Enhancement of Chondrogenic Markers by Exosomes Derived from Cultured Human Synovial Fluid-Derived Cells: A Comparative Analysis of 2D and 3D Conditions.

OBJECTIVE: The goal of this pilot study was to investigate the effects of exosomes derived from synovial fluid-derived cells (SFDCs) cultured under normoxic conditions in a two-dimensional (2D) monolayer or encapsulated within a three-dimensional (3D) matrix for chondrogenic differentiation in vitro and cartilage defect repair in vivo. DESIGN: Synovial fluid samples were obtained from three patients, and SFDCs were isolated and expanded either in a 2D monolayer culture or seeded within a transglutaminase cross-linked gelatin (Col-Tgel) to create a 3D gel culture. Exosomes derived from each environment were isolated and characterized. Then, their effects on cartilage-cell proliferation and chondrogenic differentiation were assessed using an in vitro organoid model, and their potential for enhancing cartilage repair was evaluated using a rat cartilage defect model. RESULTS: SFDCs obtained from different donors reached a state of senescence after four passages in 2D culture. However, transferring these cells to a 3D culture environment mitigated the senescence and improved cell viability. The 3D-cultured exosomes exhibited enhanced potency in promoting chondrogenic differentiation, as evidenced by the increased expression of chondrogenic genes and greater deposition of cartilage-specific extracellular matrix. Furthermore, the 3D-cultured exosomes demonstrated superior effectiveness in enhancing cartilage repair and exhibited better healing properties compared to exosomes derived from a 2D culture. CONCLUSIONS: The optimized 3D culture provided a more favorable environment for the proliferation of human synovial cells and the secretion of exosomes compared to the 2D culture. The 3D-cultured exosomes exhibited greater potential for promoting chondrogenic gene expression in vitro and demonstrated improved healing properties in repairing cartilage defects compared to exosomes derived from the 2D culture.

Orthopedic Resident and Patient Perception of Electronic Medical Record Use During the Clinic Visit.

Background The transition from paper charts to electronic medical records (EMRs) has resulted in greater efficiency and reduced medical errors. This study aimed to examine the perception of patients and orthopedic residents regarding computer use during the clinic visit. Methodology This study utilized a cross-sectional cluster design. Orthopedic resident physicians were given a one-time general pre-visit survey. Additional surveys were given to patients and resident physicians post-visit. Surveys included questions that assessed satisfaction and the perceived impact of computer usage on doctor-patient interactions. Logistic generalized estimating equations were run to determine if there was an association between patient response and clinician assessment, adjusting for repeated measures within clinicians. Results A total of 80 patients and 15 residents completed the surveys. Results from the physician pre-visit survey showed that more residents perceived the computer as having a "negative" (47%) than "positive" (26%) effect on their relationship with patients. According to the post-visit analysis, patients perceived the residents' use of the EMR as having an overall positive effect on their ability to establish a personal connection and having a positive effect on their ability to give them attention. Conclusions Overall, there was little correlation between patient and resident perception of the computer's effect on their relationship. Patients generally perceived the computer as having a positive effect on their interaction with the residents even when residents had a negative perception of the computer's effect on their interaction.

Regulatory and Ethical Aspects of Orthobiologic Therapies.

Orthobiologic therapies show significant promise to improve outcomes for patients with musculoskeletal pathology. There are considerable research efforts to develop strategies that seek to modulate the biological environment to promote tissue regeneration and healing and/or provide symptomatic relief. However, the regulatory pathways overseeing the clinical translation of these therapies are complex, with considerable worldwide variation. The introduction of novel biologic treatments into clinical practice raises several ethical dilemmas. In this review, we describe the process for seeking approval for biologic therapies in the United States, Europe, and Japan. We highlight a number of ethical issues raised by the clinical translation of these treatments, including the design of clinical trials, monitoring outcomes, biobanking, "off-label" use, engagement with the public, marketing of unproven therapies, and scientific integrity.

Preoperative Determination of the Size of the Semitendinosus and Gracilis Tendon by Multidetector Row CT Scanner for Anterior Cruciate Ligament Reconstruction.

