Intra-articular Injection Of Saline Research Articles

Therapeutic efficacy of intra-articular injection of human adipose-derived mesenchymal stem cells in a sheep model of knee osteoarthritis

BackgroundMesenchymal stem cells have great potential for repairing articular cartilage and treating knee osteoarthritis (KOA). Nonetheless, little is known about the efficacy of human adipose-derived mesenchymal stem cells (haMSCs) for KOA in large animal models.MethodsThis study evaluated the therapeutic efficacy of haMSCs in knee articular cartilage repair in a sheep model of KOA. haMSCs were isolated, cultured, and characterized. KOA was surgically induced by anterior cruciate ligament transection and medial meniscectomy, followed by intra-articular injection of saline (negative control group) or haMSCs (haMSC group) into the right knee joint at 6 and 9 weeks after surgery. Sheep were sacrificed 21 weeks after surgery, and samples (whole knee joints, femoral condyles, and tibias) were collected, processed, and analyzed. Changes in knee articular cartilage were assessed by magnetic resonance imaging, micro-computed tomography, macroscopic analysis, histology, and immunohistochemistry.ResultsKOA caused the degeneration of the medial femoral condyle in the sheep model of KOA. Conversely, haMSCs repaired chondral defects and increased the thickness of knee articular cartilage.ConclusionsThese data suggest that the intra-articular injection of haMSCs can effectively repair articular cartilage defects in the knee.

Intra-Articular Administration of Ganglioside Sugars Protects Cartilage from Progressive Degeneration in an Instability OA Rabbit Model.

Osteoarthritis (OA) is a degenerative joint disease that has no cure, and current therapies are intended to minimize pain. There is, therefore, a need for effective pharmacologic agents that reverse or slow the progression of joint damage. We report herein on an investigation of the effects of intra-articular injections of ganglioside sugars on the progression of OA in an experimental rabbit model. Knee OA was induced Japanese in White rabbits by anterior cruciate ligament transection (ACLT). Ganglioside sugars at concentrations of 0.1, 0.3, and 0.9 mg/ml were then intra-articularly injected as a possible treatment for OA. Controls received intra-articular injections of saline. Knees were assessed macroscopically, histologically, and mechanically at 13 weeks after ACLT induction. Macroscopically, knees of the groups that received ganglioside sugars at concentrations of 0.3 and 0.9 mg/ml exhibited milder cartilage degradation compared to the controls. Consistent with these results, histological scores for these knees were significantly higher than the corresponding values for the control knees. Lectin histochemistry staining revealed that the treatment with ganglioside sugars at concentrations of 0.3 and 0.9 mg/ml was associated with a remarkable increase in the levels of GalNAc-positive chondrocytes in cartilage. Coefficient of friction testing also demonstrated that cartilages treated with ganglioside sugars had a lower coefficient of frictions than the values for the control group. Intra-articular injections of ganglioside sugars prevented cartilage degeneration in an OA-instability model. These results highlight the promising therapeutic potential for using ganglioside sugars in the treatment of progressive OA.

The collagenase-induced osteoarthritis (CIOA) model: Where mechanical damage meets inflammation

ObjectiveTo characterize inflammatory and mechanical changes in the collagenase-induced OA (CIOA) model in rats. DesignSkeletally mature, 6-month-old Wistar rats received unilateral intraarticular injections of saline, 500 U or 1000 U of collagenase on days 0 and 2 of the study. Joint tissues were harvested on either day 4 or 70 to evaluate the acute and long-term changes. Blood biomarkers, gait asymmetry and mechanical hyperalgesia were assessed repeatedly up until day 70. ResultsThe intraarticular injection of collagenase triggered an increase in cartilage degeneration and bone resorption over time, particularly for 1000 U. Similarly, mild synovitis was observed on day 70 with an increased number of synovial lining cells, increased fibrosis, and infiltration of peripheral macrophages. Mechanistically, these findings were linked to a dose-related mechanical weakening of the anterior cruciate ligament (ACL), which caused persistent joint destabilization throughout the study. Furthermore, the collagenase injection triggered acute inflammation and swelling of the synovium on day 4 and an acute systemic inflammatory response with increased cytokine and peripheral blood immune cell levels. While mild synovitis persisted until day 70, the systemic inflammatory response returned to control levels after 8 days. Similarly, the observed acute changes in gait and mechanical hyperalgesia also returned to baseline after 21 days. ConclusionBy evaluating inflammatory and mechanical factors at different doses and timepoints, our characterization enables a more targeted study design and increases the clinical relevance of future studies involving the CIOA model.

