Qu, Wenchun

Abstract Posterior pilon fractures involve the medial malleolus (MM). Our purpose was to define the characteristics of posterior pilon fractures, and propose a classification system based on fracture morphology and type of management. The records of patients with posterior pilon fractures treated from 2011 to 2015 were retrospectively reviewed. The injury mechanism, fracture morphology, surgical approach, and follow-up results were reviewed and analyzed. This study was approved by the Institutional Review Board of PLA Army General Hospital. Thirty-six patients, 18 males and 18 females (mean age: 48.9 years) were included in the study. Four characteristics were used to define posterior pilon fractures. A simple posterolateral approach or a combined posterolateral and posteromedial approach was used for reduction and fixation in all patients. The mean follow-up time was 28.2 months, and at the end of follow-up, the mean American Orthopedic Foot and Ankle Society Score (AOFAS) was 82.5 points (range: 35–100 points). Based on injury mechanism and fracture morphology, we classified posterior pilon fractures into 3 types that suggest the optimal surgical approach: type I, a single complete fracture fragment; type II, a posterior malleolus fracture with 2 subtypes; type III, a posterior malleolus fracture associated with complete MM fracture with 2 subtypes. The proposed classification system based on injury mechanism and fracture morphology can guide the surgical approach to maximize outcomes.

Abstract Background The use of mesenchymal stem cells (MSCs) in clinical applications for the treatment of musculoskeletal disease is steadily increasing in office-based practice. The so-called “first generation” of MSCs is defined as autologous stem cells that have undergone minimal manipulation and are used for a homologous purpose. Systematic reviews of the clinical trials completed to date of such MSCs enable practitioners to better understand what is currently known about the outcomes and side effects of such treatments. Study Design A systematic review of human clinical studies of office-based MSC therapy for the treatment of painful degenerative musculoskeletal conditions. Methods A search of the Ovid MEDLINE, EMBASE, and Scopus databases was conducted from 2006 through September 2016. Seven hundred sixty-one records were identified from database searching, and two records from reference review of included papers. Studies with human subjects that evaluated treatment of musculoskeletal disease with minimally manipulated MSCs were included. Results Eight studies were included in this review based on selection criteria. A total of 941 patients were included, 841 of whom received cellular products, and no significant adverse events were reported. Symptomatology generally improved, though no differences were seen over controls where present. Conclusion Support in the literature is strongest for the use of bone marrow aspirate concentrate (BMAC) injections for the treatment of knee pain, but applications of the use of BMAC and peripheral blood–derived MSCs for the treatment of hip pain, tendon pain, and disc pain have all been reported. Further research is required, with large randomized controlled trials.

BackgroundTransplantation of mesenchymal stem cells (MSCs) is a promising therapy for degenerative spine conditions. However, cell therapy for painful spine degeneration presently requires use of contrast agents during fluoroscopy‐guided injections, and the effects of these agents on MSCs represents a gap in knowledge.ObjectiveTo investigate the biological effects of contrast media (CM) that are coinjected with MSCs.DesignProspective observational study.SettingAcademic medical center.ParticipantsPatient‐derived clinical‐grade culture expanded MSCs.InterventionsIohexol (Omnipaque300) was reduced to 12.5%, 25%, 50%, and 100% of the stock solution and incubated with MSCs for 30 minutes, 4 hours, and 48 hours. We also used complete media and 12.5%, 25%, 50%, 100% of phosphate‐buffered saline as a control group.Main Outcome MeasuresWe examined cytotoxicity of iohexol at different concentrations and exposure duration, as well as the potential for recovery over time. Cell counts, mitochondrial activity, and quantitative real time reverse‐transcriptase polymerase chain reaction of related genes were analyzed immediately after exposure (day 0) and after 2 days of exposure (day 2).ResultsHuman MSCs exhibit a time‐ and concentration‐dependent cytotoxic response to iodinated CM. A brief, 30‐minute exposure did not affect MSCs function and viability. However, extended treatment with iohexol for 4 hours at 50% or higher concentration had a significant impact on both viability and gene expression in MSCs.ConclusionsIohexol is cytotoxic to MSCs in a time‐and concentration‐dependent manner. Hence, the concentration of CM that accompanies MSC injections should be carefully considered during MSC therapy for disk‐degenerative diseases.Level of EvidenceIII.

ABSTRACTDegenerative disk disease of the spine is a major cause of back pain and disability. Optimization of regenerative medical therapies for degenerative disk disease requires a deep mechanistic understanding of the factors controlling the structural integrity of spinal tissues. In this investigation, we sought to identify candidate regulatory genes controlling extracellular matrix synthesis in spinal tissues. To achieve this goal we performed high throughput next generation RNA sequencing on 39 annulus fibrosus and 21 nucleus pulposus human tissue samples. Specimens were collected from patients undergoing surgical discectomy for the treatment of degenerative disk disease. Our studies identified associations between extracellular matrix genes, growth factors, and other important regulatory molecules. The fibrous matrix characteristic of annulus fibrosus was associated with expression of the growth factors platelet derived growth factor beta (PDGFB), vascular endothelial growth factor C (VEGFC), and fibroblast growth factor 9 (FGF9). Additionally we observed high expression of multiple signaling proteins involved in the NOTCH and WNT signaling cascades. Nucleus pulposus extracellular matrix related genes were associated with the expression of numerous diffusible growth factors largely associated with the transforming growth signaling cascade, including transforming factor alpha (TGFA), inhibin alpha (INHA), inhibin beta A (INHBA), bone morphogenetic proteins (BMP2, BMP6), and others. Clinical significance: this investigation provides important data on extracellular matrix gene regulatory networks in disk tissues. This information can be used to optimize pharmacologic, stem cell, and tissue engineering strategies for regeneration of the intervertebral disk and the treatment of back pain. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1356–1369, 2018.

