Hylan G-F 20 (Synvisc® and Synvisc-One®): A Comprehensive Clinical and Pharmacological Review for the Management of Knee Osteoarthritis

Introduction and Product Profile

Overview of Hylan G-F 20 as a Viscosupplementation Agent

Hylan G-F 20 is a high-molecular-weight, elastoviscous fluid classified as a viscosupplementation agent.[1] It is a sterile, nonpyrogenic, cross-linked derivative of hyaluronan, a naturally occurring glycosaminoglycan that is a critical component of healthy synovial fluid.[3] The primary therapeutic application of Hylan G-F 20 is the treatment of pain associated with osteoarthritis (OA) of the knee.[1] Its place in therapy is specifically for patients who have failed to achieve an adequate response to conservative nonpharmacologic interventions, such as exercise and physical therapy, as well as simple oral analgesics like acetaminophen.[1]

The underlying principle of its use, known as viscosupplementation, is to restore the rheological and physiological properties of the synovial fluid within an osteoarthritic joint.[16] In OA, the endogenous hyaluronan within the synovial fluid becomes depolymerized, leading to a decrease in its molecular weight and concentration. This degradation impairs the fluid's elastoviscous properties, compromising its ability to function as a lubricant and shock absorber, thereby contributing to pain and progressive joint damage.[16] By introducing an exogenous, high-viscosity hyaluronan derivative, Hylan G-F 20 aims to mechanically supplement the pathologic synovial fluid, reduce pain, and improve joint function.[1]

Commercial Formulations: Synvisc® and Synvisc-One®

Hylan G-F 20 is commercially available in two distinct formulations, which share the same active material but differ in their administration protocol:

• Synvisc®: This is the original formulation, provided as a multi-injection treatment regimen. The standard protocol involves three separate 2 mL intra-articular injections, each containing 16 mg of hylan polymers, administered one week apart for a total treatment course of three weeks.[1]
• Synvisc-One®: Developed as a more convenient alternative, this formulation is a single-injection treatment. It consists of one 6 mL prefilled syringe containing a total of 48 mg of hylan polymers, delivering the entire therapeutic dose in a single administration.[1]

Both formulations contain the identical cross-linked hylan polymer material; Synvisc-One® effectively consolidates the three doses of Synvisc® into one syringe.[14] The development of the single-injection format represents a significant evolution in the product's lifecycle, aimed at enhancing patient and physician convenience by reducing the number of required clinical visits and invasive procedures.[20] This strategic adaptation addresses potential barriers to treatment adherence and reduces the clinical burden associated with a multi-injection protocol. Clinical studies were conducted to validate that a single 6 mL injection provides a safety and efficacy profile comparable to the established three-injection regimen, ensuring this convenience did not compromise therapeutic outcomes.[20]

Classification and Regulatory Status (Medical Device vs. Drug)

The regulatory pathway for Hylan G-F 20 is noteworthy. In major markets such as the United States and Australia, it is classified and regulated as a Class III medical device, not as a pharmaceutical drug.[24] In the U.S., it falls under the purview of the Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) and was approved via the Premarket Approval (PMA) pathway for high-risk devices.[25] Similarly, in Australia, it is listed on the Australian Register of Therapeutic Goods (ARTG) as a Class III medical device.[24]

This classification is predicated on its primary, intended mode of action being physical or mechanical—the process of viscosupplementation—rather than pharmacological, metabolic, or immunological.[26] The argument presented to regulatory bodies is that the product achieves its therapeutic purpose by physically restoring the lubricating and shock-absorbing properties of the synovial fluid, without inducing a chemical interaction with the body.[26] This contrasts with other hyaluronan products, such as Hyalgan®, which are regulated as medicinal products in some jurisdictions based on claims of pharmacological action.[29]

This regulatory distinction creates a compelling paradox. While the official classification of Hylan G-F 20 is based on a simplified mechanical model, a growing body of scientific evidence points to more complex, drug-like biological activities. Research has elucidated its capacity to exert anti-inflammatory, chondroprotective, and nociceptive-modulating effects within the joint.[17] These biological actions, which are inherently pharmacological, may be responsible for the observed long-term clinical benefits that extend far beyond the product's physical presence in the joint. This discrepancy between its regulatory status as a mechanical device and its multifaceted biological mechanism of action highlights the evolving understanding of viscosupplementation and may influence how similar advanced, combination products are classified and evaluated in the future.

