3D bioprinting approaches for spinal cord injury repair.

Regenerative healing of spinal cord injury (SCI) poses an ongoing medical challenge by causing persistent neurological impairment and a significant socioeconomic burden. The complexity of spinal cord tissue presents hurdles to successful regeneration following injury, due to the difficulty of forming a biomimetic structure that faithfully replicates native tissue using conventional tissue engineering scaffolds. 3D bioprinting is a rapidly evolving technology with unmatched potential to create 3D biological tissues with complicated and hierarchical structure and composition. With the addition of biological additives such as cells and biomolecules, 3D bioprinting can fabricate preclinical implants, tissue or organ-like constructs, andin vitromodels through precise control over the deposition of biomaterials and other building blocks. This review highlights the characteristics and advantages of 3D bioprinting for scaffold fabrication to enable SCI repair, including bottom-up manufacturing, mechanical customization, and spatial heterogeneity. This review also critically discusses the impact of various fabrication parameters on the efficacy of spinal cord repair using 3D bioprinted scaffolds, including the choice of printing method, scaffold shape, biomaterials, and biological supplements such as cells and growth factors. High-quality preclinical studies are required to accelerate the translation of 3D bioprinting into clinical practice for spinal cord repair. Meanwhile, other technological advances will continue to improve the regenerative capability of bioprinted scaffolds, such as the incorporation of nanoscale biological particles and the development of 4D printing.

PSME2 offers value as a biomarker of M1 macrophage infiltration in pan-cancer and inhibits osteosarcoma malignant phenotypes.

A growing number of studies have revealed an association between proteasome activator complex subunit 2 (PSME2) and the progression of various forms of cancer. However, the effect of PSME2 on osteosarcoma progression is unknown. Pan-cancer analyses focused on the immunological activity and prognostic relevance of PSME2 have yet to be conducted. The Cancer Genome Atlas and Genome-Tissue Expression databases were leveraged to evaluate PSME2 expression and activity across 33 cancer types. Significant PSME2 dysregulation was noted in a wide range of cancer types and this gene was found to offer significant diagnostic and prognostic utility in most analyzed cancers. From a mechanistic perspective, PSME2 expression levels were correlated with DNA methylation, DNA repair, genomic instability, and TME scores in multiple cancer types. PSME2 was subsequently established as a pan-cancer biomarker of M1 macrophage infiltration based on a combination of bulk, single-cell, and spatial transcriptomic data and confirmatory fluorescent staining results. In osteosarcoma cells, overexpressing PSME2 significantly suppressed tumor proliferative, migratory, and invasive activity. Screening efforts also successfully identified the PSME2-activating drug irinotecan, which can synergistically promote the death of osteosarcoma cells when combined with the chemotherapeutic drug paclitaxel. As a biomarker of M1 macrophage infiltration, PSME2 expression levels may offer insight into tumor development and progression for a wide range of cancers including osteosarcoma, emphasizing its potential utility as a prognostic and therapeutic target worthy of further study.

Development of a novel vasculogenic mimicry-associated gene signature for the prognostic assessment of osteosarcoma patients

Background Osteosarcoma (OS) is a form of primary bone malignancy associated with poor prognostic outcomes. Recent work has highlighted vasculogenic mimicry (VM) as a key mechanism that supports aggressive tumor growth. The patterns of VM-associated gene expression in OS and the relationship between these genes and patient outcomes, however, have yet to be defined. Methods Here, 48 VM-related genes were systematically assessed to examine correlations between the expression of these genes and OS patient prognosis in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohort. Patients were classified into three OS subtypes. Differentially expressed genes for these three OS subtypes were then compared with hub genes detected in a weighted gene co-expression network analysis, leading to the identification of 163 overlapping genes that were subject to further biological activity analyses. A three-gene signature (CGREF1, CORT, and GALNT14) was ultimately constructed through a least absolute shrinkage and selection operator Cox regression analysis, and this signature was used to separate patients into low- and high-risk groups. The K–M survival analysis, receiver operating characteristic analysis, and decision curve analysis were adopted to evaluate the prognostic prediction performance of the signature. Furthermore, the expression patterns of three genes derived from the prognostic model were validated by quantitative real-time polymerase chain reaction (RT-qPCR). Results VM-associated gene expression patterns were successfully established, and three VM subtypes of OS that were associated with patient prognosis and copy number variants were defined. The developed three-gene signature was constructed, which served as independent prognostic markers and prediction factors for the clinicopathological features of OS. Finally, lastly, the signature may also have a guiding effect on the sensitivity (AU)

Development of a novel vasculogenic mimicry-associated gene signature for the prognostic assessment of osteosarcoma patients.

