Intra-articular Hyaluronic Acid Treatments for Knee Osteoarthritis: A Systematic Review of Product Properties.

INTRODUCTION: There are many intra-articular hyaluronic acid (IA-HA) products on the market that have known intrinsic differences in molecular size, source, and structure. The current review summarizes existing evidence describing and assessing these differences, while also identifying whether these differences have an impact on clinical outcomes. METHODS: This systematic review summarized all literature that specifically addresses IA-HA product differences. Included studies summarized basic science and mechanism of action comparisons of IA-HA product differences, or systematic reviews that assess differences in clinical outcomes between IA-HA product differences. RESULTS: A total of 20 investigations assessed basic science differences between IA-HA products, while 20 investigations provided assessments of the clinical outcome differences between IA-HA product characteristics. The published basic science literature provided a differentiation between low molecular weight (LMW) and high molecular weight (HMW) HA with regard to changes within the synovial fluid, driven by the interactions that these molecules have with receptors in the joint space. These differences in receptor interaction manifest within clinical outcomes, as meta-analyses comparing pain relief after IA-HA suggest that pain reduction is superior in patients who receive HMW HA as opposed to LMW HA. CONCLUSION: This review highlights differences between IA-HA characteristics, and how important the molecular weight, derivation of the product, and structure are to variances in reported clinical outcomes to treat osteoarthritis (OA) of the knee. HMW IA-HAs have shown greater efficacy compared to the alternative of LMW products, while avian-derived and cross-linked products have potentially demonstrated an increase in inflammatory events over non-avian-derived, non-cross-linked HAs.

Heterotopic Ossification Following Arthroplasty for Femoral Neck Fracture.

BACKGROUND: Heterotopic ossification (HO) is a frequent complication following hip surgery. Using data from the Hip Fracture Evaluation with Alternatives of Total Hip Arthroplasty versus Hemiarthroplasty (HEALTH) trial, we aimed to (1) determine the prevalence of HO following total hip arthroplasty (THA) for femoral neck fracture in patients ≥50 years of age, (2) identify whether HO is associated with an increased risk of revision surgery within 24 months after the fracture, and (3) determine the impact of HO on functional outcomes. METHODS: We performed a multivariable Cox regression analysis using revision surgery as the dependent variable and HO as the independent variable. We compared Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores between participants with and those without HO at 24 months. RESULTS: Of 1,441 participants in the study, 287 (19.9%) developed HO within 24 months. HO was not associated with subsequent revision surgery. Grade-III HO was associated with statistically significant and clinically relevant deterioration in the total WOMAC score, which was mainly related to the function component of the score, compared with grade I or II. CONCLUSIONS: The impact of grade-III HO on the functional outcomes and quality of life after THA for hip fracture is clinically important, and HO prophylaxis for selected high-risk patients may be appropriate. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Anti-Inflammatory Effects of Intra-Articular Hyaluronic Acid: A Systematic Review.

OBJECTIVE: Osteoarthritis (OA) is one of the leading causes of disability in the adult population. Common nonoperative treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, and intra-articular injections of hyaluronic acid (HA). HA is found intrinsically within the knee joint providing viscoelastic properties to the synovial fluid. HA therapy provides anti-inflammatory relief through a number of different pathways, including the suppression of pro-inflammatory cytokines and chemokines. METHODS: We conducted a systematic review to summarize the published literature on the anti-inflammatory properties of hyaluronic acid in osteoarthritis. Included articles were categorized based on the primary anti-inflammatory responses described within them, by the immediate cell surface receptor protein assessed within the article, or based on the primary theme of the article. Key findings aimed to describe the macromolecules and inflammatory-mediated responses associated with the cell transmembrane receptors. RESULTS: Forty-eight articles were included in this systematic review that focused on the general anti-inflammatory effects of HA in knee OA, mediated through receptor-binding relationships with cluster determinant 44 (CD44), toll-like receptor 2 (TLR-2) and 4 (TLR-4), intercellular adhesion molecule-1 (ICAM-1), and layilin (LAYN) cell surface receptors. Higher molecular weight HA (HMWHA) promotes anti-inflammatory responses, whereas short HA oligosaccharides produce inflammatory reactions. CONCLUSIONS: Intra-articular HA is a viable therapeutic option in treating knee OA and suppressing inflammatory responses. HMWHA is effective in suppressing the key macromolecules that elicit the inflammatory response by short HA oligosaccharides.