Immunotherapeutic potential of collagen V oral administration in mBSA/CFA-induced arthritis.

We hypothesized that after synovial injury, collagen V (Col V) expose occult antigens, and Col V autoantibodies develop, indicating the loss of immune tolerance against this molecule, thus leading to damage to mesenchymal-derived cells as well as the extracellular matrix in experimental arthritis. Thus, the present study investigated the effects of oral administration of Col V on the synovium after the development of inflammation in mBSA/CFA-induced arthritis. After fourteen days of intraarticular administration of mBSA, 10 male Lewis rats were orally administered Col V (500 μg/300 μL) diluted in 0.01 N acetic acid (IA-Col V group). The arthritic group (IA group, n = 10) received only intraarticular mBSA. An intra-articular saline injection (20 μL) was given to the control group (CT-Col V, n = 5). IA group presented damaged synovia, the expansion of the extracellular matrix by cellular infiltrate, which was characterized by T and B lymphocytes, and fibroblastic infiltration. In contrast, after Col V oral immunotherapy IA-Col V group showed a significant reduction in synovial inflammation and intense expression of IL-10+ and FoxP3+ cells, in addition to a reduction in Col V and an increase in Col I in the synovia compared to those in the IA group. Furthermore, an increase in IL-10 production was detected after IA-Col V group spleen cell stimulation with Col V in vitro. PET imaging did not differ between the groups. The evaluation of oral treatment with Col V, after mBSA/CFA-induced arthritis in rats, protects against inflammation and reduces synovial tissue damage, through modulation of the synovial matrix, showing an immunotherapeutic potential in inhibiting synovitis.

The impact of an illness perception conversation on open-label placebo response in knee osteoarthritis: A randomised controlled trial

ObjectiveTo compare the effect of an illness perception conversation (IPC), relative to a research participation conversation (RPC), on 2-week changes in knee pain in patients with knee osteoarthritis. MethodThis was a randomised single-blind trial. Patients were randomised to two matched conversations. An Illness Perception (IP) conversation concerning the participant’s knee pain-related IP or a research participation conversation, concerning the participant’s motivation for participating in research. Both conversations were followed by an open-label intraarticular saline injection in the most symptomatic knee. The primary outcome was change in knee pain from baseline to 2 weeks follow-up on a 100 mm Visual Analogue Scale (VAS). Key secondary outcomes included the Knee injury and Osteoarthritis Outcome Score (KOOS) subscales: Activities of daily living (ADL) and Quality of life (QoL). Main analyses were based on the intention-to-treat population using repeated measures mixed effects linear models. Results103 patients were randomised to the IPC group (n = 52) and the RPC group (n = 51). VAS knee pain scores changed statistically significantly from baseline to end of treatment in both groups, -13.7 (SE: 3.2) in the IPC group and -13.0 (SE: 3.1) in the RPC group with an adjusted between-group difference of -0.7 (95% CI: -8.3 to 6.9; P= 0.85). Likewise, no group differences were seen in KOOS ADL and KOOS QoL. ConclusionA conversation concerning knee pain-related IP did not augment the pain-relieving effect of an open-label placebo injection, when compared to a similar control conversation concerning motivations for participating in research. TRIAL REGISTRATIONNCT05225480

Limited Evidence to Support the Use of Intra-Articular Injection of Hyaluronic Acid for the Management of Hallux Rigidus: A Systematic Review.

