Objective: To systematically review and evaluate the outcomes of full thickness rotator cuff tear primary repairs with and without patch augmentation, and evaluate whether different graft materials used leads to superior clinical or structural outcomes Methods: A comprehensive literature search was conducted using PubMed and Embase databases through July 2025, following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Eligible studies included comparative clinical trials and cohort studies that evaluated outcomes of rotator cuff repair (RCR) with and without patch augmentation, with clear specification of the graft type used. Primary outcomes of interest were patient-reported measures, including the American Shoulder and Elbow Surgeons (ASES) score, Constant-Murley score, and University of California, Los Angeles (UCLA) score, as well as clinical outcomes such as retear rates. Studies were included if they reported at least one of these outcomes and had a minimum follow-up duration of one year. The initial search identified 1,808 titles, of which 98 full-text articles were reviewed for eligibility. Ultimately, 14 studies comprising 922 patients met the inclusion criteria and were included in the quantitative analysis. Results: Compared to standard RCR, patch augmented repairs resulted in significantly improved Constant scores (p=0.0038) and significant lower retear rate (p=0.0357). However, improvements in ASES (p=0.2959) and UCLA (p=0.1801) did not reach statistical significance. When stratified by patch material, dermal matrix patches demonstrated significant improvement in Constant (p=0.0049) scores and retear rate (p=0.0466). In contrast, ECM-derived patches showed no significant improvements in either Constant (p=0.2742) or UCLA (p=0.7941) scores. Additionally, retear rates were not significantly reduced with either dermal matrix (p=0.0548) or ECM-derived (p=0.6198) patches. Conclusions: Patch augmentation in RCR appears to improve certain clinical outcomes, particularly Constant and ASES scores when compared to RCR alone. Dermal matrix patches demonstrated greater clinical benefit than ECM-derived patches, though neither material was associated with statistically significant reduction in retear rates. These findings suggest that while patch material may affect functional recovery, its impact on structural integrity is less clear. Further high-quality, randomized Level 1 studies are needed to determine material-specific outcomes and guide optimal graft selection in clinical practice.

The rat model has been extensively utilized in numerous studies on the rotator cuff. This review analyzes these studies and categorizes their findings into three primary areas: (1) the effects of external interventions on the intact shoulder/supraspinatus tendon, (2) surgical healing under varied conditions, and (3) the combined impact of surgery and external interventions on the biological healing response of the supraspinatus tendon. These studies consistently highlight the Sprague-Dawley rat as a valuable animal model. Several key themes emerge from research on rat shoulders. First, both intrinsic and extrinsic mechanisms contribute to changes in the supraspinatus tendon. Second, many studies report suboptimal tendon-bone healing, emphasizing the need for improved surgical repair techniques. Timely repair of acute tears facilitates smoother surgeries, enhances healing outcomes, and reduces the risk of failure. Additionally, reduced post-surgical activity levels have been associated with superior healing. Finally, ongoing research using this model continues to advance our understanding of the complex rotator cuff healing process.

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.

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.

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.

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-1β) 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-1β 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.

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.

cuff repair. In those with chronic tendinosis who are receiving PRP as an injection therapy, leukocyte-rich PRP may aggravate the inflammation and worsen symptoms, whereas this may not affect a surgical repair to the same extent. While we appreciate the authors’ work on this study, we believe the potentially confounded results from this study may cause further misunderstandings of the effects of PRP for rotator cuff tears. We would like to echo our previous calls for greater reporting on the cytology of PRP, as it is poorly reported on and thus limits our true understanding of the area; until then, it is still unclear what we are using.

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.

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.

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.

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.