A Comparison Between Rheological Properties of Intra-articular Hyaluronic Acid Preparations and Reported Human Synovial Fluid.

INTRODUCTION: This study aims to compare the properties of currently available intra-articular hyaluronate (IA-HA) products widely available in the USA to those of healthy knee synovial fluid with respect to their bulk rheological properties. We hypothesize that products would have differing rheological properties, with some more closely resembling the properties and physiological aspects of healthy joint fluid HA. METHODS: We obtained reported HA product molecular weights, as well as measurements of the presence of cross-linking, zero shear rate viscosity, shear thinning ratio, and crossover frequency for the following IA-HA products available in the USA: Euflexxa®, Orthovisc®, Supartz®, Monovisc®, Synvisc®, Synvisc-One®, Gel-One®, and Hyalgan®. RESULTS: Differences were seen between the study products across all of the investigated parameters. Hyalgan, Supartz, Orthovisc, and Euflexxa had a linear chain structure, while Synvisc, Synvisc-One, and Monovisc were cross-linked in structure. Molecular weight, shear rates, and crossover frequencies ranged widely across tested products, with values ranging from below to above those reported for healthy knee synovial fluid HA. When compared to healthy knee parameter values reported within the current literature, observed parameters for Euflexxa and Orthovisc were typically seen to be the most similar to healthy knee synovial fluid. When comparing Euflexxa and Orthovisc directly, Euflexxa was more often similar to the properties of healthy knee synovial fluid with respect to the observed parameters of molecular structure, shear rates, and crossover frequency. CONCLUSION: Available IA-HA products vary with respect to molecular weight, presence of cross-linking, shear rate dependency of viscosity, and crossover frequency. Since IA-HA treatment for osteoarthritis aims to restore synovial fluid back to original HA property characteristics, using HA supplements resembling healthy synovial fluid is a logical approach. Our findings demonstrate that Euflexxa is the most similar to healthy synovial fluid with respect to molecular structure, shear rates, and crossover frequency. FUNDING: Ferring Pharmaceuticals, Inc.

Rheological Properties of Commercially Available Hyaluronic Acid Products in the United States for the Treatment of Osteoarthritis Knee Pain.

OBJECTIVE: The inconsistent results within the current literature regarding the efficacy of intra-articular-hyaluronic acid (IA-HA) for the treatment of knee osteoarthritis (OA) have been suggested to be due to intrinsic differences between individual HA products. The purpose of this investigation is to define the rheological differences between currently available HA products in the United States at the time of this study for the treatment of knee OA, which will help elaborate on the appropriateness of classifying HA products as a class opposed to as individual agents. METHODS: The rheological parameters for Euflexxa, Orthovisc, Supartz, Monovisc, Synvisc, Synvisc-One, Gel-One, and Hyalgan were obtained with a TA AR 2000 EX Rheometer with a cone-plate geometry (40-mm plate diameter and a 2° cone angle) at room temperature. RESULTS: The bulk rheological parameters of the different products suggest molecular structures traversing the range of dilute solution (Hyalgan, Supartz), semidilute solution (Euflexxa, Orthovisc), entangled solutions (Monovisc, Synvisc, Synvisc-One), and even gel-like (Gel-One) behavior. CONCLUSIONS: Due to the differences in rheological properties between IA-HA products, the universal assessment of these products as a class may not be appropriate. Instead, it may be more appropriate to assess each product individually. Future research should aim to link these differences in rheological properties to the differences in clinical efficacy seen across these IA-HA products.

Indomethacin reduces cell damage: shedding new light on compartment syndrome.

