Hyaluronic Acid (Joint)

BACKGROUND: Stem cells are specialised precursor cells that can replace aged or damaged cells and thereby maintain healthy tissue function. Stem cell therapy is increasingly used as a treatment for knee osteoarthritis, despite the lack of clarity around the mechanism by which stem cell therapy may slow down disease progression in osteoarthritis, and uncertainty regarding its benefits and harms. OBJECTIVES: To assess the benefits and harms of stem cell injections for people with osteoarthritis of the knee. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase on 15 September 2023, unrestricted by date or language of publication. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for relevant trial protocols and ongoing trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs), or trials using quasi-randomised methods of participant allocation, comparing stem cell injection with placebo injection, no treatment or usual care, glucocorticoid injection, other injections, exercise, drug therapy, surgical interventions, and supplements and complementary therapies in people with knee osteoarthritis. DATA COLLECTION AND ANALYSIS: Two review authors selected studies for inclusion, extracted trial characteristics and outcome data, assessed risk of bias and assessed the certainty of evidence using the GRADE approach. The primary comparison was stem cell injection compared with placebo injection. The primary time point for pain, function and quality of life was three to six months, and the end of the trial period for participant-reported success, joint structure changes and adverse event outcomes. Major outcomes were pain, function, quality of life, global assessment of success, radiographic joint progression, withdrawals due to adverse events and serious adverse events. MAIN RESULTS: We found 25 randomised trials (1341 participants) comparing stem cell injections with placebo injection (eight trials), no treatment or usual care (analgesia, we

OBJECTIVE: The efficacy and safety of arthroscopic surgery combined with hyaluronic acid in the treatment of meniscal injuries were evaluated by Meta-analysis to provide an evidence-based basis for the selection of clinical treatment options. METHODS: PubMed, Cochrane Library, EMBASE, Scopus, Web of Science English databases, and Chinese databases of China National Knowledge Infrastructure, WAN FANG, VIP, and China SinoMed had been searched up to June 2021. Quality evaluation was performed concerning the Cochrane Systematic Evaluation Tool. The obtained data were analyzed using the statistical software Review Manager 5.3. RESULTS: Eleven randomized controlled trials with a total of 955 patients were eventually included, 473 in the arthroscopic combined with hyaluronic acid group (combined treatment group) and 482 in the arthroscopy alone group (surgery group). The results of the study revealed that the excellent treatment [OR = 3.44, 95% CI (2.10, 5.65), p < .00,001], the VAS score [MD = -0.99, 95% CI (-1.50, -0.48), p = .0002], the Lysholm score [MD = 9.70, 95% CI (6.41, 12.99), p < .00,001] and the joint mobility [MD = 6.31, 95% CI (0.84, 11.78), p = .02] of the combined treatment group were significantly better than the surgery group, the difference was statistically significant. The complications rate was comparable in both groups [OR = 0.86, 95% CI (0.29, 2.53), p = .78], with no statistically significant difference. CONCLUSION: Arthroscopic surgery combined with hyaluronic acid for meniscal injury can improve the efficiency of treatment compared with arthroscopic surgery alone, as well as the efficacy in relieving joint pain and improving joint function and mobility, without increasing the incidence of complications. Arthroscopic surgery combined with hyaluronic acid administration has good effectiveness and safety profile. Therefore, hyaluronic acid supplementation is recommended after arthroscopic surgery when treating meniscal injuries.

INTRODUCTION: Osteoarthritis (OA), which has a high incidence in the elderly, brings a huge economic burden to society. MSCs (Mesenchymal Stem Cells) have shown great multidirectional differentiation potential which are expected to treat OA, and numerous clinical trials have been conducted. However, the efficacy and safety of the MSCs still need to be further integrated and analyzed. MATERIALS AND METHODS: We searched several databases (PubMed, EMBASE, Scopus, Web of Science, Cochrane Library, Ovid, and ScienceDirect) for assessing eligible trials that randomized controlled trials, hyaluronic acid as control, and MSCs injection to treat OA. Vitro studies and animal studies were excluded. Search terms were: "cartilage," "clinical trial," "mesenchymal," "stromal" and "stem cell", "osteoarthritis". The preliminary guidelines and study protocol were published online at PROSPERO. RESULTS: Many assessment scales could not be improved significantly after 6 months. However, most of the scales were significantly improved after 12 months, indicating that compared with hyaluronic acid, stem cells could relieve OA symptoms significantly. No serious adverse effect was found. CONCLUSION: There are significant therapeutic effects on joint function, symptoms, and no permanent adverse effect has been found after stem cell treatment. It is promising to apply intro-articular injection of stem cells for OA to clinical application. More researches are needed to supplement present deficiencies.

Osteoarthritis is characterized by marked pain, stiffness and reduced range of motion and is one of the most common causes of disability and reduced quality of life. The disease is diagnosed in 20% of the adult population; the prevalence rises to 50% of adults over 65 years of age. There are various treatment options in the early stages of knee osteoarthritis which are intended to postpone the need for arthroplasty, which is the gold standard treatment at the end-stage level of the disease. Evidence based medicine (EBM) facilitates optimized decision-making and treatment for an individual patient based on meta-analysis, randomize control studies and systematic reviews. Based on these studies, physical activity is an effective treatment option resulting in reduced disability and improved quality of life. Among other conservative treatment options, chondroitin, a food supplement, was found to be as effective as anti-inflammatory medication with a lower side effect profile. Similar results were found for intra-articular injections of hyaluronic acid, while intra-articular injections of platelet rich plasma (PRP) were found to be the most effective of all the above. No advantage was reported for knee arthroscopy over conservative treatment options even when examining those patients with combined symptomatic meniscal tear and knee osteoarthritis. Non-steroidal anti-inflammatory medication (NSAIDS) and opiate treatment have limited long term effect on reducing pain, disability and improving quality of life. These drugs can have a high rate of substantial side effect. Hence, their use should be limited, especially in the elderly population, and safer modalities should be explored.