Background: Many clinical trials have investigated the use of platelet-rich plasma (PRP) to treat rotator cuff–related abnormalities. Several meta-analyses have been published, but none have focused exclusively on level 1 randomized controlled trials. Purpose: To assess the efficacy of PRP for rotator cuff–related abnormalities and evaluate how specific tendon involvement, the inclusion of leukocytes, and the use of gel/nongel formulations affect pain and functional outcomes. Study Design: Systematic review and meta-analysis. Methods: The literature was screened following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Baseline, short-term, and long-term data were extracted for the Constant score, University of California, Los Angeles (UCLA) score, visual analog scale (VAS) for pain, retear rate, Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) score. The 100-point modified Coleman Methodology Score (CMS) was used to assess methodological quality. Funnel plots and the Egger test were used to screen for publication bias, and sensitivity analysis was performed to evaluate the effect of potential outliers. Results: A total of 18 level 1 studies were included in this review, 17 (1116 patients) of which could be included in quantitative analysis. The mean modified CMS was 79.4 ± 10.39. The Constant scores of patients who received PRP were significantly better short term (weighted mean difference [WMD], 2.89 [95% CI, 0.89-4.90]; P < .01) and long term (WMD, 2.66 [95% CI, 1.13-4.19]; P < .01). The VAS scores were significantly improved short term (WMD, –0.45 [95% CI, –0.75 to −0.15]; P < .01). Sugaya grade IV and V retears in PRP-treated patients were significantly reduced long term (odds ratio [OR], 0.34 [95% CI, 0.20-0.57]; P < .01). In PRP-treated patients with multiple tendons torn, there were reduced odds of retears (OR, 0.28 [95% CI, 0.13-0.60]; P < .01). Patients who received leukocyte-rich PRP had significantly better Constant scores compared with the leukocyte-poor PRP group, but there was no difference in VAS scores. Patients receiving PRP gel reported higher Constant scores compared with the controls, whereas those receiving nongel PRP treatments did not, although there was no difference in VAS scores. Long-term odds of retears were decreased, regardless of leukocyte content (leukocyte-poor PRP: OR, 0.36 [95% CI, 0.16-0.82]; leukocyte-rich PRP: OR, 0.32 [95% CI, 0.16-0.65]; all P < .05) or usage of gel (nongel: OR, 0.42 [95% CI, 0.23-0.76]; gel: OR, 0.17 [95% CI, 0.05-0.51]; all P < .01). Conclusion: Long-term retear rates were significantly decreased in patients with rotator cuff–related abnormalities who received PRP. Significant improvements in PRP-treated patients were noted for multiple functional outcomes, but none reached their respective minimal clinically important differences. Overall, our results suggest that PRP may positively affect clinical outcomes, but limited data, study heterogeneity, and poor methodological quality hinder firm conclusions.

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.

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.