The purpose of this systematic review was to evaluate outcomes following intra-articular injection of hyaluronic acid (HA) for the treatment of hallux rigidus. During April 2024, a systematic review of the MEDLINE, EMBASE, and Cochrane Library databases was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data collected and analyzed were number of patients, patient age, follow-up, subjective clinical outcomes, complications, and failures. Five studies were included. In total, 218 patients (218 feet) underwent intra-articular injection of HA at a weighted mean follow-up time of 4.4 ± 1.4 months (range, 3-6). There was an improvement in postinjection visual analog scale (VAS) pain at rest scores, VAS pain during activity scores, American Orthopaedic Foot & Ankle Society (AOFAS) scores, and Foot Health Status Questionnaire (FHSQ) scores. In total, 21 complications (10.0%) were observed, the most common of which was transient postinjection pain in 20 patients (9.6%). There were 7 patients (3.2%) who underwent secondary procedures (3.2%). One randomized control trial (RCT) demonstrated no difference in outcomes between an intra-articular injection of HA compared to an intra-articular injection of saline. One RCT demonstrated superior FHSQ scores following between an intra-articular injection of HA compared to an intra-articular injection of triamcinolone acetonide. This systematic review suggests that intra-articular injection of HA for the treatment of hallux rigidus may lead to improved clinical outcomes with a low complication rate at short-term follow-up. However, the low level and quality of evidence underscores the need for further high-quality studies to be conducted to identify the precise role of HA in the treatment of hallux rigidus.

The Effects of Extracellular Matrix Allograft Administration on Knee Inflammation Following an Anterior Cruciate Ligament Injury in Mice

Background and Hypothesis:A human placental-derived extracellular matrix (ECM) allograft has previously been developed and is indicated by the manufacturer for reducing tissue inflammation and accelerated repair. To evaluate the efficacy of this product for reducing post-anterior cruciate ligament (ACL) injury inflammation, we used a novel murine in vivo ACL injury model. This model has previously been shown to induce significant synovitis, infrapatellar fat pad (IFP) fibrosis, and articular cartilage (AC) degradation within 2 weeks following an ACL injury. We hypothesized that intra-articular injections of the allograft would correspond with a decrease in synovitis, fibrosis, and articular cartilage degradation. Experimental Design or Project Methods:Ten-week-old C57BL/6J mice were randomly placed into 4 groups (n=10/group). For all mice, the right ACL was ruptured. One group served as sham controls, with a single intra-articular saline injection 24-hours following injury. The remaining three groups received 1, 2, and 6 allograft injections respectively beginning 24-hours after injury. Mice were euthanized 14 days after injury. Following euthanasia, the degree of IFP fibrosis, knee synovitis, and AC degradation were histopathologically evaluated. Results:Thus far, 5 mice per group have been analyzed. Within this subset of mice, those that received 6 injections demonstrated a significantly higher synovitis score (p < 0.01) than the sham group. The 1-injection (p < 0.01), 2-injection (p = 0.16), and 6-injection (p = 0.03) groups each displayed greater IFP fibrosis, relative to sham. No significant differences were found in AC degeneration across groups. Conclusion and Potential Impact:If the current results hold, following the analyses of the remaining mice, then this particular orthobiologic may not be suitable for reducing the post-ACL injury inflammatory response in mice. However, there are several limitations to this pilot study that will first need to be accounted for to confirm the lack of efficacy found.

Comparative Effects of Intra-Articular versus Intravenous Mesenchymal Stromal Cells Therapy in a Rat Model of Osteoarthritis by Destabilization of Medial Meniscus.

Transplanted mesenchymal stromal cells (MSCs) exhibit a robust anti-inflammatory and homing capacity in response to high inflammatory signals, as observed in studies focused on rheumatic diseases that target articular cartilage (AC) health. However, AC degradation in osteoarthritis (OA) does not necessarily coincide with a highly inflammatory joint profile. Often, by the time patients seek medical attention, they already have damaged AC. In this study, we examined the therapeutic potential of a single bone marrow MSC transplant (2 × 106 cells/kgbw) through two different routes: intra-articular (MSCs-IAt) and intravenous (MSCs-IVt) in a preclinical model of low-grade inflammatory OA with an established AC degeneration. OA was induced through the destabilization of the medial meniscus (DMM) in female Wistar Kyoto rats. The animals received MSCs 9 weeks after surgery and were euthanized 4 and 12 weeks post-transplant. In vivo and ex vivo tracking of MSCs were analyzed via bioluminescence and imaging flow cytometry, respectively. Cytokine/chemokine modulation in serum and synovial fluid was measured using a multiplex panel. AC degeneration was quantified through histology, and hindlimb muscle balance was assessed with precision weighing. To our knowledge, we are the first group to show the in vivo (8 h) and ex vivo (12 h) homing of cells to the DMM-OA joint following MSCs-IVt. In the case of MSCs-IAt, the detection of cellular bioluminescence at the knee joint persisted for up to 1 week. Intriguingly, intra-articular saline injection (placebo-IAt) resulted in a worse prognosis of OA when compared to a non-invasive control (placebo-IVt) without joint injection. The systemic cytokines/chemokines profile exhibited a time-dependent variation between transplant routes, displaying a transient anti-inflammatory systemic response for both MSCs-IVt and MSCs-IAt. A single injection of MSCs, whether administered via the intra-articular or intravenous route, performed 9 weeks after DMM surgery, did not effectively inhibit AC degeneration when compared to a non-invasive control.

