Correlation of meniscus tear type with synovial inflammation and the therapeutic potential of docosapentaenoic acid.

BACKGROUND: Synovitis, characterized by inflammation of the synovial membrane, is commonly induced by meniscus tears. However, significant differences in inflammatory responses and the key inflammatory mediators of synovium induced by different types of meniscal tears remain unclear. METHODS: Magnetic resonance imaging (MRI) was employed to identify the type of meniscus tear, and the quantification of synovial inflammation was assessed through H&E staining assay. Transcription and expression levels of IL-1ß and IL-6 were evaluated using bioinformatics, ELISA, RT-qPCR, and IHC of CD68 staining assays. The therapeutic potential of Docosapentaenoic Acid (DPA) was determined through network pharmacology, ELISA, and RT-qPCR assays. The safety of DPA was assessed using colony formation and EdU staining assays. RESULTS: The results indicate that both IL-1ß and IL-6 play pivotal roles in synovitis pathogenesis, with distinct expression levels across various subtypes. Among tested meniscus tears, oblique tear and bucket handle tear induced the most severe inflammation, followed by radial tear and longitudinal tear, while horizontal tear resulted in the least inflammation. Furthermore, in synovial inflammation induced by specific meniscus tears, the anterior medial tissues exhibited significantly higher local inflammation than the anterior lateral and suprapatellar regions, highlighting the clinical relevance and practical guidance of anterior medial tissues' inflammatory levels. Additionally, we identified the essential omega-3 fatty acid DPA as a potential therapeutic agent for synovitis, demonstrating efficacy in blocking the transcription and expression of IL-1ß and IL-6 with minimal side effects. CONCLUSION: These findings provide valuable insights into the nuanced nature of synovial inflammation induced by various meniscal tear classifications and contribute to the development of new adjunctive therapeutic agents in the management of synovitis.

Risk Factors Affecting the Survival Rate of Collagen Meniscal Implant for Partial Meniscal Deficiency: An Analysis of 156 Consecutive Cases at a Mean 10 Years of Follow-up.

BACKGROUND: Collagen meniscal implant (CMI) is a biologic scaffold that can be used to replace meniscus host tissue after partial meniscectomy. The short-term results of this procedure have already been described; however, little is known about risk factors for failure. PURPOSE: To determine the factors that predict failure of meniscal scaffold implantation in a large series of patients treated at a single institution and to better define the indications for surgery. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The analysis included 186 consecutive patients with a minimum 5-year follow-up who underwent CMI scaffold implantation or combined procedures. Patients' characteristics and details of the surgery were obtained via chart review. Patients with a Lysholm score <65 were considered to have experienced clinical failure. Surgical failure was defined as partial or total scaffold removal. RESULTS: The final analysis included 156 patients (84%) at a mean follow-up of 10.9 ± 4.3 years. The patients' mean age at surgery was 42.0 ± 11.1 years, and the survival rate was 87.8%. Subgroup analysis identified Outerbridge grade 3-4 (Hazard ratio [HR], 3.8; P = .004) and a lateral meniscal implant (HR, 3.2; P = .048) as risk factors for failure. The survival rate was 90.4% for medial implants and 77.4% for lateral implants. An Outerbridge grade 3-4 (HR, 2.8; P < .001) and time from meniscectomy to scaffold >10 years (HR, 2.8; P = .020) were predictive of surgical or clinical failure. CONCLUSION: CMI for partial meniscal deficiency provided good long-term results, with 87.8% of the implants still in situ at a mean 10.9 years of follow-up. Outerbridge grade 3-4, lateral meniscal implants, and longer time from the meniscectomy to implantation of the CMI were identified as risk factors for clinical and surgical failure.

Anatomical description and short-term follow up clinical results for ultrasound-guided injection of medial collateral ligament bursa: New conservative treatment option for symptomatic degenerative medial meniscus tear.