Bedard et al. recently published a review on the impact of the 2013 American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guideline (CPG) on intra-articular (IA) hyaluronic acid (HA) injections, also referred to as viscosupplementation, and concluded that there were subtle but important changes in the use of IA HA following the publication of the AAOS CPG and that these changes were warranted because of the high cost of the injections, given their questionable efficacy1. However, we believe that consideration of the additional data supports a different conclusion and that the CPG has had a more detrimental impact on patient care. We submit that continued endorsement of this guideline may not be in the best interest of patients or the health-care system. Accordingly, we believe that the 2013 AAOS CPG should be reconsidered and modified to include a more comprehensive and perhaps more objective treatise on the guidelines for the nonsurgical treatment of knee pain due to osteoarthritis (OA). The Impact In 2016, the total population of the United States was 320,372,000; an estimated 292,320,000 citizens were covered by some form of health insurance. Of these, approximately 216 million citizens were covered by private insurance (Table I), of whom 178 million were covered through employer-based insurance2. While Medicare, accounting for 53.4 million lives2, covers all approved uses of IA HA injections, 17 major insurance carriers (including the largest, Anthem Blue Cross and Blue Shield3) that account for nearly 64 million lives (29.6% of all private insurance-covered lives) do not pay for IA HA injections (Table II), citing the 2013 AAOS CPG as a primary reason. This decision of noncoverage means that patients pay, at a minimum, an estimated $1,600 for a course of 3 injections of Synvisc (Genzyme Biosurgery)4 (based on the average wholesale price of IA HA products, including $62.16 as the cost of administration per injection plus a Level-1 office visit as well as visits under the Current Procedural Terminology [CPT] codes 99213 or 99214 [first visit only] of $90 [approximately $1,400 for Synvisc-One]5) compared with an estimated $320 in copayment (assuming an average 20% copayment using Medicare fee-for-service as a standard)6 under insurance coverage. TABLE I - Summary of the U.S. Population Health-Care Coverage* Source of Population No. of Lives U.S. Population Total U.S. population 320,372,000 100.0% Uncovered by health insurance 28,052,000 8.8% Covered by health insurance 292,320,000 91.2% Medicare-covered lives 53,372,000 16.7% Medicaid-covered lives 62,303,000 19.4% Private insurance-covered lives 216,203,000 67.5% *Medicare and Medicaid-covered lives include the elderly and citizens with disabilities who qualify for dual coverage. TABLE II - Summary of the U.S. Health-Care-Covered Lives and Noncoverage of IA HA Injections Major Insurance Plans Not Covering IA HA Injections* Covered Lives Privately Insured U.S. Lives Total U.S. Lives Total private health insurance-covered lives 216,203,000 100.0% 67.5% BCBS (non-coverage)† 46,574,621 21.5% 14.5% Kaiser Health Plan U.S. 9,185,680 4.2% 2.9% Medicaid (NY, NC, OK) 8,137,430 3.8% 2.5% Total private health insurance not covering IA HA injections 63,897,731 29.6% 19.9% *Published coverage policies: Anthem Blue Cross and Blue Shield (BCBS); Kaiser Health Plan U.S.; New York Medicaid; North Carolina Medicaid; Oklahoma Medicaid; BCBS of California, Florida, Massachusetts, Kansas City and Kansas, New York (Health Now), Arkansas, and Rhode Island; Regence Blue Cross; Premera BCBS; Group Health Coop; and Lifewise Health Plan of Washington.†The BCBS association is a federation of 36 separate U.S. health insurance organizations and companies providing health insurance to >100 million lives. The plans denying coverage, primarily Anthem Blue Cross and Blue Shield (BCBS), have a dominating or partial market presence in the states of AK, CA, CO, CT, FL, GA, ID, IN, KS, KY, MA, ME, MO, NH, NV, NY, RI, OH, VA, WA, and WI. The AAOS CPG and coverage decisions do not acknowledge the recently reported economic and medical benefits associated with viscosupplementation (IA HA) use, including (1) delayed time to knee replacement7-9, (2) reduced pain medication usage (corticosteroids, nonsteroidal anti-inflammatory drugs [NSAIDs], and opioids)10, (3) better cost-effectiveness compared with standard-of-care treatments11, (4) improved function9, and (5) a favorable safety profile12-14. The Evidence The 2013 AAOS CPG was based on a meta-analysis of published HA clinical studies that met the CPG and systematic review working group inclusion criteria. The guideline concluded that HA injections demonstrated significant differences in pain relief compared with saline solution injections15. However, we believe that the AAOS CPG remains debatable since its evidence synthesis rules allowed only for the inclusion of Level-I evidence (randomized clinical trials) and not Level-III and Level-IV published evidence. This may deprive patients of access to additional treatment modalities16,17, and the subjective inclusion criteria (such as age, Kellgren-Lawrence grade, primary outcome measures, activity level, comorbidities, etc.) that are used for patient selection in randomized clinical trials have been shown to substantially affect research outcomes18. Additionally, the final negative recommendation (“We cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee”; strength of recommendation: strong) was based on the conclusion that the effect size was not “clinically significant,” which the AAOS defined as “a statistically significant difference in treatment effect where the lower limit of the 95% confidence interval is greater than the minimal clinically important improvement” (MCII; MCII values were based on the published literature)15. This conclusion may have been based on flawed methodology and interpretation of minimal clinically important differences (MCIDs) of patient-reported outcomes16. At present, there is no universal standard for calculating MCIDs (we are aware of as many as 9 published methods19), especially when comparing population-based studies with individual-based studies, which has led to often disparate methodological and/or interpretation problems. Although there is value in understanding the MCID for assessing clinical appropriateness, it is only 1 of many important clinical tools (such as patient-reported outcome instruments, clinical experience, clinical study designs, demographics and patient variability, comorbidities, physical functional state, quality of life [both psychological and social aspects], tolerability, convenience, availability, physician’s preference and experience, cost, alternative treatment options, etc.) for evaluating treatment safety and effectiveness20. At this point, basing the effectiveness of an intervention solely on such an evaluation may be considered shortsighted. Furthermore, meta-analysis examining the HA class may incorporate additional levels of bias. These biases may include (1) regulatory bias, resulting from inclusion of studies from nonapproved U.S. products; (2) historical bias, resulting from comparison of studies over decades; (3) effectiveness bias, resulting from exclusion of studies not using the currently accepted or adopted outcome measures or methodology; and (4) control bias, resulting from failure to distinguish between true placebo controls and active comparators (Table III). The issue of control bias is especially important when examining the comparative effect size of IA HA injections, given the recent reports of the clinical effectiveness of IA saline solution injections, which are typically used as control comparators (including arthrocentesis and the use of up to 4 g/day of acetaminophen) in