Accurately measuring the length and diameter of the hamstring tendon autograft preoperatively is important for planning anterior cruciate ligament (ACL) reconstructive surgery. The purpose of this study was to assess the reliability of three-dimensional computed tomography (3D CT) scanning technique to produce the actual measurement of the gracilis and semitendinosus (GT and ST, respectively) tendon grafts' length and diameter for surgery. Ninety patients were scheduled for ACL reconstruction with hamstring autograft. Before the surgery, patients were examined under the multidetector row CT scanner and the ST and GT tendons were qualitatively measured by a volume-rendering technique. The length of ST and GT was measured with 3D CT compared with the length of the harvested ST and GT. The cross-sectional area (CSA) of ST and GT measured with 3D CT compared with the ST and GT graft diameter. Tendon size measured preoperatively and during surgery were statistically compared and correlated. The GT tendons length and cross-sectional area measured during surgery was both shorter and smaller compared with the ST tendon. GT and ST tendon length were correlated to patients' body index such as the height and weight (p < 0.05). However, the correlation levels were low to medium (r = 0.23-0.49). There was strong correlation between the lengths of GT (r = 0.76; p < 0.001) and ST (r = 0.87; p < 0.001) measured with the 3D CT and tendon length at surgery. There was a moderate correlation between graft diameter measured at surgery and 3D CT cross-sectional area (r = 0.31; p < 0.05). A multidetector row CT scanner can determine the ST and GT tendons' length and diameter. These measurements can be used for preoperative planning to help determine the surgical method and counsel patients on appropriate graft choices prior to surgery.

Ultrasound-Guided Knee Injections Are More Accurate Than Blind Injections: A Systematic Review of Randomized Controlled Trials.

PURPOSE: To review the current literature to determine which injection technique and needle portal placement provide the greatest accuracy for intra-articular access to the knee. METHODS: This study followed Preferred Reporting Items and Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was conducted in March 2020 and repeated in May 2020 using electronic databases PubMed, MEDLINE, and the Cochrane Library. Data on the accuracy of intra-articular knee injection (successful injections/total number of injections) were collected. Only Level I studies were included. Study design, demographic variables, needle sizes, and method of validating accuracy were recorded. The Jadad score was used to assess methodologic quality, and a risk-of-bias assessment was performed. RESULTS: A total of 12 Level I human studies (1431 patients, 1315 knees) were included in this review. Seven of the studies did a direct comparison between ultrasound-guided and blind knee injections. Ultrasound-guided injections were more accurate compared with blinded knee injections in every study. The most accurate anatomical approach was an isometric quadricep contraction method with the superolateral approach. CONCLUSIONS: This study showed that ultrasound-guided knee injections were more accurate across every anatomical needle injection site compared with blind injections. Injections made by a blind/anatomically guided method had inconsistent accuracy rates that seemed highly dependent on the portal of entry. LEVEL OF EVIDENCE: Level I, systematic review of Level I studies.

Biologic Association Annual Summit: 2020 Report.

Interest and research in biologic approaches for tissue healing are exponentially growing for a variety of musculoskeletal conditions. The recent hype concerning musculoskeletal biological therapies (including viscosupplementation, platelet-rich plasma, and cellular therapies, or "stem cells") is driven by several factors, including demand by patients promising regenerative evidence supported by substantial basic and translational work, as well as commercial endeavors that complicate the scientific and lay understanding of biological therapy outcomes. While significant improvements have been made in the field, further basic and preclinical research and well-designed randomized clinical trials are needed to better elucidate the optimal indications, processing techniques, delivery, and outcome assessment. Furthermore, biologic treatments may have potential devastating complications when proper methods or techniques are ignored. For these reasons, an association comprising several scientific societies, named the Biologic Association (BA), was created to foster coordinated efforts and speak with a unified voice, advocating for the responsible use of biologics in the musculoskeletal environment in clinical practice, spearheading the development of standards for treatment and outcomes assessment, and reporting on the safety and efficacy of biologic interventions. This article will introduce the BA and its purpose, provide a summary of the 2020 first annual Biologic Association Summit, and outline the future strategic plan for the BA.

The Efficacy of Platelet-Rich Plasma for Improving Pain and Function in Lateral Epicondylitis: A Systematic Review and Meta-analysis with Risk-of-Bias Assessment.