BACKGROUND: In this study, we investigated newly developed ultrasound (US)-guided medial collateral ligament (MCL) bursa injection as a conservative therapy for symptomatic degenerative medial meniscal (MM) tears. We aimed to describe the anatomical target and precise technique of this injection, confirm its accuracy using fresh cadaveric knees, and then evaluate preliminary clinical outcomes. METHODS: Anatomical studies were performed on three fresh cadavers. For the clinical study, 50 patients with medial knee joint pain without knee osteoarthritis were treated with US-guided MCL bursa injection. Severity of pain was assessed pre-injection, and 1 week and 4 weeks post-injection using a 0-10 numerical rating scale (NRS). Clinical success was defined as a full return to daily activities. All patients underwent magnetic resonance imaging (MRI) within 1 week of the first injection. Patients who underwent surgery within 12 months of the first injection were investigated as clinically unsuccessful cases, and MRI and arthroscopic findings were examined. RESULTS: Compared with pre-injection (6.8 ±â€¯1.2), the average NRS score was significantly lower at 1 week (1.8 ±â€¯2.0) and at 4 weeks (1.5 ±â€¯1.7) post-injection (both P < 0.01). The primary clinical success rate was 76.0%, and injection-related adverse events were not observed. Nine patients underwent surgery (arthroscopic surgery for degenerative flap tear (n = 7) and high tibial osteotomy for medial meniscus posterior root tear and proximal tibial malalignment (n = 2)). CONCLUSIONS: US-guided MCL bursa injection is safe, reproducible, and effective for symptomatic MM degenerative tears. However, US-guided injections of the MCL bursa may be ineffective for flap tears and posterior root tears.

Isolated Meniscus Tears in Adolescent Patients Treated with Platelet-Rich Plasma Intra-articular Injections: 3-Month Clinical Outcome.

OBJECTIVES: Meniscus repair is a challenge for a practitioner, as an injured meniscus can lead to osteoarthritic joint changes with a greatly disabling outcome. Platelet-rich plasma has been regarded as a promising therapy to help induce healing. The purpose of the study is to clinically assess the effectiveness of PRP treatment in adolescents with meniscal lesions. METHODS: This retrospective study analyzed 30 patients with meniscal tears, aged 12 to 17 years, who had documented MRI meniscal lesion and persistent knee pain. In order to evaluate the outcome, the Lysholm knee scoring scale and numerical rating scale were used before injection and 3 months after treatment. RESULTS: Patients had a mean age of 13.93 years, 70% girls and 30% boys. The most affected was the medial meniscus. The mean value before injection on the numerical rating scale (NRS) of pain was 7.73, after the treatment being of 2.0. After treatment, 76.7% of the patients had "excellent" and "good" outcomes, while before injection, just 3% of the patients had a "good" score. CONCLUSIONS: Platelet-rich plasma treatment can be effective in improving the clinical outcomes of adolescent patients with meniscus tears, for whom conservative management and physical therapy have failed to achieve pain relief.

Conservative vs. surgical approach for degenerative meniscal injuries: a systematic review of clinical evidence.

OBJECTIVE: Analyzing the available evidence by comparing the role of arthroscopic surgery and conservative treatment in the management of degenerative meniscopathy. MATERIALS AND METHODS: A literature search was carried out on the PubMed, EMBASE, Scopus, and PEDro databases in May 2019 to identify all the randomized controlled trials (RCTs) comparing arthroscopic surgery to conservative management of painful but stable degenerated menisci. The quality of the RCTs was assessed using the Cochrane Risk of Bias Assessment. RESULTS: A total of 10 studies, including 1525 patients and dealing with conservative treatment vs. arthroscopic surgery were included in this review. In eight studies the effectiveness of exercise therapy was compared to surgery; in one study the effectiveness of intra-articular steroid injection was compared to surgery; in one study the effectiveness of placebo surgery was compared to partial meniscectomy. In all studies, no significant inter-group difference in terms of knee pain and knee function were observed at any follow-up evaluation. CONCLUSIONS: Degenerative meniscal tears, without symptoms of locking and catching, can be successfully managed by a proper regimen of physical therapy as a first line treatment. Surgical approach might be considered in case of poor response after conservative treatment.

Degenerative tears of the posterior horn of the medial meniscus: correlation between MRI findings and outcome following intra-articular steroid/bupivacaine injection of the knee.