Physicochemical Properties and Formulation

Source Material and Derivation from Hyaluronan

The active components of Hylan G-F 20 are derived from hyaluronan (sodium hyaluronate) that is extracted and purified from avian sources, specifically rooster combs.[3] Hyaluronan is a high-molecular-weight, naturally occurring polysaccharide that is ubiquitous in the extracellular matrix of connective tissues.[6] It is a linear polymer composed of repeating disaccharide units of N-acetylglucosamine and sodium glucuronate.[3] In a healthy synovial joint, hyaluronan is the principal macromolecule responsible for the unique elastoviscous properties of the synovial fluid, which are essential for joint homeostasis, lubrication, and shock attenuation.[16] The use of an avian source for the raw material is a critical manufacturing detail, as it necessitates specific warnings and precautions regarding potential hypersensitivity reactions in patients with allergies to avian proteins, feathers, or eggs.[1]

Unique Molecular Structure: Cross-Linked Hylan A and Hylan B Polymers

The defining molecular characteristic of Hylan G-F 20, and what distinguishes it from many other hyaluronan-based viscosupplements, is the chemical modification of the native hyaluronan chains.[3] The purified hyaluronan undergoes a proprietary cross-linking process, creating modified, higher-molecular-weight derivatives known as "hylans".[3] This process results in a composite fluid containing two distinct hylan polymers:

• Hylan A: This component is a soluble, high-molecular-weight polymer with an average molecular weight of approximately 6,000,000 Daltons (6,000 kDa). It constitutes about 80% of the polymer content.[3]
• Hylan B: This component is a hydrated, insoluble gel that makes up the remaining 20% of the polymer content.[3]

This chemical cross-linking is the central innovation of the Hylan G-F 20 formulation. It was engineered to address a primary limitation of earlier, unmodified hyaluronan products: their relatively rapid degradation and clearance from the intra-articular space. By creating a more complex and robust molecular structure, particularly with the inclusion of the insoluble hylan B gel, the formulation is more resistant to enzymatic and free-radical-mediated breakdown within the joint environment. This enhanced stability leads to a significantly longer intra-articular residence time compared to linear hyaluronan products.[32] This extended duration of presence is the direct link between the product's unique chemistry and its prolonged therapeutic effect, as it provides a longer window for the material to exert not only its mechanical functions but also its more complex biological actions.

Rheological and Elastoviscous Characteristics

The combination of high molecular weight and cross-linked structure endows Hylan G-F 20 with specific rheological properties designed to mimic and, in some respects, exceed those of healthy synovial fluid.[20] The elastoviscous nature of the fluid allows it to behave dually: as a viscous lubricant during slow joint movements to reduce friction, and as an elastic shock absorber during rapid, high-impact movements to dissipate mechanical loads.[16]

Quantitative measurements of these properties for Synvisc-One® at a frequency of 2.5 Hz demonstrate an elasticity (storage modulus, $G'$) of $111 \pm 13$ Pascals (Pa) and a viscosity (loss modulus, $G''$) of $25 \pm 2$ Pa.[3] These values are comparable to those of synovial fluid from healthy young adults (G' = $117 \pm 13$ Pa and G'' = $45 \pm 8$ Pa), and are superior to the degraded synovial fluid found in osteoarthritic knees.[39]

Composition of Intra-Articular Solutions

The hylan polymers are delivered in a sterile, nonpyrogenic, buffered physiological sodium chloride solution (pH $7.2 \pm 0.3$).[4] The specific contents of each formulation are as follows:

• Synvisc®: Each 2 mL prefilled syringe contains 16 mg of hylan polymers (hylan A + hylan B).[1]
• Synvisc-One®: Each 6 mL prefilled syringe contains 48 mg of hylan polymers (hylan A + hylan B), 51 mg of sodium chloride, 0.96 mg of disodium hydrogen phosphate, 0.24 mg of sodium dihydrogen phosphate monohydrate, and water for injection to a final volume of 6.0 mL.[1]

The following table provides a comparative summary of the key product characteristics for both Hylan G-F 20 formulations.