Exercise and education vs intra-articular saline for knee osteoarthritis: a 1-year follow-up of a randomized trial

To assess the longer-term effect of the Good Life with osteoarthritis in Denmark (GLAD) exercise and education program relative to open-label placebo (OLP) on changes from baseline in core outcomes in individuals with knee osteoarthritis (OA). In this 1-year follow-up of an open-label, randomized trial, patients with symptomatic and radiographically confirmed knee OA were monitored after being randomized to either the 8-week GLAD program or OLP given as 4 intra-articular saline injections over 8 weeks. The primary outcome was the change from baseline in the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale after 1 year in the intention-to-treat population. Key secondary outcomes were the KOOS function and quality of life subscales, and Patients' Global Assessment of disease impact. 206 adults were randomly assigned: 102 to GLAD and 104 to OLP, of which only 137 (63/74 GLAD/OLP) provided data at 1 year. At one year the mean changes in KOOS pain were 8.4 for GLAD and 7.0 for OLP (Difference: 1.5 points; 95% CI-2.6 to 5.5). There were no between-group differences in any of the secondary outcomes. In this 1-year follow-up of individuals with knee OA, the 8-week GLAD program and OLP both provided minor longer-term benefits with no group difference. These results require confirmation given the significant loss to follow-up. NCT03843931.

Who are likely to benefit from the Good Life with osteoArthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial

To identify contextual factors that modify the treatment effect of the 'Good Life with osteoArthritis in Denmark' (GLAD) exercise and education programme compared to open-label placebo (OLP) on knee pain in individuals with knee osteoarthritis (OA). Secondary effect modifier analysis of a randomised controlled trial. 206 participants with symptomatic and radiographic knee OA were randomised to either the 8-week GLAD programme (n=102) or OLP given as 4 intra-articular saline injections over 8 weeks (n=104). The primary outcome was change from baseline to week 9 in the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale (range 0 (worst) to 100 (best)). Subgroups were created based on baseline information: BMI, swollen study knee, bilateral radiographic knee OA, sports participation as a young adult, sex, median age, a priori treatment preference, regular use of analgesics (NSAIDs or paracetamol), radiographic disease severity, and presence of constant or intermittent pain. Participants who reported use of analgesics at baseline seem to benefit from the GLAD programme over OLP (subgroup contrast: 10.3 KOOS pain points (95% CI 3.0 to 17.6)). Participants with constant pain at baseline also seem to benefit from GLAD over OLP (subgroup contrast: 10.0 points (95% CI 2.8 to 17.2)). These results imply that patients who take analgesics or report constant knee pain, GLAD seems to yield clinically relevant benefits on knee pain when compared to OLP. The results support a stratified recommendation of GLAD as management of knee OA. ClinicalTrials.gov Identifier: NCT03843931. EudraCT number 2019-000809-71.

Intra-articular botulinum toxin A injection for painful base-of-thumb osteoarthritis: a double-blind, randomised, controlled, phase 3 trial (RHIBOT).