PURPOSE: To assess the efficacy of platelet-rich plasma (PRP) for lateral epicondylitis and evaluate its impact on pain and functional outcomes. METHODS: This study followed Preferred Reporting Items and Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was conducted in September 2019 and repeated in April 2020 using electronic databases PubMed, MEDLINE, and the Cochrane Library. Baseline and 3-, 6-, and 12-month data were extracted for visual analog scale (VAS), Disabilities of the Arm, Shoulder, and Hand (DASH), and modified Mayo Clinic performance index for the elbow (MAYO) scores. Only level 1 studies with patients who had not undergone surgery were included. Outcomes data, study design, demographic variables, PRP formulation, and comparator treatments were recorded. Statistical analyses of pooled weighted mean differences (WMDs) were performed and compared with estimated minimal clinically important difference (MCID) values. The Coleman Methodology Score (CMS) was used to assess methodological quality, and the Cochrane risk-of-bias assessment was performed. RESULTS: This review included 16 level I studies, 9 of which (581 total patients, 281 receiving single injections of PRP) were quantitatively analyzed. The average age was 41.5 years, 56.8% of patients were female, and mean follow-up was 7.5 months. The mean CMS was 78.94 ± 12.74 (range 59 to 97), and 5 of 16 studies were at low risk for bias. Patients who received PRP had significantly improved VAS scores at 3 months (WMD -0.85; 95% confidence interval [CI] -1.03, -0.66; P < .01) and 6 months (WMD -0.74; 95% CI -0.98, -0.50; P < .01) compared with those who received autologous whole blood, though MAYO scores were statistically equivalent. Comparing PRP to corticosteroids, VAS and DASH scores were not significantly different at 3 months, although PRP was superior at 6 months for VAS (WMD -1.70; 95% CI -2.65, -0.75; P < .01) and DASH (WMD -6.23; 95% CI -10.78, -1.69; P < .01). Most differences in VAS and DASH scores exceeded the 5% absolute difference estimate for their respective MCIDs but fell short of the 10% estimate. CONCLUSION: Considering the small number of comparable studies, lack of quantification of specific PRP content, considerable heterogeneity between randomized control trials, and most effect sizes being equivocal within the framework of 2 estimated MCID values, the authors can neither scientifically support nor discourage the usage of PRP for lateral epicondylitis despite finding statistically significant improvements in pain and functional outcomes. LEVEL OF EVIDENCE: I, prognostic.

Food and Drug Administration's Position on Commonly Injected Biologic Materials in Orthopaedic Surgery.

The use of biologically based therapies is becoming a popular less-invasive therapy for relieving pain and promoting tissue regeneration. The most commonly used biologics are autologous adipose-derived products, bone marrow aspirations, and platelet-rich plasma (PRP). Birth tissue is a common allogenic source of biologics, including umbilical cord, placental membranes, and amniotic fluid. Injected biologics, depending on the indication and how they are processed, formulated, delivered, and promoted, can be subject to different regulatory pathways. The aim of this review is to provide an overview of these products and procedures and educate the musculoskeletal community about the relevant current Food and Drug Administration (FDA) regulations.

Implications of Anti-Inflammatory Nature of Exosomes in Knee Arthritis.

Exosomes are extracellular vesicles (EVs) released from cells that are a part of many biological and pathological processes, especially in intercellular communication. These vesicles are involved cell signaling, influence tissue and immune response, and serve as biomarkers for diseases. Most interesting are the exosomes that are released from mesenchymal stem cells (MSCs) for inflammation in joint diseases. Preliminary studies have demonstrated the advantages of using EVs rather than MSCs for cell free therapy. Research on exosomes have shown promising results as biomarkers for tracking the pathogenesis and prognosis of inflammatory arthritis. Therapeutically, animal studies have demonstrated immunosuppression, reversing inflammation, increasing chondrocyte proliferation, and drug delivery properties. The field of exosomes continues to develop and more basic science and clinical studies with safety and efficacy studies are needed.

Influence of Cellular Microenvironment on Human Articular Chondrocyte Cell Signaling.