Table 1: Product Characteristics of Hylan G-F 20 Formulations

Characteristic	Synvisc®	Synvisc-One®
Generic Name	Hylan G-F 20	Hylan G-F 20
Brand Name(s)	Synvisc	Synvisc-One
Total Volume	2 mL	6 mL
Hylan Polymer Content	16 mg	48 mg
Composition	Hylan A (soluble) and Hylan B (gel)	Hylan A (soluble) and Hylan B (gel)
Administration Schedule	Three 2 mL injections, one week apart	One single 6 mL injection
Average Molecular Weight	Approx. 6,000 kDa	Approx. 6,000 kDa
Source Material	Avian (Rooster Combs)	Avian (Rooster Combs)

Data compiled from sources:.[1]

Mechanism of Action in Osteoarthritis

The Pathophysiology of Synovial Fluid in Osteoarthritis

To comprehend the mechanism of Hylan G-F 20, it is essential to first understand the pathological changes that occur within an osteoarthritic joint. Osteoarthritis is a degenerative disease characterized by the progressive breakdown of articular cartilage, subchondral bone remodeling, and synovial inflammation.[16] These structural changes are accompanied by profound alterations in the synovial fluid that fills the joint capsule. In a healthy joint, this fluid is highly elastoviscous, primarily due to a high concentration of large, high-molecular-weight hyaluronan molecules.[16]

In the osteoarthritic state, the synovial environment becomes catabolic and inflammatory. Synoviocytes produce hyaluronan that is both lower in concentration and smaller in molecular size (depolymerized).[16] Consequently, the synovial fluid becomes more abundant but less viscous and elastic.[16] This degradation severely impairs its critical functions: lubrication is reduced, increasing frictional wear on cartilage surfaces, and shock absorption is compromised, leading to increased mechanical stress on the already damaged cartilage and subchondral bone.[16] This creates a vicious cycle where poor synovial fluid quality contributes to further joint degeneration and symptomatic pain.

Primary Mechanical Action: Viscosupplementation and Joint Lubrication

The foundational and most direct mechanism of action of Hylan G-F 20 is viscosupplementation.[7] This process involves the intra-articular injection of the high-viscosity Hylan G-F 20 solution to supplement or replace the deficient native synovial fluid.[16] The immediate goal is to restore a more normal mechanical and rheological environment within the joint. By introducing a fluid with superior elastoviscous properties, Hylan G-F 20 is intended to:

• Provide Lubrication: The viscous properties of the fluid reduce the coefficient of friction between the articular cartilage surfaces during movement, which can alleviate pain and potentially slow down mechanical wear.[16]
• Act as a Shock Absorber: The elastic properties of the fluid help to dissipate and absorb the high-impact forces transmitted through the joint during weight-bearing activities, thereby protecting the underlying cartilage and bone from mechanical trauma.[1]

This purely mechanical action forms the basis for the product's regulatory classification as a medical device.[26]

Extended Biological and Pharmacological Effects

A purely mechanical explanation is insufficient to account for the full clinical profile of Hylan G-F 20, particularly the observation that pain relief can persist for up to six months or longer—a duration that far exceeds the physical residence time of the injected material in the joint.[6] This discrepancy strongly suggests that the initial injection triggers a cascade of secondary biological and pharmacological effects that sustain the therapeutic benefit. These mechanisms are multifaceted and are thought to include:

• Chondroprotection and Modulation of Extracellular Matrix Synthesis: Beyond simply acting as a passive space-filler, exogenous hylans may function as a biological signaling molecule. Research indicates that Hylan G-F 20 can interact with cell surface receptors (like CD44) on chondrocytes and synoviocytes, stimulating them to increase their production of endogenous, high-molecular-weight hyaluronan.[30] This may help to restore the joint's own capacity for synovial fluid synthesis. Furthermore, it has been shown to inhibit the activity of matrix metalloproteinases (MMPs) and other catabolic enzymes that degrade cartilage, while promoting the synthesis of proteoglycans, key components of the cartilage matrix. This shifts the metabolic balance within the joint from degradation towards repair, potentially preventing further cartilage loss and promoting regeneration.[30]
• Anti-inflammatory Effects: Hylan G-F 20 exerts significant anti-inflammatory actions within the synovial environment. It has been demonstrated to reduce the production and activity of key pro-inflammatory mediators, including cytokines such as interleukin-1β (IL-1β), prostaglandins, leukotrienes, and nitric oxide.[17] By dampening this inflammatory cascade, it can help break the cycle of synovitis and pain that characterizes OA. High-molecular-weight hyaluronan also possesses antioxidant properties, which protect chondrocytes from damage induced by reactive oxygen species present in the inflamed joint.[30]
• Direct and Indirect Effects on Nociception and Pain Signaling: Hylan G-F 20 appears to directly modulate the perception of pain. In experimental models, high-molecular-weight HA, such as that in Hylan G-F 20, has been shown to significantly decrease the spontaneous and movement-evoked firing of articular nociceptive (pain-sensing) nerve fibers.[30] This analgesic effect may be mediated mechanically, by the viscoelastic fluid physically dampening the activation of stretch-activated ion channels on nerve terminals within the joint capsule.[30] The efficacy of this effect appears to be dependent on the high molecular weight of the product, as lower-molecular-weight solutions were found to be less effective or ineffective in these models.[30] Indirectly, pain is also reduced through the aforementioned anti-inflammatory effects and by inhibiting the action of pain-mediating neuropeptides like Substance P.[30]

This multifactorial mechanism, combining an immediate physical effect with delayed and sustained biological actions, provides a cohesive explanation for the product's clinical profile. The initial mechanical viscosupplementation provides some benefit, but it is the subsequent biological cascade—stimulating endogenous repair, reducing inflammation, and directly dampening pain signals—that is believed to be responsible for the long-term duration of therapeutic relief.

Clinical Application and Administration

Approved Indication: Treatment of Pain in Knee Osteoarthritis

The approved indication for both Synvisc® and Synvisc-One®, as specified by the U.S. Food and Drug Administration (FDA) and other major regulatory bodies, is for the treatment of pain in osteoarthritis of the knee.[1] While some clinical investigations and international labeling may explore its use in other synovial joints such as the hip, ankle, and shoulder, its established efficacy and safety are confined to the knee in the United States.[11] Any application outside the knee is considered off-label use in this jurisdiction.

Patient Selection Criteria and Place in Therapy

Hylan G-F 20 is not intended as a first-line treatment for knee OA. Its use is specifically reserved for patients who have not achieved satisfactory pain relief from a foundational regimen of conservative therapies.[1] The ideal candidate for Hylan G-F 20 therapy is a patient with symptomatic knee OA who has experienced an inadequate response to both:

1. Non-pharmacologic therapy: This includes lifestyle modifications such as weight loss, patient education, physical therapy, and regular exercise.[15]
2. Simple analgesics: This primarily refers to an adequate trial of acetaminophen.[1]

It is typically considered as an alternative to, or after the failure of, other pharmacological options like oral non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular corticosteroid injections, particularly when those options are contraindicated, poorly tolerated, or have provided insufficient or short-lived benefit.[3]

Administration Protocol

The administration of Hylan G-F 20 is an intra-articular procedure to be performed by a qualified healthcare professional using a strict aseptic technique to minimize the risk of infection.[3]

• Procedural Considerations: A critical step in the procedure is the preliminary removal of any existing synovial fluid or joint effusion via arthrocentesis.[3] This is done prior to the injection of Hylan G-F 20. The removal of inflammatory effusion may have a therapeutic benefit in itself, which can be a confounding factor in assessing the true efficacy of the viscosupplement. It is important to use a separate syringe for arthrocentesis and for the injection of the product.[8] An 18- to 22-gauge needle is typically recommended for the procedure.[8]
• Synvisc® (Multi-Injection Regimen): The treatment course consists of one 2 mL (16 mg) intra-articular injection administered into the affected knee. This procedure is repeated weekly for a total of three injections over three weeks.[1]
• Synvisc-One® (Single-Injection Regimen): The entire treatment course is delivered in a single session. One 6 mL (48 mg) intra-articular injection is administered into the affected knee once.[1]