Intra-articular botulinum toxin A injection might have analgesic effects in patients with joint diseases. We aimed to compare the effects of intra-articular botulinum toxin A injection with those of intra-articular saline injection for patients with painful base-of-thumb osteoarthritis. RHIBOT was a double-blind, randomised, controlled, phase 3 trial conducted at Cochin Hospital, Paris, France. We recruited adult patients with x-ray evidence of trapeziometacarpal osteoarthritis who fulfilled the 1990 American College of Rheumatology criteria for hand osteoarthritis and reported a pain intensity score of at least 30 on an 11-point numeric rating scale (0: no pain to 100: maximal pain). Participants were randomly assigned (1:1), using a computer-generated randomisation list with permuted blocks of variable size (4 or 6), to receive an ultrasound-guided injection of either botulinum toxin A (50 Allergan units) in 1 mL of saline (experimental group) or 1 mL of saline alone (control group) in the trapeziometacarpal joint, in addition to custom-made rigid splinting. The primary outcome was the mean change from baseline in base-of-thumb pain in the previous 48 h on a numeric rating scale at 3 months after injection, analysed by intention to treat. This study is registered with ClinicalTrials.gov, NCT03187626. Between Nov 2, 2018, and Nov 3, 2020, we assessed 370 individuals for eligibility and recruited 60 (16%) participants (mean age 64·9 years [SD 9·4], 47 [78%] women and 13 [22%] men), of whom 30 (50%) participants were randomly assigned to the experimental group and 30 (50%) to the control group. At baseline, base-of-thumb pain score was 60·0 of 100·0 (SD 15·9). At 3 months, the mean reduction in base-of-thumb pain was -25·7 (95% CI -35·5 to -15·8) in the experimental group and -9·7 (-17·1 to -2·2) in the control group (absolute difference -16·0 [-28·1 to -3·9]; p=0·043). Overall, 51 adverse events were reported in both groups: 27 (53%) in the experimental group and 24 (47%) in the control group. During follow-up, 14 (47%) participants in the experimental group and two (7%) participants in the control group reported mild transient motor deficit of the thenar muscle. No serious adverse events were reported. Botulinum toxin A could be considered as a fast-acting, intra-articular therapy targeting chronic pain in individuals with base-of-thumb osteoarthritis. Future studies are needed to investigate the potential mechanism of the effects observed in this trial, to replicate our findings, and to assess the effects of repeated injections over time and their clinical effectiveness, including an analysis of cost-effectiveness. Assistance Publique-Hôpitaux de Paris.

Evaluation of Intermaxillary Fixation (IMF) Screw Therapy with Craniomandibular Index Analysis for Chronic Recurrent Dislocation in the Temporomandibular Joint.

Temporomandibular joint (TMJ) hypermobility is classified as a subluxation, complete (luxation), unilateral, or bilateral, acute, chronic protracted, or chronic recurrent dislocation. This controlled randomized clinical study aims to evaluate the effectiveness of intermaxillary fixation (IMF) screw application and autologous blood injections in the treatment of chronic recurrent dislocation of TMJ in comparison with the placebo group. The patients who were admitted to the Faculty of Dentistry of the Atatürk University between October 2018 and January 2020 were evaluated. Three hundred patients diagnosed with bilateral chronic recurrent dislocation of TMJ based on clinical findings and radiographs were included in the study. The patients were randomly divided into three groups according to the evaluation criteria. Group 1 received IMF, group 2 received autologous blood injection, and group 3 (placebo group) received an intraarticular saline injection. The results of the patients who received IMF, autologous blood injection, and saline injection were evaluated by the craniomandibular index. The IMF group showed significant improvement after 1 month and 6 months (P < 0.001), while the patients who received autologous blood injection and saline injection showed no significant improvement (P > 0.05). The data were analyzed with IBM SPSS V23. The significance level was P < 0.05. In our study, the IMF gave the best results among all the study groups. The IMF technique can be used in patients with protracted chronic recurrent dislocation in whom autologous blood injection has failed.

Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial

ObjectiveTo compare the efficacy of an exercise and education programme with open-label placebo given as intra-articular injections of inert saline on pain and function in individuals with knee osteoarthritis (OA).MethodsIn...

A comparative study of the efficacy of intra-articular injection of 2% lignocaine in the treatment of osteoarthritis knee in contrast to the injection of normal saline

Osteoarthritis of the knee is a commonly occurring disorder in the elderly population worldwide. It is usually treated with first-line therapies like life-style modification, analgesics, braces, and physiotherapy. Increasingly second-line treatments – intra-articular platelet-rich plasma, hyaluronic acid, and lignocaine are being offered. We compared 50 knee joints of 25 patients of advanced knee osteoarthritis by treating 25 knee joints with intra-articular 2% lignocaine and other 25 knee joints (allocated randomly) with intra-articular saline injection as a placebo and using NPRS scale and WOMAC SCALE for results.