OBJECTIVE: Alteration of the cellular microenvironment may influence the intra- and intercellular communication and contribute to cartilage injury and repair. The purpose of this study was to investigate how matrix elasticity/stiffness affects chondrogenic activities, including cell survival, phenotypic expression, and the release of both pro- and anti-inflammatory cytokines. DESIGN: Human articular chondrocytes (HACs) cultured on traditional 2-dimensional (2D) plastic surfaces were compared with those cultured within 3D hydrogel matrices of varying stiffness. Chondrogenic proliferation, differentiation, and the expression of pro- and anti-inflammatory cytokines were evaluated. Both interleukin-1-beta (IL-1ß) and human synovial fluid-derived cells (hSFCs) were introduced to study the effects of matrix stiffness on chondrocyte response. RESULTS: Cells demonstrated the most robust chondrogenic differentiation and secreted the least pro-inflammatory cytokines when the matrix stiffness was close to their native microenvironment. The IL-1ß effects were attenuated when HACs were co-cultured with hSFCs. CONCLUSION: Modifying the matrix stiffness to mimic the native cartilage microenvironment not only optimized chondrogenic expression but also was essential for the regulation of physiological homeostasis. This study proposed a new toolkit to study cell-molecule, cell-cell, and cell-matrix influence on cartilage physiology.

Illustrative review of knee meniscal tear patterns, repair and replacement options, and imaging evaluation.

This review article aims to reinforce anatomical concepts about meniscal tears while linking associated treatment options. The main teaching points start with the basic meniscal anatomy and key differences between the medial and lateral menisci. Subsequently, various meniscal tear patterns along with their associated history and physical exam findings will be discussed with corresponding illustrations and MR images. Additional discussion will involve the different surgical repair techniques (with arthroscopic correlates), their indications with pertinent imaging findings, imaging related to previous meniscal tear repairs, and novel surgical techniques. Lastly, keys to evaluating for retear with an emphasis on MRI arthrogram findings will be reviewed. While each of these topics is not discussed in totality, the key points of the review article will enforce key concepts and help radiologists evaluate the menisci on imaging.

Synovial Fluid Mesenchymal Stem Cells for Knee Arthritis and Cartilage Defects: A Review of the Literature.

Mesenchymal stem cells (MSCs) are adult stem cells that have the ability to self-renew and differentiate into several cell lineages including adipocytes, chondrocytes, tenocytes, bones, and myoblasts. These properties make the cell a promising candidate for regenerative medicine applications, especially when dealing with sports injuries in the knee. MSCs can be isolated from almost every type of adult tissue. However, most of the current research focuses on MSCs derived from bone marrow, adipose, and placenta derived products. Synovial fluid-derived MSCs (SF-MSCs) are relatively overlooked but have demonstrated promising therapeutic properties including possessing higher chondrogenic proliferation capabilities than other types of MSCs. Interestingly, SF-MSC population has shown to increase exponentially in patients with joint injury or disease, pointing to a potential use as a biomarker or as a treatment of some orthopaedic disorders. In this review, we go over the current literature on synovial fluid-derived MSCs including the characterization, the animal studies, and discuss future perspectives.

Evaluation of Knee Cartilage Diurnal, Activity, and BMI-Related Variations Using Quantitative T2 Mapping MRI and Fitbit Activity Tracking.

The aim of this study is to evaluate diurnal variation in knee cartilage 3 Tesla magnetic resonance imaging (MRI) T2 mapping relaxation times, as well as activity- and body mass index (BMI)-dependent variability, using quantitative analysis of T2 values from segmented regions of the weight-bearing articular surfaces of the medial and lateral femoral condyles and tibial plateaus. Ten healthy volunteers' daily activity (steps) were tracked with Fitbit pedometers. Sagittal MRI T2 maps were obtained in the morning and afternoon on days 2 and 3. Mean T2 values were analyzed for variation related to the number of steps taken (activity), time of day (diurnal variation), and BMI using mixed effect model. Significant (albeit small) differences in the medial femoral and medial tibial cartilage regions were identified between morning and afternoon scans (diurnal variation). Daily activity did not result in significant changes and increasing BMI only demonstrated a slight increase in T2 values for the lateral tibial plateau. These findings suggest that it may be necessary to control diurnal variation when using quantitative MRI T2 mapping to assess articular cartilage longitudinally in healthy participants. Further investigation is needed to confirm these findings and determine if they also apply to symptomatic patients.