Background Results of animal studies assessing efficacy of bone marrow stromal cell therapy for ischemic stroke remain inconsistent. Aims The aims are to assess efficacy of bone marrow stromal cell therapy for ischemic stroke in animal studies. Methods Randomized controlled animal trials assessing efficacy of bone marrow stromal cell therapy were eligible. Stroke therapy academic industry round table was used to assess methodologic quality of included studies. Primary outcomes were total infarction volume and modified Neurological Severity Score. Multiple prespecified sensitivity analyses and subgroup analyses were conducted. Random effects models were used for meta-analysis. Results Thirty-three randomized animal trials were included with a total of 796 animals. The median quality score was 6 (interquartile range, 5–7). Bone marrow stromal cell therapy decreased total infarction volume (standardized mean difference, 0.897; 95% confidence interval, 0.553–1.241; P < .001) at follow-up. Overall standardized mean difference between animals treated with bone marrow stromal cell and controls was 2.47 (95% confidence interval, 1.84–3.11; P < .001) for modified Neurological Severity Score; 1.27 (95% confidence interval, 0.72–1.82; P < .001) for adhesive removal test; and 2.13 (95% confidence interval, 0.65–3.61; P < .001) for rotarod test. Significant heterogeneity among studies was observed. Effect of all outcomes stayed significant in various sensitivity analyses and subgroup analyses, except in a few subgroup analyses with small sample size or with short time follow-up. No significant difference between groups was observed except for study location, in which significantly larger estimates were found in Asian countries. On the basis of this meta-analysis, larger sample sizes are warranted for future animal studies. Conclusions Bone marrow stromal cell therapy significantly decreased total infarction volume and increased neural functional recovery in randomized controlled animal models of ischemic stroke.

AbstractAdipose-derived mesenchymal stem cells (AMSCs) offer potential as a therapeutic option for clinical applications in musculoskeletal regenerative medicine because of their immunomodulatory functions and capacity for trilineage differentiation. In preparation for a phase I clinical trial using AMSCs to treat patients with osteoarthritis, we carried out preclinical studies to assess the safety of human AMSCs within the intra-articular joint space. Culture-expanded human AMSCs grown in human platelet-lysate were delivered via intra-articular injections into normal healthy rabbit knees and knees at risk for the development of osteoarthritis after bilateral medial anterior hemimeniscectomy. Treatment outcomes and safety were evaluated by assessing the general health, function, and behavior of the animals. Joint tissues were analyzed by x-ray, magnetic resonance imaging, and histopathology. Intra-articular AMSC therapy was well tolerated in this study. We did not observe adverse systemic reactions, nor did we find evidence of damage to intra-articular joint tissues. Thus, the data generated in this study show a favorable safety profile for AMSCs within the joint space in support of a phase I clinical trial evaluating the clinical utility of AMSCs to treat osteoarthritis.

A recent publication reported the incidence of postdural puncture headache (PDPH) in conjunction with intrathecal drug delivery system (IDDS) implantation to be nearly 23 percent. Many patients responded to conservative measures but a percentage needed invasive treatment with an epidural blood patch (EBP). There is limited data to describe the technical details, success rates, and complications associated with EBP in this population. This study aims to provide a retrospective report of EBP for patients suffering from PDPH related to IDDS implantation. A chart review established a cohort of patients that required EBP in relation to a PDPH after IDDS implantation. This cohort was evaluated for demographic data as well as details of the EBP including technical procedural data, success rates, and complications. All patients received a trial of conservative therapy. Standard sterile technique and skin preparation were utilized with no infectious complications. The EBP was placed below the level of the IDDS catheter in 94% of procedures. Fluoroscopy was utilized in each case. The mean EBP volume was 18.6 cc and median time of EBP was day 7 after implant. There were no complications associated with EBP. EBP appears to be an effective intervention in this subset of PDPH patients.

Objective: To determine the optimal environmental conditions for chondrogenic differentiation of human adipose tissue–derived mesenchymal stromal/stem cells (AMSCs). In this investigation we specifically investigate the role of oxygen tension and 3-dimensional (3D) culture systems. Design: Both AMSCs and primary human chondrocytes were cultured for 21 days in chondrogenic media under normoxic (21% oxygen) or hypoxic (2% oxygen) conditions using 2 distinct 3D culture methods (high-density pellets and poly-ε-caprolactone [PCL] scaffolds). Histologic analysis of chondro-pellets and the expression of chondrocyte-related genes as measured by reverse transcriptase quantitative polymerase chain reaction were used to evaluate the efficiency of differentiation. Results: AMSCs are capable of expressing established cartilage markers including COL2A1, ACAN, and DCN when grown in chondrogenic differentiation media as determined by gene expression and histologic analysis of cartilage markers. Expression of several cartilage-related genes was enhanced by low oxygen tension, including ACAN and HAPLN1. The pellet culture environment also promoted the expression of hypoxia-inducible cartilage markers compared with cells grown on 3D scaffolds. Conclusions: Cell type–specific effects of low oxygen and 3D environments indicate that mesenchymal cell fate and differentiation potential is remarkably sensitive to oxygen. Genetic programming of AMSCs to a chondrocytic phenotype is effective under hypoxic conditions as evidenced by increased expression of cartilage-related biomarkers and biosynthesis of a glycosaminoglycan-positive matrix. Lower local oxygen levels within cartilage pellets may be a significant driver of chondrogenic differentiation.