Safety and Efficacy of an Amniotic Suspension Allograft Injection Over 12 Months in a Single-Blinded, Randomized Controlled Trial for Symptomatic Osteoarthritis of the Knee

The purpose of this study is to determine the efficacy of amniotic suspension allograft (ASA) compared to hyaluronic acid (HA) and saline at up to 12 months of follow-up through the use of patient-reported outcomes, immunoglobulin levels, and anti-human leukocyte antigen (HLA) levels. Within this multicenter study, 200 patients were randomized 1:1:1 to a single intra-articular injection of saline, HA, or ASA. Patient-reported outcomes, including Knee Injury and Osteoarthritis Outcome Score (KOOS) and visual analog scale (VAS) score, were collected at multiple time points (baseline, 1 week, 6 weeks, 3 months, 6 months) out to 12 months to assess improvements in pain and function. Radiographs at baseline and 12 months were taken to determine radiographic changes, while blood was collected at baseline, 6 weeks, and 6 months to determine changes in immunoglobulins and anti-HLA levels. Statistical analyses were performed using last observation carried forward and mixed effects model for repeated measures. Treatment with ASA resulted in significant improvements in KOOS and VAS scores that were maintained through 12 months (P < .05). Treatment with ASA resulted in a 63.2% responder rate at 12 months using the Outcome Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International simplified definition. There were no significant differences between groups for radiographic measures in the index knee, immunoglobulins, C-reactive protein, or anti-HLA serum levels (P > .05). The number and type of adverse events (AEs) reported for ASA were comparable to the HA injection group, while no treatment-emergent AEs were reported for the saline group. This randomized controlled trial of ASA vs HA and saline for the treatment of symptomatic knee osteoarthritis demonstrated clinically meaningful improved outcomes with ASA over the controls out to 12 months postinjection. No concerning immunologic or adverse reactions to the ASA injection were identified with regards to severe AEs, immunoglobulin, or anti-HLA levels. Level I, randomized controlled multicenter trial.

Is intra-articular saline injection effective for the treatment of osteoarthritis?

Lurtsema, Ryan D. MD; Rosalez, Rafael MD; Morera, Paulino MD; Edwards, David S. MD Author Information

Comparison of Effects of a Thrombin-Based Hemostatic Agent and Topical Tranexamic Acid on Blood Loss in Patients with Preexisting Thromboembolic Risk Undergoing a Minimally Invasive Total Knee Arthroplasty. A Prospective Randomized Controlled Trial.

Background The efficacy of a thrombin-based hemostatic agent (Floseal®) on reducing postoperative blood loss after total knee arthroplasty (TKA) was still unclear. The aim of our study was to conduct a prospective randomized controlled study to compare the blood conservation effects of Floseal® and topical TXA in patients with preexisting thromboembolic risk undergoing primary minimally invasive TKA. Methods Our power analysis of this study was based upon the following description, to obtain a statistical power of 0.90 and an alpha error of 0.05, 30 patients were required in each group. Therefore, we enrolled a total of 103 patients with at least one of the risk factors for thromboembolism who underwent unilateral primary minimally invasive TKA, and the participants were randomly divided into the topical TXA group (n = 34), receiving intra-articular injection of 3 g of TXA in 100 mL saline after TKA, the topical Floseal® group (n = 34), receiving 10 mL of Floseal® intra-articularily during surgery, and the placebo group (n = 35), receiving an intra-articular saline injection only. The total blood loss (TBL) and hemoglobin (Hb) drop were compared among the 3 groups. Results The TXA group had a lower TBL of 645 mL (227 to 1090) in comparison with 1145 mL (535 to 1942) in the Floseal® group and 1103 mL (424 to 1711) in the placebo (p < 0.001, respectively). The TBL was similar between the Floseal® group and the placebo group (p = 0.819). No patients in any group had symptoms of venous thromboemblism. Conclusion Our prospective randomized controlled study showed that intra-articular application of TXA was superior to hemostatic matrix (Floseal®) in terms of blood conservation in patients with preexisting thromboembolic risk undergoing minimally invasive TKA. This trial is registered with Clinicaltrials.gov (NCT02865174) on 08/09/2016.