Post-Injection Patient Guidance and Activity Restrictions

Following the intra-articular injection, patients are given specific guidance to manage potential local reactions and optimize the treatment outcome. A consistent recommendation is for the patient to limit activity for approximately 48 hours post-injection.[1] This restriction is a direct risk mitigation strategy linked to the most common adverse events associated with the procedure—namely, transient pain, swelling, and effusion at the injection site.[1] Strenuous or high-impact activities can increase mechanical stress on the newly injected joint, potentially exacerbating this local inflammatory response.

Patients are advised to avoid:

• Strenuous activities like jogging, tennis, or soccer.
• Prolonged weight-bearing activities.
• Standing for more than one hour at a time.

To manage any mild to moderate post-injection discomfort, the application of an ice pack to the knee for short periods may be recommended.[46] Patients should consult their physician regarding the appropriate time to resume normal activities.

Clinical Efficacy: A Review of Evidence

The clinical efficacy of Hylan G-F 20 has been evaluated in numerous clinical trials, systematic reviews, and meta-analyses, comparing its performance against placebo, other viscosupplements, intra-articular corticosteroids, and oral analgesics.

Pivotal Trials and Evidence of Superiority over Placebo

The foundational evidence for the efficacy of Hylan G-F 20 comes from randomized, controlled trials (RCTs) demonstrating its superiority over intra-articular placebo (saline) injections.

• Synvisc® (3-injection): Pivotal trials for the three-injection regimen established its efficacy. One key study demonstrated that patients treated with Synvisc® experienced a statistically significant greater improvement in pain during weight-bearing activities and pain at rest during the night compared to those receiving saline placebo, with benefits sustained at 26 weeks.[4] Another analysis reported that up to 56% of patients receiving Synvisc® were free or nearly free of pain on weight-bearing at 10-24 weeks post-injection, a stark contrast to the less than 13% response rate in the saline group.[6]
• Synvisc-One® (single-injection): The efficacy of the single-injection formulation was established in the SOUND (Single Osteoarthritis knee iNjection D-001-31) trial. This large, randomized, double-blind, multicenter European study involving 253 patients demonstrated that a single 6 mL injection of Hylan G-F 20 provided a statistically significant, although modest, improvement in the primary endpoint—the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A pain subscore—over 26 weeks compared to placebo ($p=0.047$).[4]
• The Confounding Placebo Effect: A critical consideration when interpreting these results is the remarkably strong placebo effect observed in trials of intra-articular injections for knee OA. This effect is likely multifactorial, stemming from patient expectations, the therapeutic ritual of the procedure, and the potential therapeutic benefit of the mandatory pre-injection arthrocentesis. The magnitude of this effect was highlighted in a large RCT of Synvisc-One® in a Chinese population, where both the treatment and placebo groups showed significant improvement from baseline. However, the study failed to establish the superiority of Hylan G-F 20 over placebo, as 68.2% of patients in the placebo group reported a clinically important reduction in pain.[4] This underscores that the true therapeutic effect of Hylan G-F 20 is the marginal benefit observed above this high placebo baseline, a fact that has fueled debate regarding its clinical meaningfulness.[51]

The following table summarizes the results of the pivotal placebo-controlled trials for both Hylan G-F 20 formulations.

Table 2: Summary of Pivotal Clinical Trials vs. Placebo

Formulation	Study Identifier	N (Treatment/Placebo)	Primary Endpoint	Follow-up	Key Efficacy Result (vs. Placebo)	p-value
Synvisc®	Wobig et al.	52 / 57	Pain on weight-bearing (VAS)	26 weeks	Significantly greater reduction in pain	0.005
Synvisc-One®	Chevalier et al. (SOUND Trial)	124 / 129	Change in WOMAC A (pain) score	26 weeks	Statistically significant greater improvement in pain	0.047

Data compiled from sources:.[4]

Comparative Efficacy Analysis

The clinical utility of Hylan G-F 20 is best understood by comparing its performance against other established treatments for knee OA.