INTRODUCTION: Indomethacin may preserve tissue viability in compartment syndrome. The mechanism of improved tissue viability is unclear, but the anti-inflammatory effects may alter the relative contribution of tissue necrosis versus apoptosis to cellular injury. Existing studies have only considered indomethacin administration before induction of elevated intracompartment pressure. The purpose of this study was to determine the effect of timing of indomethacin administration on muscle damage in elevated intracompartment pressure and to assess apoptosis as a cause of tissue demise. METHODS: Twenty-four Wistar rats were randomized to elevated intracompartmental pressure (EICP) for either 45 or 90 minutes (30 mmHg). In the 45-minute cohort, indomethacin was withheld in Group 1 (CS45), given before induction of EICP in Group 2 (CS45Indo0), or given after 30 minutes of EICP/15 minutes before fasciotomy in Group 3 (CS45Indo30). In the 90-minute cohort, indomethacin was withheld in Group 4 (CS90) or given after 30 or 60 minutes of EICP in Groups 5 (CS90Indo30) and 6 (CS90Indo60). Intravital microscopy and fluorescent staining assessed capillary perfusion, cell damage, and inflammatory activation within extensor digitorum longus muscle. Apoptosis was assessed using spectrophotometric assessment of caspase levels. Groups 1 to 3 and 4 to 6 were compared using analysis of variance with P < 0.05 deemed significant. RESULTS: Perfusion and tissue viability improved in indomethacin-treated groups. Nonperfused capillaries decreased from Group 1 (CS45) (50.1 +/- 2.5) to Group 2 (CS45Indo0) (38.4 +/- 1.8) and Group 3 (CS45Indo30) (14.13 +/- 1.73) (P < 0.05). Similarly, Group 5 (CS90Indo30) and Group 6 (CS90Indo60) had 25% fewer nonperfused capillaries compared with Group 4 (CS90) (P < 0.0001). Group 2 (CS45Indo0) and Group 3 (CS45Indo30) showed fewer damaged cells (1% +/- 0.5% and 8.7% +/- 2%) compared with Group 1 (CS45) (20% +/- 14%) (P < 0.0001). Group 5 (CS90Indo30) showed decreased cell damage (13% +/- 1%) compared with Group 4 (CS90) (18% +/- 1%) (P < 0.01). Group 6 (CS90Indo60) also showed decreased cell damage (11% +/- 1%) compared with Group 4 (CS90) (18% +/- 1%); however, this difference was not significant (P > 0.05). Apoptotic activity was present with elevated intracompartment pressure. At 30 minutes, there were elevated caspase levels in Group 4 and Group 6 EICP groups (0.47 +/- 0.08) compared with control subjects (0.19 +/- 0.02) (P < 0.003). However, indomethacin-treated groups did not differ from control subjects with regard to caspase levels (P > 0.05). CONCLUSION: Indomethacin decreased cell damage and improved perfusion in elevated intracompartment pressure. The benefits of indomethacin were partially time-dependent; some improvement in tissue viability occurred regardless of timing of administration. Although apoptosis was common in elevated intracompartment pressure, the protective effect of indomethacin does not appear to be related to apoptosis. CLINICAL RELEVANCE: Adjuvant treatment with indomethacin may improve outcome in compartment syndrome.

Functional and radiographic results of patients with syndesmotic screw fixation: implications for screw removal.

OBJECTIVE: Screw fixation of the injured syndesmosis restores stability but may reduce motion. The purpose of this study is to determine whether functional outcomes and radiographic results after ankle fracture are affected by the status of the syndesmosis screw. DESIGN: Retrospective review of a consecutive clinical series. SETTING: Level 1 academic trauma center. PATIENTS: One hundred six adults were reviewed radiographically; mean follow up was 15 months (range, 4-30 months). Seventy-six of the 106 patients completed formal functional testing; mean follow up was 23 +/- 13 months (range, 12-32 months). INTERVENTION: Open reduction and internal fixation, including fixation of the tibiofibular syndesmosis. MAIN OUTCOME MEASUREMENTS: Patients with intact, broken or loose, or removed syndesmosis screws were compared. Functional outcomes were measured using the Lower Extremity Measure and the Olerud Molander ankle score. Radiologic review included tibiofibular clear space, tibiofibular overlap, and medial clear space. RESULTS: Functional outcomes were improved in patients with fractured, loosened, or removed screws compared with those with intact screws. The Lower Extremity Measure score for patients with intact screws was 70 +/- 6 compared with 85 +/- 3 for fractured, loosened, or removed screws (P = 0.01). The Olerud Molander ankle score for patients with intact screws was 47 +/- 8.0 compared with 64 +/- 4 for fractured, loosened, or removed screws (P = 0.04). There was no difference in outcome comparing fractured, loosened, and removed screws. The tibiofibular clear space was narrowed in patients with intact screws compared with removed, fractured, or loose screws. The tibiofibular clear space for intact screws was 3.1 +/- 0.2 compared with 4.1 +/- 0.2 for removed, fractured, or loosened screws (P = 0.005). There was no difference in outcome comparing large and small fragment screws. CONCLUSIONS: An intact syndesmosis screw was associated with a worse functional outcome compared with loose, fractured, or removed screws. However, there were no differences in functional outcomes comparing loose or fractured screws with removed screws. Screw removal is unlikely to benefit patients with loose or fractured screws but may be indicated in patients with intact syndesmosis screws.