Exercise therapy and patient education versus intra-articular saline injections in the treatment of knee osteoarthritis: an evidence-based protocol for an open-label randomised controlled trial (the DISCO trial)

BackgroundKnee osteoarthritis (OA) is a highly prevalent musculoskeletal condition causing pain, physical disability, and reduced quality of life. Exercise and patient education are non-pharmacological interventions for knee OA unanimously recommended as first-line treatments based on extensive research evidence. However, none of the numerous randomised controlled trials of exercise and education for knee OA has used adequate sham/placebo comparison groups because the ‘active’ ingredients are unknown. Designing and executing an adequate and ‘blindable placebo’ version of an exercise and education intervention is impossible. Therefore, using an open-label study design, this trial compares the efficacy of a widely used ‘state-of-art’ exercise and education intervention (Good Life with osteoarthritis in Denmark; GLAD) with presumably inert intra-articular saline injections on improvement in knee pain in patients with knee OA.MethodsIn this open-label randomised trial, we will include 200 patients with radiographically verified OA of the knee and randomly allocate them to one of two interventions: (i) 8 weeks of exercise and education (GLAD) or (ii) Intra-articular injections of 5 ml isotonic saline every second week for a total of 4 injections. Outcomes are taken at baseline, after 8 weeks of treatment (week 9; primary endpoint) and after an additional 4 weeks of follow-up (week 12). The primary outcome is change from baseline in the Knee Injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale score. Secondary outcomes include the Physical function in Activities of Daily Living, Symptoms, and Knee-related Quality of Life subscales of the KOOS, the patients’ global assessment of disease impact, physical performance tests, and presence of knee joint swelling.DiscussionThis current trial compares a presumably active treatment (GLAD) with a presumably inert treatment (IA saline injections). Both study interventions have well-established and anticipated similar effects on knee OA symptoms, but the underlying mechanisms are unknown. The interpretation of the results of this trial will likely be difficult and controversial but will contribute to a better understanding of the bias introduced in the effect estimation of classically unblindable exercise and education interventions for knee OA.Trial registrationwww.ClinicalTrials.govNCT03843931. Prospectively registered on 18 February 2019.

The relationship between synovial inflammation, structural pathology, and pain in post-traumatic osteoarthritis: differential effect of stem cell and hyaluronan treatment

BackgroundSynovitis is implicated in the severity and progression of pain and structural pathology of osteoarthritis (OA). Increases in inflammatory or immune cell subpopulations including macrophages and lymphocytes have been reported in OA synovium, but how the particular subpopulations influence symptomatic or structural OA disease progression is unclear. Two therapies, hyaluronan (HA) and mesenchymal stem cells (MSCs), have demonstrated efficacy in some clinical settings: HA acting as device to improve joint function and provide pain relief, while MSCs may have immunomodulatory and disease-modifying effects. We used these agents to investigate whether changes in pain sensitization or structural damage were linked to modulation of the synovial inflammatory response in post-traumatic OA.MethodsSkeletally mature C57BL6 male mice underwent medial-meniscal destabilisation (DMM) surgery followed by intra-articular injection of saline, a hyaluronan hexadecylamide derivative (Hymovis), bone marrow-derived stem cells (MSCs), or MSC + Hymovis. We quantified the progression of OA-related cartilage, subchondral bone and synovial histopathology, and associated pain sensitization (tactile allodynia). Synovial lymphocytes, monocyte/macrophages and their subpopulations were quantified by fluorescent-activated cell sorting (FACS), and the expression of key inflammatory mediators and catabolic enzyme genes quantified by real-time polymerase chain reaction (PCR).ResultsMSC but not Hymovis significantly reduced late-stage (12-week post-DMM) cartilage proteoglycan loss and structural damage. Allodynia was initially reduced by both treatments but significantly better at 8 and 12 weeks by Hymovis. Chondroprotection by MSCs was not associated with specific changes in synovial inflammatory cell populations but rather regulation of post-injury synovial Adamts4, Adamts5, Mmp3, and Mmp9 expression. Reduced acute post-injury allodynia with all treatments coincided with decreased synovial macrophage and T cell numbers, while longer-term effect on pain sensitization with Hymovis was associated with increased M2c macrophages.ConclusionsThis therapeutic study in mice demonstrated a poor correlation between cartilage, bone or synovium (histo)pathology, and pain sensitization. Changes in the specific synovial inflammatory cell subpopulations may be associated with chronic OA pain sensitization, and a novel target for symptomatic treatment.