INTRODUCTION: Despite advances in the development of mesenchymal stem cells (MSCs), the ultimate benefits of MSCs against current cell-based therapies are still limited. This study aimed to assess the safety, feasibility, and efficacy of Cytopeutics® umbilical cord-derived MSCs (Chondrocell-EX) in patients with knee cartilage injury. MATERIALS AND METHODS: The study was conducted in two parts: a phase I feasibility study (PI) followed by a phase II randomized controlled trial (PII). Both studies were approved by UKM Research Ethics Committee (PI: UKM PPI/111/8; PII: UKM PPI/111/8/JEP-2019-304). Six patients were involved in the PI study in which all patients received Chondrocell-EX and 28 patients in the following PII study, where 17 patients received Chondrocell-EX with Hyaluronic acid (HA) (Arm A) and 11 patients received commercially available cell-based therapy, which is Bone Marrow Aspirate Concentrate (BMAC) with Hyaluronic acid-based scaffold (HA-S) (Arm B). Safety was assessed based on the occurrence of adverse events, while clinical outcomes were assessed based on the Knee Injury and Osteoarthritis Outcome Score (KOOS) and Pain Visual Analog Scale (VAS). Second-look arthroscopy and histological assessment were performed to assess their structural outcomes at 12 months. RESULTS: In the PI feasibility study, significant pain reduction began at 3 months, with mean VAS decreasing from 6.83 ± 0.98 at baseline to 4.83 ± 1.17 (p < 0.01), 3.00 ± 0.00 at 6 months (p < 0.01), and 1.83 ± 0.75 at 12 months (p < 0.01). In the PII study, Arm A (Chondrocell-EX + HA) demonstrated significant VAS improvements at all follow-up points compared to baseline (p < 0.001), whereas Arm B (BMAC + HA-S) showed significant reductions only from 3 months onward. After adjustment for baseline age and VAS, Arm A achieved significantly lower pain scores than Arm B at 6 months (2.56 ± 1.41 vs 3.09 ± 1.22; p = 0.015) and 12 months (2.27 ± 1.49 vs 2.50 ± 1.35; p = 0.043), indicating earlier and sustained pain relief with Chondrocell-EX injection. Functional outcomes mirrored pain improvements. In PI, KOOS scores improved significantly from 3 months, reaching 85.83 ± 11.87 at 12 months (p

Temporomandibular joint osteoarthritis (TMJ-OA) is a progressive degenerative disorder, for which therapeutic interventions remain limited. The disruption of metabolic homeostasis plays a critical role in the pathogenesis and advancement of TMJ-OA. However, it remains unclear whether extracellular vesicles (EVs) as cellular metabolites are correlated with the pathogenesis, treatment and diagnosis of TMJ-OA. In this study, we demonstrated that autologous circulating extracellular vesicles (C-EVs) possessed significant therapeutic potential for TMJ-OA through the targeted removal of senescent chondrocytes. In a randomized clinical trial (ChiCTR2200063153), C-EV administration was found to significantly enhance condylar bone regeneration and alleviate symptoms relative to hyaluronic acid controls, without eliciting any adverse effects. Comparative analysis revealed that joint cavity-derived EVs from TMJ-OA patients (OA-EVs) exhibited structural abnormalities, diminished expression of canonical EV markers, and pro-inflammatory characteristics. In contrast, C-EVs were significantly enriched with functional proteins C1q binding protein (C1QBP). And the level of C1QBP-positive EVs was positively correlated with therapeutic outcomes, thereby establishing C1QBP as a potential predictive biomarker for TMJ-OA. Furthermore, C-EVs reestablished joint homeostasis by regulating the immune microenvironment and tissue regeneration capacity. Mechanistically, C1QBPhigh C-EVs upregulated the expression of membrane C1q on senescent chondrocytes, thereby initiating C1q-C1QBP binding, p14ARF translocation to mitochondria, and subsequent cytochrome C/caspase-3-dependent apoptosis. Our findings demonstrate that C-EVs serve a dual therapeutic role by facilitating the clearance of senescent cells via the C1QBP/C1q/p14ARF axis, while promoting tissue regeneration and regulating metabolites homeostasis, offering a novel biological strategy for TMJ-OA treatment. © 2026 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.

OBJECTIVE: Temporomandibular joint disorders (TMDs) are a common source of orofacial pain and dysfunction. Arthrocentesis of the temporomandibular joint (TMJ) is a minimally invasive treatment that can be augmented with intra-articular injections. This study aimed to compare the clinical efficacy of platelet-rich plasma (PRP) versus hyaluronic acid (HA) injections following TMJ arthrocentesis in patients with TMDs unresponsive to conservative therapy. METHODS: Sixty patients (72 joints) were randomized into three equal groups. Group A underwent arthrocentesis with Ringer's lactate (RL) alone (control), Group B received PRP injection post-arthrocentesis, and Group C received HA injection post-arthrocentesis. Pain intensity (VAS), maximum mouth opening (MMO), and TMJ sounds were evaluated at baseline, 1 week, 12 weeks, and 24 weeks. Repeated-measures ANOVA and chi-square tests were used for analysis (p < 0.05). RESULTS: All groups showed significant improvements in pain and MMO over time. Mean VAS pain scores decreased from ~ 4.8 to < 1.0 at 24 weeks (p < 0.001), while MMO increased from ~ 32 mm to ~ 40 mm (p < 0.001). No significant differences were found between the PRP and HA groups in pain or function at any follow-up point, nor between either treatment group and the control group. TMJ clicking resolved or improved in > 95% of joints across all groups. No adverse events were recorded. CONCLUSION: TMJ arthrocentesis alone provides substantial pain relief and functional gains. PRP and HA did not confer additional benefit over lavage alone within the 6-month timeframe. Further studies are required to assess any potential long-term differences. © 2026. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

