding Template Designed by Three-dimensional Printing Data for the Insertion of Sacroiliac Screws: a New Clinical Technique.

This study is aimed to explore the clinical application of the guiding template designed by three-dimensional printing data for the insertion of sacroiliac screws. A retrospective study of 7 cases (from July 2016 to December 2016), in which the guiding template printed by the threedimensional printing technique was used for the insertion of sacroiliac screws of patients with posterior ring injuries of pelvis, was performed. Totally, 4 males and 3 females were included in template group, aged from 38 to 65 years old (mean 50.86±8.90). Of them, 5 had sacral fractures (3 with Denis type I and 2 with type II) and 2 the separation of sacroiliac joint. Guiding templates were firstly made by the three-dimensional printing technique based on the pre-operative CT data. Surgical operations for the stabilization of pelvic ring by applying the guiding templates were carried out. A group of 8 patients with sacroiliac injuries treated by percutaneous sacroiliac screws were analyzed as a control group retrospectively. The time of each screw insertion, volume of intra-operative blood loss, and the exposure to X ray were analyzed and the Matta's radiological criteria were used to evaluate the reduction quality. The Majeed score was used to evaluate postoperative living quality. The visual analogue scale (VAS) was applied at different time points to judge pain relief of coccydynia. All the 7 patients in the template group were closely followed up radiographically and clinically for 14 to 20 months, mean (16.57±2.44) months. Totally 9 sacroiliac screws for the S1 and S2 vertebra were inserted in the 7 patients. The time length for each screw insertion ranged from 450 to 870 s, mean (690.56±135.68) s, and the number of times of exposure to X ray were 4 to 8, mean (5.78±1.20). The intra-operative blood loss ranged from 45 to 120 mL, mean (75±23.32) mL. According to Matta's radiology criteria, the fracture and dislocation reduction were excellent in 6 cases and good in 1. The pre-operative VAS score ranged from 5.2 to 8.1, mean (7.13±1.00). The average one-week/six-month post-operative VAS was (5.33±0.78) and (1.33±0.66), respectively (P<0.05 when compared with pre-operative VAS). The 12-month postoperative Majeed score ranged from 86 to 92, mean (90.29±2.21). The three-dimensional printed guiding template for sacroiliac screw insertion, which could significantly shorten the operation time, provide a satisfied outcome of the stabilization of the pelvic ring, and protect doctors and patients from X-ray exposure, might be a practical and valuable new clinical technique.

Low-intensity treadmill exercise promotes rat dorsal wound healing.

In order to investigate the promoting effect of low-intensity treadmill exercise on rat dorsal wound healing and the mechanism, 20 Sprague-Dawley rats were randomly divided into two groups: exercise group (Ex) and non-exercise group (non-ex). The rats in Ex group were given treadmill exercise for one month, and those in non-ex group raised on the same conditions without treadmill exercise. Both groups received dorsal wound operation with free access to food and water. By two-week continuous observation and recording of the wound area, the healing rate was analyzed. The blood sample was collected at day 14 post-operation via cardiac puncture for determination of the number of endothelial progenitor cells (EPCs) by flow cytometry, and the concentrations of relevant cytokines such as basic fibroblast growth factor (bFGF), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were measured by ELISA. The skin tissue around the wound was dissected to observe the vascular density under the microscope after HE staining, to detect the mRNA level of VEGFR2 and angiopoietin-1 (Ang-1) receptor using RT-qPCR, and protein expression of a-smooth muscle actin (αSMA) and type III collagen (ColIII) using Western blotting. It was found that the wound area in Ex group was smaller at the same time point than in non-ex group. The number of circulating EPCs was greater and the concentrations of vasoactive factors such as VEGF, eNOS and bFGF were higher in Ex group than in non-ex group. HE staining displayed a higher vessel density in Ex group than in non-ex group. Moreover, the mRNA expression of VEGFR2 and Ang-1 detected in the wound tissue in Ex group was higher than in non-ex group. Meanwhile, the protein expression of αSMA and ColIII was more abundant in Ex group than in non-ex group. Conclusively, the above results demonstrate Ex rats had a higher wound healing rate, suggesting low-intensity treadmill exercise accelerates wound healing. The present work may provide some hint for future study of treating refractory wound.