Factors Associated With Distal Femoral Osteotomy Survivorship: Data From the California Office of Statewide Health Planning and Development (OSHPD) Registry.

BACKGROUND: Malalignment of the lower extremity can lead to early functional impairment and degenerative changes. Distal femoral osteotomy (DFO) can be performed with arthroscopic surgery to correct lower extremity malalignment while addressing intra-articular abnormalities or to help patients with knee osteoarthritis (OA) changes due to alignment deformities. PURPOSE: To examine survivorship after DFO and identify the predictors for failure. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Data from the California Office of Statewide Health Planning and Development, a statewide discharge database, were utilized to identify patients between the ages of 18 and 40 years who underwent DFO from 2000 to 2014. Patients with a history of lower extremity trauma, infectious arthritis, rheumatological disease, skeletal dysplasia, congenital deformities, malignancy, or concurrent arthroplasty were excluded. Failure was defined as conversion to total or unicompartmental knee arthroplasty, and the identified cohort was stratified based on whether they went on to fail. Age, sex, race, diagnoses, concurrent procedures, and comorbidities were recorded for each admission. Statistically significant differences between patients who required arthroplasty and those who did not were identified using the Student t test for continuous variables and a chi-square test for categorical variables. Kaplan-Meier survivorship curves were constructed to estimate 5- and 10-year survival rates. A Cox proportional hazards model was used to analyze the risk for conversion to arthroplasty. RESULTS: A total of 420 procedures were included for analysis. Overall, 53 knees were converted to arthroplasty. The mean follow-up time was 4.8 years (range, 0.0-14.7 years). The 5-year survivorship was 90.2% (range, 85.7%-93.4%), and the 10-year survivorship was 73.2% (range, 64.7%-79.9%). The mean time to failure was 5.9 years (range, 0.4-13.9 years). Survivorship significantly decreased with increasing age (P = .004). Hypertension and a primary diagnosis of osteoarthrosis were significant risk factors for conversion to arthroplasty (odds ratio [OR], 3.12 [95% CI, 1.38-7.03]; P = .006, and OR, 2.42 [95% CI, 1.02-5.77]; P = .045, respectively), along with a primary diagnosis of traumatic arthropathy (OR, 10.19 [95% CI, 1.71-60.65]; P = .01) and a comorbid diagnosis of asthma (OR, 2.88 [95% CI, 1.23-6.78]; P = .02). Patients with Medicaid were less likely (OR, 0.11 [95% CI, 0.01-0.88]; P = .04) to undergo arthroplasty compared with patients with private insurance, while patients with workers' compensation were 3.1 times more likely (OR, 3.08 [95% CI, 1.21-7.82]; P = .02). CONCLUSION: Older age was an independent risk factor for conversion to arthroplasty after DFO in patients ≥18 years but ≤60 years. Hypertension, asthma, and a diagnosis of osteoarthrosis or traumatic arthropathy at the time of surgery were predictors associated with failure, reinforcing the need for careful patient selection. The high survivorship rate of DFO in this analysis supports this procedure as a reasonable alternative to arthroplasty in younger patients with valgus deformities about the knee and symptomatic unicompartmental OA.

Intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells in patients with symptomatic bilateral knee osteoarthritis: a Phase I pilot study.

Aim: This study investigated the safety and clinical outcomes of expanded allogeneic human adipose-derived mesenchymal progenitor cells injected into patients with symptomatic, bilateral knee osteoarthritis. Design: In this single-site, randomized, double-blind, dose-ranging, Phase I study, patients were randomized to three treatment groups (low dose, 1 × 107 cells; medium dose, 2 × 107 cells; high dose, 5 × 107 cells). All patients received two bilateral intra-articular injections: week 0 (baseline) and week 3. The primary end point was adverse events within 48 weeks. Secondary end points were measured with Western Ontario and McMaster Universities Osteoarthritis index, visual analog scale, short form-36 at weeks 12, 24 and 48. Quantitative MRI measurements of cartilage volume were compared from baseline and week 48. Results: A total of 22 subjects were enrolled of which 19 (86%) completed the study. Adverse events were transient, including mild to moderate pain and swelling of injection site. Improvements from baseline were measured in the secondary end points. MRI assessments showed slight improvements in the low-dose group. Conclusion: Safety and improvements in pain and function after intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells into arthritic patients was demonstrated.