AIM: To evaluate the response of symptomatic degenerative tears of the posterior horn of the medial meniscus to guided intra-articular knee steroid/bupivacaine injection and to correlate clinical outcomes with preprocedural findings at magnetic resonance imaging (MRI). MATERIALS AND METHODS: Sixty patients who had clinical and MRI evidence of a symptomatic degenerative tear of the posterior horn of the medial meniscus, isolated or accompanied by additional features of degenerative arthritis, who had failed conservative approaches (physiotherapy, non-steroidal anti-inflammatories, and 3 months rest/knee bracing) were included in the study. Patients underwent intra-articular knee steroid/bupivacaine injection and were followed clinically for a minimum of 6 months. Preprocedural MRI findings were correlated with duration of symptoms, clinical response to injection (recorded as complete, partial or no response) and duration of response to injection. RESULTS: Forty-nine of 60 patients (82%) reported an improvement in symptoms following guided intra-articular knee steroid/bupivacaine injection (complete: 25 patients (42%), partial: 24 (40%) patients). Improvement was sustained in 32 of 60 patients (53%) at follow-up. Thirteen of 18 patients (72%) who had an isolated degenerative tear of the posterior horn of the medial meniscus recorded a complete resolution of symptoms. This was sustained at follow-up in 10 patients (56%). CONCLUSION: Intra-articular steroid/bupivacaine knee joint injection reduced pain symptoms in the majority of patients (81.7%) with degenerative tears of the posterior horn of the medial meniscus, usually with a sustained response. Preprocedural MRI appearances correlate with response to injection. Patients with isolated tears are more likely to have a favourable outcome.

Effect of dose and release rate of CTGF and TGFß3 on avascular meniscus healing.

Meniscus tears in the avascular region rarely functionally heal due to poor intrinsic healing capacity, frequently resulting in tear propagation, followed by meniscus deterioration. Recently, we have reported that time-controlled application of connective tissue growth factor (CTGF) and transforming tissue growth factor ß3 (TGFß3) significantly improved healing of avascular meniscus tears by inducing recruitment and step-wise fibrocartilaginous differentiation of mesenchymal stem/progenitor cells (MSCs). In this study, we investigated effects of the dose of CTGF and the release rate of TGFß3 on avascular meniscus healing in our existing explant model. Our hypothesis was that dose and release rate of CTGF and TGFß3 are contributing factors for functional outcome in avascular meniscus healing by stem cell recruitment. Low (100 ng/ml) and high (1,000 ng/ml) doses of CTGF as well as fast (0.46 ± 0.2 ng/day) and slow (0.29 ± 0.1 ng/day) release rates of TGFß3 were applied to our established meniscus explant model for meniscus tears in the inner-third avascular region. The release rate of TGFß3 was controlled by varying compositions of poly(lactic-co-glycolic acids) (PLGA) microspheres. The meniscus explants were then cultured for 8 weeks on top of mesenchymal stem/progenitor cells (MSCs). Among the tested combinations, we found that a high CTGF dose and slow TGFß3 release are most effective for integrated healing of avascular meniscus, demonstrating improvements in alignment of collagen fibers, fibrocartilaginous matrix elaboration and mechanical properties. This study may represent an important step toward the development of a regenerative therapy to improve healing of avascular meniscus tears by stem cell recruitment. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1555-1562, 2019.

Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model.

OBJECTIVE: To investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials. METHODS: Male Lewis rats underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10 mg/kg), isotype control or vehicle for 7, 14 or 28 days. Gait deficiency was measured to assess weight-bearing on the operated limb. Joint damage was assessed via histopathology. A second arm, delayed onset of treatment (starting 3-8 weeks after MMT surgery) was used to control for analgesia early in the disease process. A third arm, mid-tibial amputation, evaluated the dependency of the model on weight-bearing. RESULTS: Gait deficiency in untreated rats was present 3-7 days after MMT surgery, with a return to normal weight-bearing by days 14-28. Prophylactic treatment with tanezumab prevented gait deficiency and resulted in more severe cartilage damage. When onset of treatment with tanezumab was delayed to 3-8 weeks after MMT surgery, there was no increase in cartilage damage. Mid-tibial amputation completely prevented cartilage damage in untreated MMT rats. CONCLUSIONS: These data suggest that analgesia due to NGF inhibition during the acute injury phase is responsible for increased voluntary weight-bearing and subsequent cartilage damage in the rat MMT model. This model failed to replicate the hypotrophic bone response observed in tanezumab-treated patients with RPOA.

Local Administration of Simvastatin Stimulates Healing of an Avascular Meniscus in a Rabbit Model of a Meniscal Defect.