BACKGROUND: Osteosarcoma (OS) is a form of primary bone malignancy associated with poor prognostic outcomes. Recent work has highlighted vasculogenic mimicry (VM) as a key mechanism that supports aggressive tumor growth. The patterns of VM-associated gene expression in OS and the relationship between these genes and patient outcomes, however, have yet to be defined. METHODS: Here, 48 VM-related genes were systematically assessed to examine correlations between the expression of these genes and OS patient prognosis in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohort. Patients were classified into three OS subtypes. Differentially expressed genes for these three OS subtypes were then compared with hub genes detected in a weighted gene co-expression network analysis, leading to the identification of 163 overlapping genes that were subject to further biological activity analyses. A three-gene signature (CGREF1, CORT, and GALNT14) was ultimately constructed through a least absolute shrinkage and selection operator Cox regression analysis, and this signature was used to separate patients into low- and high-risk groups. The K-M survival analysis, receiver operating characteristic analysis, and decision curve analysis were adopted to evaluate the prognostic prediction performance of the signature. Furthermore, the expression patterns of three genes derived from the prognostic model were validated by quantitative real-time polymerase chain reaction (RT-qPCR). RESULTS: VM-associated gene expression patterns were successfully established, and three VM subtypes of OS that were associated with patient prognosis and copy number variants were defined. The developed three-gene signature was constructed, which served as independent prognostic markers and prediction factors for the clinicopathological features of OS. Finally, lastly, the signature may also have a guiding effect on the sensitivity of different chemotherapeutic drugs. CONCLUSION: Overall, these analyses facilitated the development of a prognostic VM-associated gene signature capable of predicting OS patient outcomes. This signature may be of value for both studies of the mechanistic basis for VM and clinical decision-making in the context of OS patient management.

Preclinical Studies and Clinical Trials on Cell-Based Treatments for Meniscus Regeneration.

This study aims at performing a thorough review of cell-based treatment strategies for meniscus regeneration in preclinical and clinical studies. The PubMed, Embase, and Web of Science databases were searched for relevant studies (both preclinical and clinical) published from the time of database construction to December 2022. Data related to cell-based therapies for in situ regeneration of the meniscus were extracted independently by two researchers. Assessment of risk of bias was performed according to the Cochrane Handbook for Systematic Reviews of Interventions. Statistical analyses based on the classification of different treatment strategies were performed. A total of 5730 articles were retrieved, of which 72 preclinical studies and 6 clinical studies were included in this review. Mesenchymal stem cells (MSCs), especially bone marrow MSCs (BMSCs), were the most commonly used cell type. Among preclinical studies, rabbit was the most commonly used animal species, partial meniscectomy was the most commonly adopted injury pattern, and 12 weeks was the most frequently chosen final time point for assessing repair outcomes. A range of natural and synthetic materials were used to aid cell delivery as scaffolds, hydrogels, or other morphologies. In clinical trials, there was large variation in the dose of cells, ranging from 16 × 106 to 150 × 106 cells with an average of 41.52 × 106 cells. The selection of treatment strategy for meniscus repair should be based on the nature of the injury. Cell-based therapies incorporating various "combination" strategies such as co-culture, composite materials, and extra stimulation may offer greater promise than single strategies for effective meniscal tissue regeneration, restoring natural meniscal anisotropy, and eventually achieving clinical translation. Impact Statement This review provides an up-to-date and comprehensive overview of preclinical and clinical studies that tested cell-based treatments for meniscus regeneration. It presents novel perspectives on studies published in the past 30 years, giving consideration to the cell sources and dose selection, delivery methods, extra stimulation, animal models and injury patterns, timing of outcome assessment, and histological and biomechanical outcomes, as well as a summary of findings for individual studies. These unique insights will help to shape future research on the repair of meniscus lesions and inform the clinical translation of new cell-based tissue engineering strategies.

MicroRNA expression in osteoarthritis: a meta-analysis.

