Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system, and its dysfunction has been implicated in numerous pathologies. Here we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling. We also developed a topical small interfering RNA (siRNA)–based therapy to restore redox homeostasis within diabetic wounds. Western blotting demonstrated that chronic hyperglycemia–associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response, and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA-based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration.

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Background: Changes in the joint microenvironment after an injury to the articular surface of the knee have been implicated in the pathogenesis of osteoarthritis. While prior studies focused on changes in this microenvironment after anterior cruciate ligament ruptures, few have explored the biomarker changes that occur in the setting of meniscal injuries. Purpose: To determine whether meniscal injury results in significant alterations to synovial fluid biomarker concentrations as compared with noninjured contralateral knees. Additionally, to explore the relationship between synovial fluid biomarkers and the degree of cartilage injury seen in these patients. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients undergoing surgery for unilateral meniscal injury were prospectively enrolled from October 2011 to December 2016, forming a cohort that had synovial fluid samples collected from both the injured knee and the contralateral uninjured knee at the time of meniscal surgery. Synovial fluid samples were collected just before incision, and the concentrations of 10 biomarkers of interest were determined with a multiplex magnetic bead immunoassay. The concentrations of synovial fluid biomarkers from the operative and contralateral knees were compared. Additionally, the synovial fluid biomarker concentrations of operative knees from patients with associated high-grade cartilage lesions were compared with those with low-grade lesions. Results: The current analysis included synovial fluid samples from 82 knees (41 operative and 41 contralateral) from 41 patients undergoing arthroscopic surgery to treat a symptomatic meniscal injury. The mean ± SD age of patients was 49.86 ± 11.75 years. There were significantly greater concentrations of 4 of the 5 proinflammatory biomarkers (IL-6, MCP-1, MIP-1β, and MMP-3) in symptomatic knees as compared with asymptomatic knees when controlling for the duration of symptoms, body mass index, age, and the random effects of by-patient variability. In the injured knees, associated high-grade cartilage lesions were predictive of elevated MCP-1, MIP-1β, and VEGF levels. Low synovial fluid concentration of TIMP-1 or a greater ratio of MMP-3 to TIMP-1 was associated with the presence of synovitis. Increasing age was found to be an independent predictor of increased IL-6, MCP-1, and VEGF concentrations in the setting of symptomatic meniscal injury. Conclusion: The authors identified 4 proinflammatory synovial fluid biomarkers whose concentrations were significantly different after meniscal injury as compared with uninjured contralateral knees. Furthermore, they describe the effects of associated cartilage damage, synovitis, and patient age on biomarker concentrations.

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Background: It is unclear whether leukocyte-poor (LP) or leukocyte-rich (LR) varieties of platelet-rich plasma (PRP) as an adjuvant to arthroscopic rotator cuff repair (ARCR) result in improved tendon healing rates. Purpose: To perform a network meta-analysis of the randomized controlled trials in the literature to ascertain whether there is evidence to support the use of LP- or LR-PRP as an adjunct to ARCR. Methods: The literature search was based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Randomized controlled trials comparing LP- or LR-PRP with a control alongside ARCR were included. Clinical outcomes, including retears and functional outcomes, were compared using a frequentist approach to network meta-analysis, with statistical analysis performed using R. The treatment options were ranked using the P-score. Results: There were 13 studies (868 patients) included, with 9 studies comparing LP-PRP with a control and 4 studies comparing LR-PRP with a control. LP-PRP was found to significantly reduce the rate of retear and/or incomplete tendon healing after fixation, even among medium-large tears; it also improved outcomes on the visual analog scale for pain, Constant score, and University of California Los Angeles score. LP-PRP had the highest P-score for all treatment groups. LR-PRP did not result in any significant improvements over the control group, except for visual analog scale score for pain. However, post hoc analysis revealed that LP-PRP did not lead to significant improvements over LR-PRP in any category. Conclusion: The current study demonstrates that LP-PRP reduces the rate of retear and/or incomplete tendon healing after ARCR and improves patient-reported outcomes as compared with a control. However, it is still unclear whether LP-PRP improves the tendon healing rate when compared with LR-PRP.

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Background: The purpose of this study was to examine the geographic and demographic variations and time trends of different types of meniscal procedures in New York State to determine whether disparities exist in access to treatment. Methods: The New York Statewide Planning and Research Cooperative System (SPARCS) outpatient database was reviewed to identify patients who underwent elective, primary knee arthroscopy between January 1, 2003, and December 31, 2015, for 1 of the following diagnosis-related categories: Group 1, meniscectomy; Group 2, meniscal repair; and Group 3, meniscal allograft transplantation, with or without anterior cruciate ligament reconstruction (ACLR). The 3 groups of meniscal procedures were compared on geographic distribution, patient age, insurance, concomitant ACLR, and surgeon and hospital volume over the study period. Results: A total of 649,470 patients who underwent knee arthroscopy between 2003 and 2015 were identified for analysis. Both meniscectomies and meniscal repairs had a scattered distribution throughout New York State, with allograft volume concentrated at urban academic hospitals. The majority of patients who underwent any meniscal procedure had private insurance, with Medicaid patients having the lowest rates of meniscal surgery. At high-volume hospitals, meniscal repairs and allografts are being performed with increasing frequency, especially in patients <25 years of age. Meniscal repairs are being performed concomitantly with ACLR with increasing frequency. Conclusions: Meniscal repairs and allografts are being performed at high-volume hospitals for privately insured patients with increasing frequency. Geographic access to these treatments, particularly allografts, is limited. Clinical Relevance: Disparities in the availability of advanced meniscal treatment require further investigation and understanding to improve access to care.

Purpose of ReviewThe purpose of the current article is to review the available literature related to bone marrow-derived mesenchymal stem cell therapy in the management of musculoskeletal pathologies and demonstrate the critical need for additional well-designed clinical studies. Recent Findings In recent years, there has been a rapid increase in interest regarding the use of bone marrow-derived mesenchymal stem cells in the treatment of musculoskeletal injury and disease. The clinical use of BM-MSCs and other forms of stem cell therapy has far outpaced the basic and translational science evidence required to elucidate the potential efficacy of this orthobiologic treatment approach. Early studies have demonstrated potential clinical benefit of utilizing bone marrow-derived mesenchymal stem cell therapy in the management of knee osteoarthritis, focal chondral lesions, shoulder pathology including rotator cuff tears and glenohumeral arthritis, and degenerative disk disease in the spine. To date, most published studies are small case series often lacking a control group or a standardized method of treatment. Summary Bone marrow-derived mesenchymal stem cell therapy is becoming an increasingly common treatment for musculoskeletal injuries and disease. Although early clinical studies have shown promising outcomes, methodological flaws and lack of standardization among trials have limited the conclusions that can be drawn from the existing literature. A better understanding of the underlying mechanism of action and more carefully designed clinical trials will help reveal the efficacy and utility of BM-MSCs as a treatment modality for various orthopedic pathologies.