BACKGROUND: Treatments for knee osteoarthritis (OA) include injections such as hyaluronic acid (HA), which stabilizes joints but degrades quickly due to reactive oxygen species. The experimental product JETKNEE combines non-crosslinked HA (20 mg/ml) with 0.5 % mannitol, that may slow HA degradation and extend its effect, but with a limited clinical evidence base. OBJECTIVE: To evaluate the efficacy and safety of a single intra-articular injection of JETKNEE versus saline in patients with symptomatic knee OA. METHODS: In this double-blind randomized trial, 132 patients with Kellgren-Lawrence grade 2-3 OA received 2 ml of either JETKNEE or saline. The primary outcome was change in visual analog scale (VAS) pain score at 6 months. Secondary outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne index, ultrasound evaluation of cartilage thickness, quadriceps muscle thickness, OA cartilage grading, and adverse events. RESULTS: VAS pain improved significantly in both groups without between-group difference. JETKNEE showed significantly greater improvement in WOMAC pain, function, and total scores across all time points (P < 0.05). Lequesne index improved more rapidly at early visits. No significant differences were observed in ultrasound findings or patient satisfaction. Adverse events were more frequent in the JETKNEE group but were mostly mild. CONCLUSION: A single injection of JETKNEE did not show superiority to placebo in the primary outcome (VAS pain), but demonstrated improvements in secondary functional outcomes for 6 months in patients with knee OA.

INTRODUCTION/OBJECTIVE: Patellofemoral osteoarthritis (PFOA) is unicompartmental arthritis with a hallmark of anterior knee pain, disturbing quality of life. Unlike tibiofemoral osteoarthritis, there is still a lack of evidence regarding intra-articular injection for isolated PFOA patients. This study aims to evaluate the efficacy of intra-articular hyaluronic acid (HA) in comparison to corticosteroid (CS) injections for pain reduction and improvement in knee function in isolated PFOA patients. METHODS: This was a prospective, double-blind, randomized controlled trial. Patients with isolated PFOA based on clinical and radiographic features were randomized 1:1 to receive a single-shot, 2 ​ml intra-articular 2% sodium hyaluronate plus 0.5% mannitol or a 2 ​ml solution comprising 1 ​ml of 40 ​mg triamcinolone acetonide and 1% lidocaine. The visual analog scale (VAS) for anterior knee pain, Kujala score, pain during injection, and adverse events were assessed during a 6-month follow-up. RESULTS: A total of 60 patients were included. Both groups demonstrated statistically significant improvements in VAS pain and Kujala scores from 48 ​h post-injection to 6 months compared to baseline (p ​< ​0.05). At the 6-month follow-up, there were no significant between-group differences in VAS pain (mean difference [95% CI]: -4.46 [-11.2, 2.28]; p ​= ​0.270) or Kujala scores (2.56 [-4.08, 9.2]; p ​= ​0.45). However, at 48 ​h, 72 ​h, and 1 week post-injection, the CS group reported statistically significantly greater pain relief compared to the HA group (mean differences: 10.33, 9.67, and 7.67; p ​= ​0.002, 0.003, and 0.013, respectively). No significant differences were observed in pain during injection or adverse events. CONCLUSION: Intra-articular HA and CS injections provide comparable pain reduction and functional score improvement at 6-month follow-up in patients with PFOA, with better pain relief in the first week for the CS group. Intra-articular HA may be an alternative to CS, with equivalent results but without increasing the risk of chondrotoxicity and cartilage volume loss, especially in isolated PFOA patients whose tibiofemoral compartment cartilage is relatively pres

Early-stage knee osteoarthritis (knee OA) lacks effective regenerative therapies. This study aimed to compare the cartilage regenerative effects, clinical efficacy, and safety of intra-articular injections of autologous adipose-derived mesenchymal stem cells (ADSCs) versus hyaluronic acid (HA). Forty-eight patients with early knee OA were enrolled in a prospective open-blinded multi-center study at Suranaree University of Technology Hospital and Phramongkutklao Hospital. Participants were randomized into either the ADSC or HA group. Primary outcomes included MRI-based cartilage lesion volume, synovial thickness via ultrasound, and WOMAC scores over 6 months. MRI results revealed significant and progressive cartilage regeneration in the ADSC group. In particular, medial femoral cartilage lesion volume decreased by 50.06 mm3, whereas the HA group showed an increase of 36.44 mm3. Synovial thickness also declined significantly in the ADSC group at 3 and 6 months. Both groups demonstrated reduced symptoms, but the ADSC group achieved superior and sustained improvements in WOMAC pain, stiffness, and function scores throughout the 6-month follow-up. The clinical benefits were consistent and more pronounced compared with HA. No serious adverse events occurred. In conclusion, intra-articular ADSC injections show superior cartilage restoration on MRI and better clinical outcomes than HA injection, making them a promising treatment for early-stage knee OA.

PURPOSE: Abnormal patellar alignment is closely linked to patellofemoral osteoarthritis (PFOA), with laterally tilted patellae often worsening pain. This study investigates the relationship between imaging parameter changes and pain levels by analyzing the effects of Tui Na (TN) and intra-articular hyaluronic acid injections (IAHA) intervention. METHODS: This study included 126 PFOA patients from Wangjing Hospital of the China Academy of Traditional Chinese Medicine, between October 8, 2022, and December 31, 2024. Participants were randomly assigned to the TN or IAHA group. The IAHA group received one injection per week for five weeks, while the TN group underwent three Tui Na sessions per week for four weeks. The Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and patellar imaging indices (Lateral Patellar Displacement (LPD), Congruence Angle (CA), Lateral Patellofemoral Angle (LPFA), Patellofemoral Index (PFI)) were assessed before and one week after treatment. To investigate the correlation between imaging parameters and VAS scores, Spearman rank correlation analysis was applied to non-normally distributed data, with scatter plots used to elucidate trends in the association between pain and imaging parameters. A multiple linear regression model was constructed to assess the independent effects of imaging parameters on changes in VAS scores. RESULTS: Both TN and IAHA treatments significantly reduced VAS and WOMAC scores (p < 0.05). No significant difference was observed in VAS score improvements between the two groups (p > 0.05). However, the TN group showed a significantly greater improvement in WOMAC scores (p < 0.05). The TN group also exhibited better improvements in LPD and CA compared to the IAHA group (p < 0.05). Spearman's correlation showed no significant link between imaging indices and VAS scores (p > 0.05). Multiple regression analysis revealed that reductions in VAS scores were associated with decreases in LPD (β = 0.274, p = 0.038) and CA (β = 0.309, p = 0.033). CONCLUSION: Tui Na is as effective as IAHA in relieving pain in PFOA patients, potentially alleviating pain through reductions in LPD