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases globally, leading to chronic disability and poor prognosis. One of the approaches for optimizing OA treatment is to find early effective diagnostic biomarkers. The contribution of microRNAs (miRNAs) in OA progression is now being increasingly recognized. This review provides a comprehensive summary on studies reporting the expression profiling of miRNAs in OA and associated signaling pathways. We performed a systematic search of the Embase, Web of Science, PubMed, and Cochrane library databases. This systematic review is reported according to the PRISMA checklist. Studies which identified miRNAs with aberrant expression compared to controls during OA progression were included, and a meta-analysis was performed. Results from the random effects model were provided as log10 odds ratios (logORs) and 95% confidence intervals. Sensitivity analysis was conducted to confirm the accuracy of the results. Subgroup analysis was conducted based on tissue source. The target genes of miRNAs identified in this study were extracted from the MiRWalk database, and these target genes were enriched in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. A total of 191 studies reporting 162 miRNAs were included in our meta-analysis. Among them, 36 miRNAs distributed across 96 studies were expressed in the same direction in at least two studies (13 up-regulated and 23 down-regulated). Subgroup analysis of tissue source revealed that the highest number of studies was conducted using articular cartilage, where the most up-regulated miRNAs were miR-146a-5p (logOR 7.355; P < 0.001) and miR-34a-5p (logOR 6.955; P < 0.001), and the most down-regulated miRNAs were miR-127-5p (logOR 6.586; P < 0.001) and miR-140-5p (logOR 6.373; P < 0.001). Enrichment analysis of 752 downstream target genes of all identified miRNAs was performed, and the regulatory relationships among them were displayed. Mesenchymal stem cells and transforming growth factor-ß were found to be the most important downstream effectors regulated by miRNA in OA. This study highlighted the importance of miRNA signaling in OA progression and identified a number of prominent miRNAs including miR-146a-5p, miR-34a-5p, miR-127-5p, and miR-140-5p which might be considered as potential biomarkers for OA.

Biomaterials for Tissue-Engineered Treatment of Tendinopathy in Animal Models: A Systematic Review.

To conduct a systematic review of studies reporting the treatment of tendon injury using biomaterials in animal models. A systematic search was conducted to retrieve studies involving animal models of tendon repair using biomaterials, in PubMed (database construction to August 2022) and Ovid-Embase (1946 to August 2022). Data related to tendon repair with biomaterials were extracted by two researchers, respectively. Risk of bias was assessed following the Cochrane Handbook for Systematic Reviews of Interventions. A statistical analysis was performed based on the classification of tendon repair biomaterials included in our study. A total of 8413 articles were retrieved, with 78 studies included in our analysis. For tendon repair in animal models using biomaterials, the most commonly seen characteristics were as follows: naturally derived biomaterials, rabbits and rats as animal models, surgery as the injury model, and the Achilles tendon as the injury site. The histology and biomechanical recovery of tendon injury following repair are affected by different biomaterials. Studies of tendon repair in animal models indicate that biomaterials can significantly improve repair outcomes, including tendon structure and biomechanics. Among effective biomaterial strategies are the use of new composites and incorporation of cells or growth factors into the material, both of which provide obvious benefits for tendon healing. More high-quality preclinical studies are required to encourage the translation of biomaterials into clinical practice for tendon repair.

Failure modes after anterior cruciate ligament reconstruction: a systematic review and meta-analysis.

PURPOSE: The reason for graft failure after anterior cruciate ligament reconstruction (ACLR) is multifactorial. Controversies remain regarding the predominant factor and incidence of failure aetiology in the literature. This review aimed to provide a meta-analysis of the literature to evaluate the relative proportion of various failure modes among patients with ACLR failure. METHODS: The PubMed, Embase, Cochrane Library, Web of Science, and EBSCO databases were searched for literature on ACLR failure or revision from 1975 to 2021. Data related to causes for ACLR surgical failure were extracted, and a random effects model was used to pool the results, which incorporates potential heterogeneity. Failure modes were compared between different populations, research methods, graft types, femoral portal techniques, and fixation methods by subgroup analysis or linear regression. Funnel plots were used to identify publication bias and small-study effects. RESULTS: A total of 39 studies were analyzed, including 33 cohort studies and six registry-based studies reporting 6578 failures. The results showed that among patients with ACLR failure or revision, traumatic reinjury was the most common failure mode with a rate of 40% (95% CI: 35-44%), followed by technical error (34%, 95% CI: 28-42%) and biological failure (11%, 95% CI: 7-15%). Femoral tunnel malposition was the most common cause of the technical error (29%, 95% CI: 18-41%), with more than two times higher occurrence than tibial tunnel malposition (11%, 95% CI: 6-16%). Traumatic reinjury was the most common factor for ACLR failure in European populations and in recent studies, while technical errors were more common in Asian populations, earlier studies, and surgery performed using the transtibial (TT) portal technique. Biological factors were more likely to result in ACLR failure in hamstring (HT) autografts compared to bone-patellar tendon-bone (BPTB) autografts. CONCLUSION: Trauma is the most important factor leading to surgical failure or revision following ACLR. Technical error is also an important contributing factor, with femoral tunnel malposition being the leading cause of error resulting in failure.