HA studies21,22. The use of IA saline solution as a control comparator can diminish the net effect size of an IA HA intervention because the comparator is an active clinical intervention (arthrocentesis, saline solution injection of diluting pain mediators, and access to up to 4 g/day of acetaminophen) instead of a true placebo (control bias). Reliance on a single outcome measure also has been challenged, with a combination of patient-reported outcomes and responder analysis being proposed as a more appropriate standard for outcome assessment23. TABLE III - Types of Bias No. Bias Description 1 Regulatory Resulting from the inclusion of clinical studies of nonapproved U.S. products (products not approved may provide a negative bias) 2 Historical Resulting from the comparison of clinical trials over decades, which may have led to the exclusion of studies not meeting current practices and thereby may not include studies of the first approved products 3 Effectiveness Resulting from the exclusion of studies utilizing validated outcome measures at the time of design but not using the currently accepted or adopted outcome measures or methodology (excludes earlier studies) 4 Control Resulting from the failure to distinguish true placebo controls from active comparators (saline solution injections) We believe that the AAOS workgroup, in their CPG review, potentially applied a somewhat flawed methodology16 to make a strong recommendation against the use of IA HA, given that all of the evidence that we believe to be relevant should have been considered further. These selection biases can be easily tested, and we recommend stratifying these variables. The CPG concluded that the benefits were exceeded by the potential harm and/or the quality of the supporting evidence for this recommendation is high. However, results from clinical studies and postmarketing reports have demonstrated that IA HA injections are not harmful13,14. The adverse reactions that the CPG cite also are limited and seem to be restricted to a single product, which may be related to the chemical cross-linking manufacturing process24. Accordingly, we question the basis of the “strong” recommendation against the use of IA HA injections. In contrast, 2 of what we believe are the most comprehensive and perhaps least biased meta-analyses of HA effectiveness (based on affiliation or sponsorship: research sponsored by the Cochrane Collaboration25 and the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services26) concluded that IA HA injections were statistically superior to IA saline solution injections, with a clinically meaningful difference. Using a network meta-analysis, Bannuru et al. showed that IA HA injections have a clinical effect size that is 2 to 3 times greater than that of standard-of-care oral pain medications26 (Table IV). More importantly, Bannuru et al.27 and Altman et al.21 have shown that IA saline solution injections (a standard control comparator to IA HA injections in clinical trials) are not placebos but are active comparators (Table V) as their effect size is comparable with standard-of-care NSAIDs. Therefore, using IA saline solution as a placebo comparator could dilute and diminish the effect size that is observed with IA HA injections (control bias). TABLE IV - Intra-Articular HA Clinical Effect Size Versus Other Treatments for OA Knee Pain* Comparator Placebo APAP IA Saline Solution† Celebrex Naproxen Ibuprofen Diclofenac IA Steroids IA HA 0.63 0.45 0.34 0.30 0.25 0.19 0.11 0.02 *HA = hyaluronic acid, OA = osteoarthritis, APAP = acetaminophen, and IA = intra-articular.†IA saline solution control = arthrocentesis, dilution with saline solution injection, and prn (as needed) APAP. Adapted, with permission, from: Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015 Jan 6;162(1):46-54. TABLE V - Placebo Pill, IA Saline Solution, and Oral NSAID Effect Size for Treatment of Knee OA* Comparator APAP IA Saline Solution Celebrex Naproxen Placebo pill 0.18 0.29 0.33 0.38 APAP 0.11 0.15 0.20 IA saline solution† 0.04 0.09 Celebrex 0.05 *IA = intra-articular, NSAID = nonsteroidal anti-inflammatory drug, OA = osteoarthritis, and APAP = acetaminophen.†IA saline solution control = arthrocentesis, dilution with saline solution injection, and prn (as needed) APAP. Adapted, with permission, from: Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015 Jan 6;162(1):46-54. The Osteoarthritis Research Society International (OARSI) guidelines for the nonsurgical management of knee OA concluded that IA HA injections had an estimated effect size (standardized mean difference) of 0.37 to 0.46 for pain, based on “good quality of evidence,” which equaled or exceeded the effect size for NSAIDS28. However, based on some inconsistent conclusions among the meta-analyses and conflicting results regarding the safety of some IA HA products, the panel voted to recommend IA HA injections with an “uncertain” designation for knee-only OA and as “not appropriate” for multiple-joint OA28. In a 2011 meta-analysis that was included in the OARSI guidelines, IA HA demonstrated a small but statistically significant reduction in OA knee pain by week 4, with a peak at week 8 (reaching moderate clinical significance) and residual benefit until 24 weeks29. Another meta-analysis from 2012 found moderate benefits of IA HA for pain and physical function in knee OA, although sensitivity analyses, including analysis of only larger studies with adequate blinding, found only a small effect size for pain30. The differences in the conclusions between the 2011 and 2012 analyses could have been due to the exclusion of studies with a smaller sample size and the inclusion of an additional 5 unpublished studies that reported nonsuperiority of HA compared with placebo in the 2012 meta-analysis31. Furthermore, systematic reviews published after the AAOS and OARSI guidelines had been issued also have drawn inconsistent conclusions regarding the clinical utility of HA injections. A meta-analysis of double-blinded sham-controlled studies found no clinically important improvement in pain or other outcomes with HA treatment versus placebo32. In contrast, a 2018 systematic review showed “strong evidence” for clinically important treatment effects for knee OA when using IA HA formulations with a molecular mass between 1,500 kDa and >6,000 kDa compared with nonoperative treatments33. In the recent OARSI guidelines, IA HA was conditionally recommended in individuals with knee OA in all groups34. Furthermore, it was noted that IA HA may have beneficial effects on pain at week 12 of treatment and beyond, as well as a more favorable long-term safety profile compared with repeated IA corticosteroids34. Notably, the American Medical Society for Sports Medicine (AMSSM) recommended the use of HA for appropriate patients with knee OA based on the number of participants meeting the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria, which are different and might be considered more relevant than methods used in the earlier AAOS CPG35. The continued contradictory recommendations from meta-analyses, together with a lack of treatment consensus among clinicians, underscore the need for well-designed, prospective, large population-based studies (pragmatic studies)36 to evaluate the real-world effectiveness of IA HA for knee OA and inform decision-makers regarding the comparative balance of benefits, burdens, and risks of IA HA. The Clinical Options The value (clinical benefit) and associated risk (safety) of IA HA in controlling OA knee pain should be compared with those of other nonsurgical treatments. Guidelines generally recommend exercise, weight loss, and physical therapy, followed by simple analgesics, NSAIDs, or other analgesics37. While some studies have shown these