BACKGROUND: Repair of an avascular meniscus is challenging because of its low capacity for healing. Several reports have shown that simvastatin stimulates the anabolic activity of intervertebral fibrochondrocytes, suggesting that simvastatin may be used for the treatment of meniscal defects. PURPOSE: To test whether the local administration of simvastatin stimulates healing of an avascular meniscus in rabbits. STUDY DESIGN: Controlled laboratory study. METHODS: In 30 Japanese White rabbits, a cylindrical defect (1.5-mm diameter) was introduced into the avascular zone of the anterior part of the medial meniscus in bilateral knees. Either a gelatin hydrogel (control group) or simvastatin-conjugated gelatin hydrogel (simvastatin group) was implanted into the defect. Histological assessments were performed using qualitative scoring systems, and immunohistochemical analysis was performed at 12 weeks after surgery. The occupation ratio (OR) and safranin O staining occupation ratio (SOR) were evaluated quantitatively at each time point. Stiffness of the regenerated tissue was analyzed biomechanically at 12 weeks after surgery. Rabbit meniscal cells were cultured in the presence or absence of 0.5 µM simvastatin, and then real-time polymerase chain reaction was performed to evaluate gene expression. RESULTS: The qualitative score was significantly higher in the simvastatin group after 8 and 12 weeks (P = .031 and .035, respectively). The mean OR and SOR were also significantly higher in the simvastatin group (OR at 8 weeks: 0.396 ± 0.019 [control] vs 0.564 ± 0.123 [simvastatin], P = .008; OR at 12 weeks: 0.451 ± 0.864 [control] vs 0.864 ± 0.035 [simvastatin], P = .001; SOR at 8 weeks: 0.071 ± 0.211 [control] vs 0.487 ± 0.430 [simvastatin], P = .009; SOR at 12 weeks: 0.093 ± 0.088 [control] vs 0.821 ± 0.051 [simvastatin], P = .006). Immunohistochemical analysis showed that at 12 weeks, the reparative tissue was more strongly positive for type I collagen (COL1), type II collagen (COL2), bone morphogenetic protein 2 (BMP-2), and BMP-7 in the simvastatin group than in the control group. Biomechanical analysis showed significantly higher stiffness in the simvastatin group (2.417 ± 1.593 N/ms [control] vs 5.172 ± 1.078 N/ms [simvastatin]; P = .005). In rabbit meniscal cells, BMP-2 and BMP-7 were upregulated after 4 and 8 hours and after 7 and 14 days, whereas COL1A1 and COL2A1 were significantly upregulated by simvastatin after 7 and 14 days. CONCLUSION: The local administration of simvastatin promotes the regeneration of an avascular meniscus in the rabbit model of a meniscal defect. The mechanism may involve the upregulation of BMPs and the subsequent upregulation of COL1 and COL2. CLINICAL RELEVANCE: This study suggests that simvastatin stimulated intrinsic healing of an avascular meniscus. The local administration of simvastatin is safe and inexpensive and seems to be a promising treatment of meniscal injuries.

[Effect of HBP-A on meniscal injury and pathological hypertrophy and calcification of the meniscus].

OBJECTIVE: To investigate the effect of HBP-A on meniscal injuries and the expressions of genes associated with pathological hypertrophy and calcification of the meniscusinduced by abnormal loading. METHODS: Bovine meniscus explants were subjected to 25% strain at 0.3 Hz for 3 h and treated with 0.6 mg/mL of HBP-A. The cell viability in the meniscus explants after 72 hin culture was determined using live/dead staining and the expression levels of genes associated with pathological hypertrophy and calcification of the meniscus (ANKH, ENPP1, ALP, MMP13, and IL-1) were measured using real-time PCR and Western blotting. The conditioned medium was collected for testing sulfated glycosaminoglycan (GAG) release. RESULTS: The number of dead cells, loss of proteoglycan content, and the expressions of ANKH, ENPP1, ALP and MMP13, and IL-1 at both the mRNA and protein levels were all significantly lower in the meniscus explants treated with 0.6 mg/mL HBP-A than in the explants with only 25% abnormal pressure stimulation (n=3, P<0.05). CONCLUSION: HBP-A can effectively alleviate meniscal injuries induced by abnormal loading and suppress the expressions of genes related with pathological hypertrophy and calcification of the meniscus, and can serve as a potential drug for treatment of knee osteoarthritis.