INTRODUCTION: The goal of using ultrasound-guided (USG) arthrocentesis is to reduce number of needle insertion attempts, which is hypothesized to reduce procedure time, postoperative pain, and consequently, limitation in range of motion. PURPOSE: The objective of this study was to compare the therapeutic and operative efficiency of USG Single-Puncture Arthrocentesis (SPA) Type 2 and SPA Type 2 arthrocentesis without ultrasound guidance in the treatment of temporomandibular joint (TMJ) internal derangement (ID) "disc displacement without reduction (DDWOR)." MATERIALS AND METHODS: A double-blinded prospective randomized clinical trial (RCT) was conducted from December 2022 to December 2023 at Ain Shams University Hospital. It enrolled females with a mean age of 27.00 ± 3.70 years with DDWOR and failed conservative treatment, excluding those with malocclusion, parafunctional habits, systemic diseases, psychological disorders or requiring special needs. In the study, 40 female patients with DDWOR were randomly divided into a control group (SPA Type 2 arthrocentesis) and an intervention group (USG SPA Type 2 arthrocentesis). Patients were assessed for needle insertion attempts as the primary outcome. procedure time, pain measured using visual analogue scale (VAS), and maximum mouth opening (MMO) were also assessed. Follow-up was conducted at 4, 8, and 12 weeks. Patients with differences in age and gender, malocclusion, parafunctional habits, systemic diseases, or psychological disorders were excluded. RESULTS: The intervention group had fewer needle insertion attempts (1.6 vs. 2.9) and shorter procedure time (11.75 vs. 16 min, p < 0.001). Pain scores (p = 0.846) and maximum mouth opening (p = 0.341) showed no statistically significant differences after 12 weeks. Data were summarized as mean, SD, median, and IQR, with normality assessed by examining the distribution and using the Shapiro-Wilk test. Non-parametric variables were compared using the Mann-Whitney U test. Linear mixed models were assessed via residual plots, Q-Q plots, Shapiro-Wilk, Breusch-Pagan, and VIF tests. Fixed effects were analyzed with ANOVA or Wald Chi-Square tests, followed by Tukey's post-hoc c

BACKGROUND: The efficacy of hyaluronic acid (HA) after arthrocentesis in temporomandibular joint (TMJ) disorders is recognized, but the therapeutic effect of different HA doses remains unclear. PURPOSE: The study purpose was to measure and compare the therapeutic efficacy of different HA doses among patients with intra-articular pain and dysfunction undergoing arthrocentesis. STUDY DESIGN, SETTING, SAMPLE: Subjects with intra-articular pain and dysfunction presented to Afyonkarahisar University of Health Sciences between September 2022 and December 2023 were screened for study inclusion. The inclusion criteria were over 18 years of age, with magnetic resonance imaging-confirmed disc displacement without reduction, and classified as stage 3 to 4 according to Wilke's classification. The exclusion criteria were the presence of systemic disease, pregnancy, TMJ ankylosis, myofascial pain, hypersensitivity to local anesthetics, and a history of TMJ surgery. PREDICTOR VARIABLE: The predictor variable was HA dose. Subjects were randomly assigned to receive 10 mg/ml (HA10) or 20 mg/ml (HA20). OUTCOME VARIABLE: The primary outcome variable was the therapeutic effect, which was assessed using visual analog scale (VAS) and maximum incisal opening (MIO). The secondary outcomes were lateral excursions, protrusion, and joint sounds. All measurements were recorded at baseline (T0), month 1 (T1), and month 3 (T2). COVARIATES: The covariates were demographics (age and sex), perioperative (Wilke's classification), and side of the arthrocentesis procedure (unilateral or bilateral). ANALYSES: Statistical analysis using IBM SPSS included Mann-Whitney U test, χ2 test, and Fisher's exact test for group comparisons, with significance at P < .05. RESULTS: The study sample was composed of 36 subjects with a mean age of 32.78 (SD = 9.53), and 29 (80.6%) were female. There were 18 subjects in each study group. For the TMJ, VAS scores decreased from 7.33 ± 2.06 to 0.97 ± 1.24 in HA10 and from 7.78 ± 3.26 to 1.82 ± 2.11 in HA20 (P = .3 at T0, P = .07 at T2). MIO increased from 37.44 ± 8.3 to 45.06 ± 6.8 in HA10 and from 37 ± 10.84 to 42.94 ± 10.54 in HA20 (P = .9 at T0, P = .5 at T2). No stat

OBJECTIVE: To evaluate the feasibility and clinical outcomes of computer-guided injection of sodium hyaluronate visco-supplementation and arthrocentesis in the treatment of temporomandibular joint disorder compared with conventional injection. STUDY DESIGN: Twenty patients with Wilkes stage I & II internal derangement were selected and randomly allocated into the intervention group, managed with computer-guided intra-articular visco-supplementation, and the control group, managed with conventional technique. The efficacy of the computer-guided procedure was appraised by the assessment of the need for needle relocation and the duration of the procedure in both groups. Clinical evaluation was performed for the assessment of pain intensity, maximum unassisted vertical mouth opening, and maximum lateral mandibular deviation during opening in both groups. RESULTS: Computer-guided group demonstrated a statistically significant difference from the free-hand group regarding the total procedural time and number of needle relocations. The guided group didn't require any needle relocation with a mean procedural time of 8.35 ± 0.47 minutes. All patients in both groups reported immense improvement in all clinical parameters, with no statistically significant difference between the two groups. CONCLUSIONS: The use of computer-guided visco-supplementation for the treatment of internal derangement is a promising practice with improvement in the procedural accuracy and effectiveness of the injectable material. Additionally, it makes the procedure more reproducible and simpler for both clinicians and patients.