treatments to be cost-effective38,39, advocating the use of nonsurgical management plans for knee OA in the absence of workable blueprints and practical means of implementation of a clear and well-substantiated consensus on treatment algorithms will render most nonsurgical plans for knee OA ineffective in real-world situations. Oral Pain Medications Although acetaminophen is often the first oral pain medication that is recommended in treatment algorithms for OA knee pain, recent studies have concluded that there is no role for single-agent acetaminophen for the treatment of patients with chronic OA pain, irrespective of dose40,41. In addition, the potential toxicity associated with acetaminophen has further called into question its use based on this associated risk (potential safety profile)42. Although NSAIDs are used as standard nonsurgical treatment of chronic OA knee pain, while effective, safety issues associated with NSAIDs need to be carefully considered43-45, especially since patients with knee OA often have comorbidities that can exacerbate these adverse effects. Due to safety concerns, in 2005, the U.S. Food and Drug Administration (FDA) also required all NSAID (including cyclooxygenase-2 [COX-2]-selective inhibitor) manufacturers to include “black box” warnings highlighting the potential for increased risk of cardiovascular events and serious gastrointestinal bleeding46. Solomon et al. examined all-cause mortality for Medicare beneficiaries with a diagnosis of rheumatoid arthritis or OA who were receiving a nonselective NSAID or a selective COX-2 inhibitor45. The estimated all-cause mortality incidence rate was 48/1,000 person-years for nonselective NSAIDs and 47/1,000 person-years for selective COX-2 inhibitors45. Furthermore, based on conservative calculations, at least 16,500 NSAID-related deaths occur per year in arthritis patients47. In contrast, there have been no reported product-associated deaths with HA injections14. The concerns regarding opioid use for chronic pain management are well-documented and irrefutable and they are not a viable option in the treatment paradigm. Solomon et al. noted that the all-cause mortality, primarily from overdosing with opioids, for Medicare beneficiaries was 75/1,000 person-years45. Using the same assumptions as above, this could translate to almost 80,000 deaths annually. An epidemiologic study presented at the American Academy of Addiction Psychiatry 23rd Annual Meeting and Scientific Symposium reported that approximately 20% of individuals who are ≥65 years old take analgesics several times per week and the rate of abuse or addiction in those with chronic pain is 18%48. Data from the Substance Abuse and Mental Health Services Administration indicated that 2.8 million elderly patients in the U.S. abused prescription drugs in 2012, which is expected to increase to >4.4 million by 202049. Other Local Therapies IA injections can deliver therapy locally if the symptoms of OA are isolated, which is particularly desirable when comorbidities and drug-drug interactions are of particular concern in certain patient populations. IA corticosteroid injections are perhaps the most common treatment option for OA knee pain, and recent reviews have demonstrated moderate efficacy over 1 to 2 weeks and small-to-moderate efficacy over 4 to 6 weeks after the end of treatment50. While in vitro studies have demonstrated deleterious effects of corticosteroids on cartilage51,52, there is little clinical evidence that repeat corticosteroid injections every 3 months alter the progression of OA53. This notion has recently been refuted in a review by Kompel et al., in which they summarized the clinical data supporting the adverse joint events after IA corticosteroid injections54. Other IA injections, such as platelet-rich plasma (PRP) and cell-based therapies, show some promise in the treatment of OA knee pain but are awaiting large well-controlled clinical studies25,55. Despite some positive results in early published clinical studies, the complexity and inherent variability in the preparation of PRP, as well as cell-based therapy preparations, suitable control comparators, well-defined sourcing of cells, and appropriate delivery systems, have meant that definitive conclusions are difficult to make with respect to the general adoption of these therapies into the nonsurgical treatment paradigm. Furthermore, since none of these therapies are approved by the FDA (only the instruments used in their preparation are FDA-“cleared” as Class-II medical devices by a 510[k] process) and are therefore not reimbursed, the out-of-pocket costs can be prohibitive to patients and further limit their widescale adoption. Despite the fact that the evidence supporting the use of PRP, stem cells, and other injections for the management of OA knee pain is conflicting, the AAOS nonetheless provided an “inconclusive” recommendation regarding their use in contrast to IA HA. We believe that a substantial body of evidence, as outlined in this paper, suggests that IA HA injections can be a valuable treatment option to the clinician in the management of OA knee pain. Clinical Selection Several international expert groups have provided recommendations for the use of IA HA in specific patient populations56. For example, a workgroup of clinical experts developed appropriate use criteria to identify the types of patients for whom HA use is appropriate57. This group determined that the use of HA injections in OA knee treatment is appropriate for patients with confirmed mild or moderate knee OA who have not received other therapies, or for those who have been unsuccessful with or have had an incomplete response to other nonpharmacologic or pharmacologic therapies for the knee. The group also concluded that HA injections are contraindicated in patients with a local skin infection at the injection site and/or an active joint infection57. This clinical selection is similar to that observed in other conditions, such as with vertebroplasty, in which a rigorous selection of patients is of utmost importance58, and with epidural steroid injections for patients with lumbar spinal stenosis, where there is limited evidence to support their long-term benefit59. The technique of injection is of importance for efficacy and tolerance, with the lateral-patellar approach being preferable60. In contrast to palpation-guided anatomical injections, ultrasound-guided knee injections have been shown to have improved injection accuracy, resulting in improved patient-reported outcomes and cost-effectiveness61. Summary We believe that eliminating the use of IA HA as one of the nonsurgical treatment options available to clinicians would not be judicious56. While there may be some debate on the efficacy of HA injections, several meta-analyses and systematic reviews support their use25,37,62,63 with minimal safety concerns, and numerous studies have offered reasonable and scientifically valid explanations to clarify the discrepancies in conclusions from various reports64-66. What is not in question is the safety profile of the product class, particularly in the targeted patient population, along with the lack of product-drug interactions. In addition, there is no issue with patient compliance or overuse as there is with oral pain medications. We believe that a more judicious approach to appropriate OA treatment would be to adopt the more recent recommendations to optimize the outcomes of IA HA with better patient selection and earlier treatment57,67. Furthermore, we believe that restricting the availability of a safe and effective treatment option such as HA clearly does not help our patients, limits our treatment repertoire as clinicians, and therefore warrants the reevaluation of the AAOS CPG on IA HA treatment.