Evaluation of Comparative Efficacy and Safety of Surgical Approaches for Total Hip Arthroplasty: A Systematic Review and Network Meta-analysis.

Importance: Each approach for primary total hip arthroplasty (THA) has a long learning curve, so a surgeon's choice to change their preferred approach needs to be guided by clear justifications. However, current evidence does not suggest that any of the THA approaches are more beneficial than others, and the choice of approach is mainly based on the knowledge and experience of the surgeon and individual patient characteristics. Objective: To assess the efficacy and safety associated with different surgical approaches for THA. Data Sources: A comprehensive search of PubMed, EMBASE, and Cochrane databases from inception to March 26, 2022; reference lists of eligible trials; and related reviews. Study Selection: Randomized clinical trials (RCTs) comparing different surgical approaches, including the 2-incision approach, direct anterior approach (DAA), direct lateral approach (DLA), minimally invasive direct lateral approach (MIS-DLA), minimally invasive anterolateral approach (MIS-ALA), posterior approach (PA), minimally invasive posterior approach (MIS-PA), and supercapsular percutaneously assisted total hip arthroplasty (SuperPath), for primary THA. Data Extraction and Synthesis: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, 2 reviewers independently extracted data on study participants, interventions, and outcomes as well as assessed the risk of bias using the Cochrane risk of bias tool and the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation framework. A frequentist framework was used to inform a series of random-effects network meta-analyses. Main Outcomes and Measures: The outcomes were hip score (range, 0-100, with higher scores indicating better overall hip condition), pain score (range, 0-100, with higher scores indicating more pain), hospitalization time, operation time, quality of life score, blood loss, cup abduction angle, and cup anteversion angle. Results: Of 2130 retrieved studies, 63 RCTs including 4859 participants (median [IQR] age, 64.0 [60.3-66.5] years; median [IQR] percentage male, 46.74% [38.64%-54.74%]) were eligible for analysis. Eight surgical approaches were evaluated. For hip score, DAA (mean difference [MD], 4.04; 95% CI, 1.92 to 6.16; moderate certainty), MIS-ALA (MD, 3.00; 95% CI, 0.43 to 5.59; moderate certainty), MIS-DLA (MD, 3.37; 95% CI, 1.05 to 5.68; moderate certainty), MIS-PA (MD, 4.46; 95% CI, 1.60 to 7.31; moderate certainty), PA (MD, 4.37; 95% CI, 1.87 to 6.88; high certainty), and SuperPath (MD, 5.00; 95% CI, 0.58 to 9.42; high certainty) were associated with greater improvement in hip score compared with DLA. DLA was associated with lower decrease in pain score than SuperPath (MD, 1.16; 95% CI, 0.13 to 2.20; high certainty) and MIS-DLA (MD, 0.90; 95% CI, 0.04 to 1.76; moderate certainty). PA was associated with shorter operation times compared with 2-incision (MD, -23.85 minutes; 95% CI, -36.60 to -11.10 minutes; high certainty), DAA (MD, -13.94 minutes; 95% CI, -18.79 to -9.08 minutes; moderate certainty), DLA (MD, -10.50 minutes; 95% CI, -16.07 to -4.94 minutes; high certainty), MIS-ALA (MD, -6.76 minutes; 95% CI, -12.86 to -0.65 minutes; moderate certainty), and SuperPath (MD, -13.91 minutes; 95% CI, -21.87 to -5.95 minutes; moderate certainty). The incidence of 6 types of complications did not differ significantly between the approaches. Conclusions and Relevance: In this study, moderate to high certainty evidence indicated that compared with PA, all surgical approaches except DLA were associated with similar improvements of hip score but longer operation time. DLA was associated with smaller improvement of hip score. The safety of the different approaches did not show significant differences. These findings will help health professionals and patients with better clinical decision-making and also provide references for policy makers.