We previously found that modified citrus pectin (MCP), an inhibitor of pro-inflammatory factor Galectin-3 (Gal-3), has significant anti-inflammatory and chondroprotective effects. In this study, a hyaluronate (HA) gel-based sustained release system of MCP (MCP-HA) was developed as an anti-inflammatory agent for chronic inflammation for osteoarthritis (OA) treatment. The MCP-HA gel was injected into the knee joint cavities of OA rabbit models induced by anterior cruciate ligament transection (ACLT) or modified Hulth method once a week for five weeks. We found that MCP-HA could improve the symptoms and signs of OA, protect articular cartilage from degeneration, suppress synovial inflammation, and therefore alleviate OA progression. Proteomic analysis of the synovial fluid obtained from the knee joints of OA rabbits revealed that MCP-HA synergistically regulated the levels of multiple inflammatory mediators and proteins involved in metabolic pathways. Taken together, our results demonstrate that the MCP-HA shows a synergistic effect of HA and MCP by modulating both inflammation and metabolic processes, thereby alleviating OA progression. The MCP-HA sustained release system has promising potential for long-term use in OA treatment.

PURPOSE: Prostate cancer (PCa) is the second leading cause of cancer-related death among men in developed countries. Cabazitaxel (CBZ) is recommended as one of the most active chemotherapy agents for PCa. This study aimed to develop a hyaluronic acid (HA) decorated, cabazitaxel-prodrug (HA-CBZ) and orlistat (ORL) co-loaded nano-system against the prostate cancer in vitro and in vivo. METHODS: Cabazitaxel-prodrug was firstly synthesized by conjugating HA with CBZ through the formation of ester bonds. HA contained ORL and CBZ prodrug co-loaded lipid-polymer hybrid nanoparticles (ORL/HA-CBZ/LPNs) were constructed and characterized in terms of particle size, zeta potential, drug loading capacity and stability. The antitumor efficiency and systemic toxicity of LPNs were evaluated in vitro and in vivo. RESULTS: The resulting ORL/HA-CBZ/LPNs were 150.9 nm in particle size with narrow distribution and high entrapment efficiency. The minimum combination index of 0.57 was found at a drug ratio of 1:2 (ORL:HA-CBZ, w/w) in the drug co-loaded formulations, indicating the strongest synergism effect. ORL/HA-CBZ/LPNs demonstrated an enhanced in vitro and in vivo antitumor effect compared with single drug loaded LPNs and free drug formulations. CONCLUSION: ORL/HA-CBZ/LPNs showed remarkable synergism cytotoxicity and the best tumor inhibition efficiency in mice with negligible systemic toxicity. ORL/HA-CBZ/LPNs can be highly useful for targeted prostate cancer therapy. © 2021 Qu et al.

Osteoarthritis (OA) is one of the most common cartilage disorder that results from breakdown of joint cartilage and underlying bone tissues. Once OA is induced in the joint, subsequent immune reaction leads to chronic inflammation that results in the progression of OA and deconstruction of the cartilage. In this study, an injectable hydrogel with epigallocatechin-3-gallate (EGCG) is introduced to control inflammation and enhance cartilage regeneration. EGCG has intrinsic properties that can modulate inflammation and scavenge radical species. Hyaluronic acid (HA), as a major component of the cartilage ECM, is commonly used for cartilage tissue engineering. In this study, EGCG was combined with tyramine-conjugated HA and gelatin to create a composite hydrogel at an optimized concentration of 50 μM EGCG and 5% w/v HA. The composite hydrogel provided protection to chondrocytes against the pro-inflammatory factor, IL-1β. Additionally, the composite hydrogel led to chondrogenic regeneration in vitro. Histological analysis in vivo showed that EGCG-HA/Gelatin hybrid hydrogel minimized cartilage loss in surgically induced OA model. This study demonstrates that inflammation-modulating HA-based hydrogel may provide a therapeutic option for OA treatment.

Osteoarthritis (OA) progression is associated with joint pain and stiffness. Intra-articular hyaluronic acid (IAHA) injection in knee OA restores the viscoelasticity of the joint and prevents cartilage damage. Shea nut oil extract (SNO) was shown to provide chondroprotection on surgically-induced OA progression in rats. Here we aim to examine IAHA injection supplemented with SNO diet for a synergetic evaluation on the disease progression in OA rats. We employed an anterior cruciate ligament transection plus medial meniscectomy-induced knee OA rat model with up to 12 weeks of sign/behavior observation (knee width, weight-bearing) and histological assessments of joint damage. We found both IAHA and SNO alone significantly attenuated histological changes of cartilage degeneration and synovial reactions in these knee OA rats. Nonetheless, oral SNO alone mitigated OA pain and inflammation while IAHA alone had no significant impact on the weight-bearing test and knee joint swelling. Moreover, with IAHA-treated rats fed with oral SNO diet, additional anti-inflammatory and anti-nociceptive effects were found, which further enhanced and maintained IAHA protection. Given the differential phenotype of oral SNO vs. IAHA, a regimen of IAHA coupled with SNO supplement provides a long-term effect of IAHA treatment. Taken together, the SNO supplement can be safely used as an adjuvant diet for chronic symptomatic relief of OA coupled with IAHA management.