Adipose-derived stem cells may adhere when properly applied to a cartilage defect in rabbits, whereas injected stem cells may not adhere. Stem cell harvesting, isolation, quantification, typing, and expansion are specific; complex cartilage regeneration remains unproven; and translation to a human model is enigmatic.

BACKGROUND:The prospect of treating knee cartilage injury/pathology with mesenchymal stem cells (MSCs) has garnered considerable attention in recent years, but study heterogeneity and a lack of randomized controlled trials (RCTs) preclude quantitative analysis. The purpose of this review was to provide clinicians with an overview of RCTs that addresses 2 key areas that have been largely overlooked: nomenclature inconsistency and selective outcome reporting. METHODS:RCTs that purported to use stem cells or MSCs to treat knee cartilage were identified with use of PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses). Study variables were compiled, and methodological quality was assessed. The cell treatments and the methods used to characterize them were recorded and compared. Clinical, radiographic, and arthroscopic outcomes were extracted and evaluated qualitatively. RESULTS:There was extensive variation among the treatments, adjuvant therapies, and outcome measures. Treatments did not coincide with terminology. Significant differences in clinical outcomes were reported infrequently, and intra-group improvements or inter-group subscore differences were consistently highlighted, particularly when inter-group comparisons were left unreported. CONCLUSIONS:Overall, there are isolated cases in which positive efficacy results have been published, but our results suggest that the generally positive efficacy conclusions concerning stem cell therapy for knee cartilage pathology may be overstated. Nevertheless, it is important to understand that the efficacy of stem cell therapies should not be considered in aggregate. Cells that are procured or processed differently produce entirely different drugs. When evaluating the efficacy of "stem cell" therapies, clinicians must consider the methodological quality, nomenclature, and inherent distinctness of each treatment.