Intra-articular Injection of Chloramphenicol Reduces Articular Cartilage Degeneration in a Rabbit Model of Osteoarthritis.

Osteoarthritis (OA) is characterized by degeneration of articular cartilage. Studies have found that enhancement of autophagy, an intracellular catabolic process, may limit the pathologic progression of OA. Chloramphenicol is a potent activator of autophagy; however, the effects of chloramphenicol on articular cartilage are unknown. Using human OA knee chondrocytes in vitro, we asked, does chloramphenicol (1) activate autophagy in chondrocytes; (2) protect chondrocytes from IL-1β-induced apoptosis; and (3) reduce the expression of matrix metallopeptidase (MMP)-13 and IL-6 (markers associated with articular cartilage degradation and joint inflammation). Using an in vivo rabbit model of OA, we asked, does an intra-articular injection of chloramphenicol in the knee (4) induce autophagy; (5) reduce OA severity; and (6) reduce MMP-13 expression? Human chondrocytes were extracted from 10 men with OA undergoing TKA. After treatment with 25 μg/mL, 50 μg/mL, or 100μg/mL chloramphenicol, the autophagy of chondrocytes was detected with Western blotting, transmission electron microscopy, or an autophagy detection kit. There were four groups in our study: one group was untreated, one was treated with 100 μg/mL chloramphenicol, another was treated with 10 ng/mL of IL-1β, and the final group was treated with 10 ng/mL of IL-1β and 100 μg/mL of chloramphenicol. All groups were treated for 48 hours; cell apoptosis was detected with Western blotting and flow cytometry. Inflammation marker IL-6 in the cell culture supernatant was detected with an ELISA. Articular cartilage degradation-related enzyme MMP-13 was analyzed with Western blotting. A rabbit model of OA was induced by intra-articular injection of type II collagenase in 20 male 3-month-old New Zealand White rabbits' right hind leg knees; the left hind leg knees served as controls. Rabbits were treated by intra-articular injection of saline or chloramphenicol once a week for 8 weeks. Autophagy of the articular cartilage was detected with Western blotting and transmission electron microscopy. Degeneration of articular cartilage was analyzed with Safranin O-fast green staining and the semi-quantitative index Osteoarthritis Research Society International (OARSI) grading system. Degeneration of articular cartilage was evaluated using the OARSI grading system. The expression of MMP-13 in articular cartilage was detected with immunohistochemistry. Chloramphenicol activated autophagy in vitro in the chondrocytes of humans with OA and in an in vivo rabbit model of OA. Chloramphenicol inhibited IL-1-induced apoptosis (flow cytometry results with chloramphenicol, 25.33 ± 3.51%, and without chloramphenicol, 44.00 ± 3.61%, mean difference, 18.67% [95% CI 10.60 to 26.73]; p = 0.003) and the production of proinflammatory cytokine IL-6 (ELISA results, with chloramphenicol, 720.00 ± 96.44 pg/mL, without chloramphenicol, 966.67 ± 85.05 pg/mL; mean difference 74.24 pg/mL [95% CI 39.28 to 454.06]; p = 0.029) in chondrocytes. After chloramphenicol treatment, the severity of cartilage degradation was reduced in the treatment group (OARSI 6.80 ± 2.71) compared with the control group (12.30 ± 2.77), (mean difference 5.50 [95% CI 1.50 to 9.50]; p = 0.013). Furthermore, chloramphenicol treatment also decreased the production of MMP-13 in vitro and in vivo. Chloramphenicol reduced the severity of cartilage degradation in a type II collagen-induced rabbit model of OA, which may be related to induction of autophagy and inhibition of MMP-13 and IL-6. Our study suggests that an intra-articular injection of chloramphenicol may reduce degeneration of articular cartilage and that induction of autophagy may be a method for treating OA. The animal model we used was type II collagen-induced OA, which was different from idiopathic OA and post-traumatic OA. Therefore, we need to use other types of OA models (idiopathic OA or a surgically induced OA model) to further verify its effect, and the side effects of chloramphenicol also need to be considered, such as myelosuppression.