LL-37 is the only human cathelicidin-family host defense peptide and has been reported to interact with invading pathogens causing inflammation at various body sites. Recent studies showed high levels of LL-37 in the synovial-lining membrane of patients with rheumatoid arthritis, a common type of inflammatory arthritis. The present study aims to investigate the role of LL-37 on mechanisms associated with pathogenesis of inflammatory arthritis. The effects of LL-37 on the expression of proinflammatory cytokines, hyaluronan (HA) metabolism-related genes, cell death-related pathways, and cell invasion were investigated in SW982, a human synovial sarcoma cell line. Time-course measurements of proinflammatory cytokines and mediators showed that LL-37 significantly induced IL6 and IL17A mRNA levels at early time points (3-6 hr). HA-metabolism-related genes (i.e., HA synthase 2 (HAS2), HAS3, hyaluronidase 1 (HYAL1), HYAL2, and CD44) were co-expressed in parallel. In combination, LL-37 and IL17A significantly enhanced PTGS2, TNF, and HAS3 gene expression concomitantly with the elevation of their respective products, PGE2, TNF, and HA. Cell invasion rates and FN1 gene expression were also significantly enhanced. However, LL-37 alone or combined with IL17A did not affect cell mortality or cell cycle. Treatment of SW982 cells with both LL-37 and IL17A significantly enhanced IKK and p65 phosphorylation. These findings suggest that the chronic production of a high level of LL-37 may synchronize with its downstream proinflammatory cytokines, especially IL17A, contributing to the co-operative enhancement of pathogenesis mechanisms of inflammatory arthritis, such as high production of proinflammatory cytokines and mediators together with the activation of HA-metabolism-associated genes and cell invasion.

Intra-articular (IA) injection of hyaluronic acid (HA) in combination with nonsteroidal anti-inflammatory drugs, such as ketorolac (KL), have been clinically investigated to provide more rapid and profound pain relief in patients with osteoarthritis. However, its safety, local tolerance, and potential for pharmacokinetic interaction have not been assessed. In this study, the pharmacokinetics and toxicity of a combination of HA and KL were evaluated in normal rats following four-week repeated-dose injection. Rats received HA or KL alone at 4 mg/kg or 16 mg/kg, respectively, or HA/KL combination at 4/4 mg/kg, 4/8 mg/kg, or 4/16 mg/kg on a weekly basis. The rats exhibited temporal, reversible changes in hematology, serum chemistry, and urinalysis caused primarily by KL treatment. No deleterious effects were observed on the joint following repeated IA HA/KL administration, which showed only minimal to mild levels of temporary inflammatory changes in synovial membrane. The plasma KL level following IA injection rose as fast as that of intra-muscular injection, with no alteration with the co-administered HA. In conclusion, repeated IA administration of HA/KL combination was tolerated well in normal rats, encouraging future studies of IA injection of HA/KL combination on osteoarthritis-induced animal models and even patients.

Cross-linked hyaluronic acid hydrogel (cHA gel) and dexamethasone (Dex) have been used to treat knee osteoarthritis (OA) in clinical practice owing to their chondroprotective and anti-inflammatory effects, respectively. The aim of the present study was to compare the treatment effects of the cHA gel pre-mixed with/without Dex in a surgery-induced osteoarthritis model in rats. Anterior cruciate ligament transection (ACLT) surgery was performed on the right knee of rats to induce OA. Male 2-month-old Sprague-Dawley rats were randomly divided into five groups (n = 10/per group): (1) ACLT + saline; (2) ACLT + cHA gel; (3) ACLT + cHA-Dex (0.2 mg/mL) gel; (4) ACLT + cHA-Dex (0.5 mg/mL) gel; (5) Sham + saline. Intra-joint injections were performed four weeks after ACLT in the right knee. All animals were euthanized at 12 weeks post-surgery. Cartilage damage and changes in the synovial membrane were assessed by micro X-ray, Indian ink articular surface staining, Safranin-O/Fast Green staining, immunohistochemistry, hematoxylin and eosin staining of the synovial membrane, and quantitative reverse transcription-polymerase chain reaction for changes in gene expression. Micro X-ray revealed that the knee joint treated with the cHA-Dex gel was wider than those treated with cHA gel alone or saline. The cHA-Dex gel group had less Indian ink staining (indicator of cartilage fibrillation) than the cHA gel or saline injection groups. Safranin-O/Fast Green staining indicated that increased proteoglycan staining and less cartilage damage were found in the cHA-Dex gel group compared with the cHA gel or saline injection groups. Quantification of histology findings from saline, cHA gel, cHA-Dex (0.2 mg/mL) gel, cHA-Dex (0.5 mg/mL) gel, and sham groups were 5.84 ± 0.29, 4.50 ± 0.87, 3.00 ± 1.00, 2.00 ± 0.48, and 0.30 ± 0.58 (p < 0.05), respectively. A strong staining of type II collagen was found in both the cHA-Dex gel groups compared with saline group or cHA alone group. Similar result was found for the mRNA level of aggrecan and opposite result for type X collagen. Hematoxylin and eosin staining in the synovial membrane showed less synovial lining cell layers and reduced inflammator

Fluoroquinolones (FQs) are frequently used for septic arthritis. Increased antibacterial activity has been associated with mammalian cell cytotoxicity that may increase the risk of developing osteoarthritis. This study compared the direct effects of two different FQs, enrofloxacin (Enro) and marbofloxacin (Mar), on normal primary canine chondrocytes and inflammatory-stimulated chondrocytes, in addition to their administration in combination with hyaluronan (HA). Cell viability, cell apoptosis, s-GAG production, and expression patterns of inflammatory, extracellular matrix (ECM) component and protease genes were measured. Enro co-culturing with HA could modify s-GAG synthesis compared with the negative control group. Co-treatment with both FQs and HA significantly decreased cell viability and induced more total apoptotic cell death compared with the negative control and pre-IL-1β-stimulated group. Enro regulated IL-1β-stimulated cells to overexpress IL-1β, TNF, and MMP3, whereas Mar induced upregulation of PTGS2 and NFKB1 and enhanced the expression of ECM component genes HAS1, COL2A1, and ACAN as well as TIMP1 and MMP9. Simultaneous use of HA with Enro can effectively reduce the expression of IL-1β, TNF, and MMP3 in pre-IL-1β-stimulated chondrocytes. These results suggest the beneficial effects of HA in reducing the adverse effects of Enro treatment at the transcriptional level. © 2016 John Wiley & Sons Ltd.