Governmental Regulations and Increasing Food and Drug Administration Oversight of Regenerative Medicine Products: What's New in 2020?

The United States Food and Drug Administration (FDA) is responsible for protecting and promoting public health through rules and regulations. Over the past few years, the field of regenerative medicine and cell therapy have garnered significant interest, and this evolving new biology is changing fast and challenging regulatory bodies. The FDA has published a series of guidance documents outlining steps to protect consumers against potentially dangerous and unproven treatments. The agency has offered a grace period for "stem cell clinics" until November 2020 to come into compliance by obtaining Investigational New Drug applications and working to secure premarket approval of their products. With the documentation of hundreds of "stem cell clinics," the FDA needs to enforce the adherence to their outlined standards to protect patients. The aim of this review was to provide an overview of these FDA regulations and some current issues within the industry. The purpose is to educate and inform the musculoskeletal community about the current government regulations of this new expanding biology. LEVEL OF EVIDENCE: Level V, expert opinion.

Minimal clinically important difference (MCID) for patient-reported shoulder outcomes.

BACKGROUND: The minimal clinically important difference (MCID) is used when interpreting the importance of outcome data. However, a consensus regarding the MCID for commonly used patient-reported outcomes in shoulder surgery has not been established. The purpose of this systematic review was to evaluate the available literature on shoulder MCID to improve clinical interpretation of shoulder outcome data. METHODS: A systematic review of the literature was conducted to identify studies reporting anchor-based MCID values for the patient-reported outcomes recommended by the American Shoulder and Elbow Surgeons (ASES): Veterans Rand 12 score, ASES score, Single Assessment Numeric Evaluation (SANE) score, Western Ontario Rotator Cuff (WORC) score, Western Ontario Osteoarthritis Score (WOOS), Western Ontario Shoulder Instability Index (WOSI), Pennsylvania Shoulder Score, and Oxford Shoulder Score (OSS). RESULTS: A total of 14 articles reporting anchor-based MCID values were included in the final analysis. No studies reporting the Western Ontario Osteoarthritis Score (WOOS) were identified. The ASES score (6 studies), OSS (4 studies), and WORC score (2 studies) were the only instruments investigated in more than 1 study. The average reported MCID values for the ASES, OSS, and WORC scores were 15.5 (15% total difference), 275.7 (13% total difference), and 6 (13% total difference), respectively. The vast majority of studies failed to report information necessary to validate the credibility of these MCID values. DISCUSSION AND CONCLUSION: The current utility of the MCID for patient-report shoulder outcome instruments is limited by poor study methodology, inadequate reporting, and a lack of data. Further research is needed to more clearly define the MCID values for commonly used patient-reported outcomes in shoulder surgery.

Pharmacotherapeutic considerations and options for the management of osteoarthritis in women.

Introduction: Osteoarthritis is a chronic disease that leads to the destruction of articular cartilage and joints. As the most common joint disorder, osteoarthritis poses a great burden to the healthcare system. Most importantly, osteoarthritis is a heterogeneous disease characterized by a wide range of clinical features, phenotypes, and treatments. The burden of osteoarthritis is not equally distributed between men and women. Women have an increased risk of developing osteoarthritis, with worse symptoms, and poorer outcomes.Areas covered: In this paper, the authors discuss pathophysiological considerations such as the wide spectrum of OA phenotypes. Women share many OA phenotypes with men including genetics, age, and trauma. Specific phenotypes from metabolic, anatomical, and hormonal influences vary greatly between the two sexes. This paper discusses the various current pharmacological treatment options for osteoarthritis including NSAIDs, Acetaminophen, Opioids, Duloxetine, SYSADOAs, monoclonal antibodies, intra-articular injections and hormonal therapy.Expert opinion: Further investigations of the pathophysiology of osteoarthritis are necessary to improve treatment options specific to women. As our understanding of the complex biology of osteoarthritis and the information surrounding it improves, newer and more effective treatments may decrease the suffering of osteoarthritis in a more efficient and less costly way.