Articular cartilage is a complex tissue with unique properties that are essential for normal joint function. Many processes can result in cartilage injury, ranging from acute trauma to degenerative processes. Articular cartilage lacks vascularity, and therefore most chondral defects do not heal spontaneously and may require surgical repair. A variety of cartilage repair techniques have been developed and include bone marrow stimulation (microfracture), osteochondral autograft transfer system (OATS) or osteochondral allograft transplantation, autologous chondrocyte implantation (ACI), matrix-assisted chondrocyte implantation (MACI), and other newer processed allograft cartilage techniques. Although arthroscopy has long been considered as the gold standard for evaluation of cartilage after cartilage repair, magnetic resonance (MR) imaging is a non-invasive method to assess the repair site and can be scored using Magnetic resonance Observation of Cartilage Repair Tissue (MOCART). MR also provides additional evaluation of the subchondral bone and for other potential causes of knee pain or internal derangement. Conventional MR can be used to evaluate the status of cartilage repair and potential complications. Compositional MR sequences can provide supplementary information about the biochemical contents of the reparative tissue. This article reviews the various types of cartilage repair surgeries and their postoperative MR imaging appearances.

Background: High tibial osteotomy (HTO) was developed to treat early medial compartment osteoarthritis in varus knees. Purpose: To evaluate the midterm and long-term outcomes of HTO in a large population-based cohort of patients. Study Design: Case-control study; Level of evidence, 3. Methods: Data from the California Office of Statewide Health Planning and Development were used to identify patients undergoing HTO from 2000 to 2014. Patients with infectious arthritis, rheumatological disease, congenital deformities, malignancy, concurrent arthroplasty, or skeletal trauma were excluded. Demographic information was assessed for every patient. Failure was defined as conversion to total or unicompartmental knee arthroplasty. Differences between patients requiring arthroplasty and those who did not were identified using univariate analysis. Multivariate analysis was performed, and Kaplan-Meier survivorship estimates for 5- and 10-year survival were computed. Results: A total of 1576 procedures were identified between 2000 and 2014; of these, 358 procedures were converted to arthroplasty within 10 years. Patients who went on to arthroplasty after HTO were older (48.23 ± 6.76 vs 42.66 ± 9.80 years, respectively; P < .001), had a higher incidence of hypertension (25.42% vs 17.82%, respectively; P = .001), and had a higher likelihood of having ≥1 comorbidity (38.0% vs 31.4%, respectively; P = .044). Patients were 8% more likely to require arthroplasty for each additional year in age (relative risk [RR], 1.08). Female patients were also at an increased risk of conversion to arthroplasty compared with male patients (RR, 1.38). Survivorship at 5 and 10 years was 80% and 56%, respectively, and the median time to failure was 5.1 years. Conclusion: HTO may provide long-term survival in select patients. Careful consideration should be given to patient age, sex, and osteoarthritis of the knee when selecting patients for this procedure.