179. Cell Physiol Biochem. 2015;37(5):1792-806. doi: 10.1159/000438542. Epub 2015 Nov 13. Synergistic Effects of a Mixture of Glycosaminoglycans to Inhibit Adipogenesis and Enhance Chondrocyte Features in Multipotent Cells. Petrov PD, Granados N, Chetrit C, Martínez-Puig D, Palou A, Bonet ML. BACKGROUND/AIMS: Multipotent mesenchymal stem cells affect homeostasis of adipose and joint tissues. Factors influencing their differentiation fate are of interest for both obesity and joint problems. We studied the impact of a mixture of glycosaminoglycans (GAGs) (hyaluronic acid: dermatan sulfate 1:0.25, w/w) used in an oral supplement for joint discomfort (Oralvisc™) on the differentiation fate of multipotent cells. METHODS: Primary mouse embryo fibroblasts (MEFs) were used as a model system. Post-confluent monolayer MEF cultures non-stimulated or hormonally stimulated to adipogenesis were chronically exposed to the GAGs mixture, its individual components or vehicle. The appearance of lipid laden cells, lipid accumulation and expression of selected genes at the mRNA and protein level was assessed. RESULTS: Exposure to the GAGs mixture synergistically suppressed spontaneous adipogenesis and induced the expression of cartilage extracellular matrix proteins, aggrecan core protein, decorin and cartilage oligomeric matrix protein. Hormonally-induced adipogenesis in the presence of the GAGs mixture resulted in decreased adipogenic differentiation, down-regulation of adipogenic/lipogenic factors and genes for insulin resistance-related adipokines (resistin and retinol binding protein 4), and up-regulation of oxidative metabolism-related genes. Adipogenesis in the presence of dermatan sulfate, the minor component of the mixture, was not impaired but resulted in smaller lipid droplets and the induction of a more complete brown adipocyte-related transcriptional program in the cells in the adipose state. CONCLUSIONS: The Oralvisc™ GAGs mixture can tip the adipogenic/chondrogenic fate balance of multipotent cells away from adipogenesis while favoring chondrocyte related gene expression. The mixture and its dermatan sulfate component also have modulatory effects of interest on hor

The effectiveness of systemic rheumatoid arthritis (RA) treatments is limited by difficulties in achieving therapeutic doses within articular joints. We evaluated the ability of intra-articular administration of injectable formulations to synergistically enhance repair of RA joints. Methotrexate-loaded hyaluronic acid (Met-HA), dexamethasone-loaded microcapsules (Dex-M), and Dex-M dispersed inside Met-HA were prepared as viscous emulsions and injected into articular joints using a needle to form a drug depot. By near-infrared (NIR) fluorescence imaging, we confirmed the local release of NIR from the depot injected into the articular joint over an extended period. In comparison with the subjects treated with Met-HA or Dex-M alone, subjects treated simultaneously with Met-HA and Dex-M exhibited faster and more significant RA repair. Collectively, these results indicated that the drug depot formed after intra-articular injection of Met-HA/Dex-M induced long-lasting drug release and allowed Met and Dex to effectively act in the articular joint, resulting in enhanced RA repair.

Erratum in Nutrients. 2024 Jun 20;16(12):1961. doi: 10.3390/nu16121961. Osteoarthritis is a significant global health problem. Many patients seek more effective alternatives to nonsteroidal anti-inflammatory medicines or commercial supplements to manage joint pain and inflammation. FlexPro MD® (FP-MD) combines krill oil, astaxanthin, and lower molecular weight hyaluronic acid to support joint health. A 12-week, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of FP-MD and placebo once daily in participants (n = 100) with mild osteoarthritis of the knee or hip joint. For the primary endpoint of joint pain score, per-protocol participants (n = 75) in the FP-MD group (n = 37) had a statistically significantly greater mean reduction from baseline in the Korean Visual Analog Scale (K-VAS) at week 12 compared with participants in the placebo group (n = 38) (20.8 ± 16.16 mm vs. 10.6 ± 17.58, p = 0.0105). The Korean Western Ontario and McMaster Universities Osteoarthritis Index (K-WOMAC) total score was also significantly improved in the FP-MD group at week 12 compared with placebo (-13.0 ± 13.62 vs. -5.5 ± 18.08, p = 0.0489), especially an improvement in pain score (-2.5 ± 2.92 vs. -1.3 ± 3.94, p = 0.02635). FP-MD group had greater improvement in joint function scoring by investigator assessment (p = 0.0127) and by group participants (p = 0.0070). A statistically significantly greater number of patients reported adverse events in the placebo group compared with the FP-MD group (16% vs. 4%, p = 0.0455), most commonly gastrointestinal disorders in both of the groups. These findings suggest that FP-MD is well tolerated and can be effectively used to address joint pain in patients diagnosed with mild osteoarthritis, the main symptom of this condition.