• Hylan G-F 20 vs. Other Hyaluronic Acid Formulations: The evidence comparing Hylan G-F 20 with other lower-molecular-weight (LMW), non-cross-linked HA products is mixed. The theoretical advantage of Hylan G-F 20 lies in its unique high-molecular-weight, cross-linked structure, which provides superior rheological properties and a longer intra-articular residence time.[32] Some clinical data support this theoretical advantage. A head-to-head RCT found that Synvisc® provided significantly greater improvement in knee pain compared to a LMW sodium hyaluronate (Hyalgan®) at the 6-month endpoint ($p=0.02$).[49] However, other studies have found no significant difference in clinical outcomes. A preliminary trial comparing single 6 mL injections of Synvisc-One® and Hyalgan® reported similar improvements at 26 weeks but highlighted that the significantly higher cost of Synvisc-One® made the LMW product more cost-effective.[53] Furthermore, some meta-analyses have concluded that there is a lack of evidence for the superior effectiveness of Hylan G-F 20 over other HA products, and it may be associated with a higher risk of local adverse events.[53]
• Hylan G-F 20 vs. Intra-Articular Corticosteroids (IACS): The comparison between Hylan G-F 20 and IACS reveals a distinct difference in their temporal efficacy profiles, creating a basis for their differential use in clinical practice.
• Short-Term Efficacy (<3 months): Corticosteroids, with their potent anti-inflammatory action, generally provide more rapid and pronounced pain relief in the short term. An RCT comparing a single injection of Hylan G-F 20 to triamcinolone found that at 2 weeks, the corticosteroid provided significantly greater improvement in both pain and function.[52]
• Long-Term Efficacy (≥6 months): The therapeutic effect of Hylan G-F 20 is characterized by a slower onset but a significantly more durable response. A head-to-head superiority trial demonstrated that Synvisc® was significantly more effective than triamcinolone hexacetonide in improving WOMAC A1 pain scores at week 12, with this superiority maintained through the 26-week endpoint ($p=0.0129$).[49] This finding is supported by a network meta-analysis which concluded that while Hylan G-F 20 and IACS may be equivalent in the short term, Hylan G-F 20 demonstrated a statistically significant benefit over IACS by 6 months.[54] Other analyses have shown similar long-term WOMAC improvements but superior VAS pain scores for HA.[55] This suggests that IACS may be more suitable for managing acute inflammatory flares, whereas Hylan G-F 20 is better positioned for providing long-term, baseline symptom control.
• Hylan G-F 20 vs. Oral Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The comparison with oral NSAIDs highlights a critical trade-off between local and systemic therapy. A 12-week, randomized, double-blind trial directly compared a three-injection course of Hylan G-F 20 with daily oral diclofenac (100 mg) and placebo. In this study, Hylan G-F 20 was found to be superior to both diclofenac ($p=0.03$) and placebo ($p=0.04$) in improving the primary endpoint of WOMAC A pain scores.[56] Perhaps more importantly, this superior efficacy was achieved with a significantly better systemic safety profile. The diclofenac group experienced a substantially higher rate of systemic adverse events, predominantly gastrointestinal, at 48%, compared to 22% in the hylan group and 11% in the placebo group.[56] This positions Hylan G-F 20 as a valuable therapeutic option for patients, particularly the elderly and those with comorbidities, who are at high risk for the systemic adverse effects associated with chronic NSAID use. It offers a targeted, intra-articular approach that can achieve comparable or superior pain relief while avoiding systemic exposure.

The following table summarizes the comparative efficacy of Hylan G-F 20 against other common intra-articular therapies for knee OA.