We evaluated and compared the effectiveness of intra-articular injection of hip joint using hyaluronic acid and steroid in patients with femoroacetabular impingement (FAI). Thirty patients with FAI clinically and radiologically were enrolled and underwent hip injection using steroid (TA) or hyaluronic acid (HA) at 0-weeks with cross-over injection at 2-weeks in patients without clinical response of decrease of pain intensity less than 2-point. Patients were followed up to 12-weeks for pain intensity (Numeric rating scale, NRS: 0-10), hip disability score (HOOS), oral medication and adverse events. In 17 patients without cross-over, HOOS at 2-weeks was improved significantly in patients with HA injection (mean increase of HOOS = 13.8 with HA vs. -2.2 with TA, P = 0.031) without difference of NRS (P = 0.943). In 13 patients with cross-over, NRS was significantly improved at 2-weeks with first TA injection (mean decrease of NRS= 1.7 with first TA vs. 0.3 with first HA, P = 0.036), without difference of HOOS (P = 0.431). At 4-weeks, NRS and HOOS were significantly different according to injection drugs (NRS: 0.9 with TA first and HA later vs. 2.7 with HA first and TA later, P = 0.001; mean increase of HOOS: 5.3 with TA first and HA later vs. 10.2 with HA first and TA later, P = 0.032). Intra-articular hip injection may be effective in FAI, with faster effect of pain improvement by TA and more delayed effect of function improvement by HA.

Hyaluronic acid is a component of synovial fluid, in osteoarthritis (OA) and shows a change of property of hyaluronic acid especially its viscoelasticity causing degradation of the cartilage. Injection of hyaluronic acid into OA of the knee (Hyalgan 2 ml/wk for 4 doses) in international multicentres gave dramatic responses: decreased pain, increased mobility of the joint after 49 days of injections compared to a placebo (2 ml of normal saline) p<0.01.

BACKGROUND: Chondromalacia patellae (CMP) is a cartilaginous degeneration of patellofemoral joint caused by a variety of reasons. Recent studies have shown that the incidence of patellomalacia is getting higher and higher. Our meta-analysis is used to illustrate the clinical effect of external treatment of traditional Chinese medicine combined with joint cavity injection of sodium hyaluronate in the treatment of patellomalacia. METHODS: Literature searches were carried out in various databases, such as PubMed, Cochrane Library, China Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang, and Weipu, with the search timeline extending from the inception of each database until April 2024. Two investigators independently conducted literature screening, data extraction, and quality assessment of the included studies. Review Manager 5.4 software was used to perform a meta-analysis, which evaluated changes in the clinical efficacy rate, visual analogue scale (VAS) scores, and time of symptom onset before and after treatment. RESULTS: The study included a total of 11 randomized controlled trials (RCTs) involving 1,279 patients. The meta- analysis results indicated that compared to the standalone injection of sodium hyaluronate, the combination of TCM topical therapy significantly enhanced the clinical efficacy rate in treating CMP [RR=1.17, 95% CI=[1.12,1.22], P<0.00001]. Furthermore, the addition of TCM topical therapy lowered the VAS score in patients with CMP five weeks post-treatment compared to the control group. In comparison to the standalone injection of sodium hyaluronate, the combination of TCM topical therapy showed a quicker onset, thus reducing patients' pain [RR=-7.44, 95% CI=(-9.86,-5.01), P<0.00001]. CONCLUSION: The combination of TCM topical therapy and sodium hyaluronate intra-articular injection demonstrated superior clinical efficacy over the sole intra-articular injection of sodium hyaluronate. This combination effectively mitigated pain in patients and had a faster onset.

This letter addresses methodological considerations in a recent randomized controlled trial comparing platelet-rich plasma (PRP) and hyaluronic acid (HA) after temporomandibular joint (TMJ) arthrocentesis. We highlight a ceiling effect in which the control group achieved near-complete symptom resolution, leaving no room for adjunctive treatments to demonstrate superiority. We discuss the mechanistic mismatch between regenerative (PRP) and biomechanical (HA) approaches and emphasize the critical need for standardized PRP reporting. A systematic review found that only 10% of PRP clinical trials provided comprehensive protocol reporting. We recommend that future studies adopt minimum reporting standards, including relative centrifugal force, platelet concentration, leukocyte content, and activation method, to enable cross-study comparisons and advance the field toward precision medicine approaches in TMJ disorders. © 2026. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

BACKGROUND: This network meta-analysis (NMA) aims to evaluate the comparative efficacy of 13 intra-articular pharmacologic interventions in improving maximal mouth opening (MMO), pain relief, and functional recovery in patients with temporomandibular disorders (TMD) and restricted jaw mobility. METHODS: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science to identify randomized controlled trials (RCTS) evaluating the effects of 13 intra-articular drug injections in patients with limited mouth opening TMD. The methodological quality of the included studies was assessed using the risk of bias (ROB) tool, and data were independently extracted by two researchers. Primary outcomes included maximum mouth opening (MMO) and pain intensity; secondary outcomes included joint lateral and protrusive movements. RESULTS: A total of 38 RCTs involving 1533 TMD patients were included. Thirteen different agents (including HA: hyaluronic acid, PRF: platelet-rich fibrin, PDGF: platelet-derived growth factor, PRP: platelet-rich plasma, MOR: morphine, LA: local anesthetic, MA: micro-fragment fat, TRA: tramadol, SAL: Saline, GC: glucocorticoid, GLU: glucose, NS: non-steroidal, and ARTH: arthrocentesis only) were evaluated. NMA results showed that PRF injection after arthrocentesis significantly improved the maximum temporomandibular joint opening (surface under the cumulative ranking curve (SUCRA): 99.1%) compared with arthrocentesis alone. MA injection following arthrocentesis was most effective for pain reduction (SUCRA: 84.7%), followed by PRF (SUCRA: 78.2%). PRF also led to significant improvements in lateral jaw movement (SUCRA: 95.5%) and protrusive movement (SUCRA: 63.5%) compared to arthrocentesis alone. CONCLUSIONS: Based on the network ranking chart, PRF injection after arthrocentesis offers the greatest benefits for functional recovery in TMD patients. However, additional rigorous literature is required to validate this assertion. CLINICAL TRIAL REGISTRATION: Registration number is INPLASY202450107. ©2025 The Author(s). Published by MRE Press.