Table 3: Comparative Efficacy of Hylan G-F 20 vs. Other Intra-Articular Therapies

Comparator	Study Type	Key Outcome Measure(s)	Short-Term Finding (<3 months)	Long-Term Finding (≥6 months)	Conclusion
LMW Hyaluronic Acid (e.g., Hyalgan®)	RCTs, Meta-analysis	Pain (VAS), WOMAC	Mixed evidence; some studies show superiority of Hylan G-F 20, others show no difference.	Mixed evidence; one RCT showed superiority of Hylan G-F 20 at 6 months.	Evidence is conflicting; Hylan G-F 20 may offer superior efficacy, but this is not consistently demonstrated.
Intra-Articular Corticosteroids (IACS)	RCTs, Meta-analysis	Pain (VAS, WOMAC), Function	IACS provide faster and greater relief (e.g., at 2 weeks).	Hylan G-F 20 provides more durable and superior relief at 12-26 weeks.	Different temporal profiles; IACS are better for acute, short-term relief, while Hylan G-F 20 is better for sustained, long-term control.

Data compiled from sources:.[49]

Long-Term Efficacy and Repeat Treatment Cycles

The benefits of Hylan G-F 20 are not limited to a single treatment course. A systematic review and meta-analysis focusing on long-term outcomes concluded that both the single-injection and multi-injection regimens of Hylan G-F 20 provide effective and safe improvements in WOMAC pain, physical function, and stiffness that are sustained for at least one year following the initial injection.[59] Furthermore, real-world observational data suggest that patients can receive repeat cycles of treatment with sustained clinical benefits in pain and function.[60]

Comprehensive Safety and Tolerability Profile

The safety profile of Hylan G-F 20 is well-characterized and is dominated by local, transient adverse events related to the intra-articular injection procedure. Systemic events are rare.

Adverse Events

• Common Local Reactions: The most frequently reported adverse events are mild to moderate, transient, and localized to the injected knee. These include pain, swelling, joint effusion, stiffness, warmth, redness, or puffiness at the injection site.[1] In clinical trials of the original three-injection Synvisc®, these local events were reported in approximately 7.2% of patients.[10] For the single-injection Synvisc-One®, the most common events reported in its pivotal trial were arthralgia (joint pain) in 25.2% of patients, joint stiffness in 8.1%, and joint effusion in 5.7%.[3] It is important to note that these events also occurred in the saline placebo group, indicating that a significant portion of the risk is attributable to the injection procedure itself rather than solely to the product.
• Acute Inflammatory Reactions: In some cases, a more pronounced acute inflammatory reaction can occur following an injection. This is characterized by significant joint pain, swelling, and effusion, sometimes accompanied by warmth and stiffness.[3] This reaction, sometimes referred to as a pseudoseptic reaction, is non-infectious. Analysis of the aspirated synovial fluid reveals an aseptic fluid with no crystals.[3] These reactions are typically self-limiting and respond well within a few days to conservative management, which may include rest, ice, NSAIDs, intra-articular steroid injection, and/or arthrocentesis.[9] Clinical data suggests that the risk of these local adverse events may increase with repeated courses of treatment. The incidence of local AEs in patients receiving a second course of Synvisc® was reported to be 22.3%, compared to 7.2% in patients receiving their first course, suggesting a potential for immune sensitization with subsequent exposures.[10]
• Systemic and Rare Adverse Events: Systemic adverse events are uncommon. Post-marketing surveillance has identified rare occurrences of rash, hives (urticaria), itching (pruritus), fever, nausea, headache, dizziness, muscle cramps, paresthesia, peripheral edema, and respiratory difficulties.[3] Rare cases of thrombocytopenia (low platelet count) have also been reported coincident with Hylan G-F 20 injection.[9]

Contraindications

The use of Hylan G-F 20 is strictly contraindicated in patients with the following conditions:

• Known Hypersensitivity: Patients with a known hypersensitivity or allergy to hyaluronan preparations or any component of the Hylan G-F 20 formulation.[3]
• Active Infection: Patients with active infections in the target knee joint or with skin diseases or infections in the area of the injection site.[1]

Warnings and Precautions

• Hypersensitivity and Avian Allergies: Severe, life-threatening allergic reactions, including anaphylaxis, anaphylactoid reactions, and angioedema, have been reported rarely.[6] Due to the derivation of hyaluronan from rooster combs, caution must be exercised when administering Hylan G-F 20 to patients with known allergies to avian proteins, feathers, or egg products.[1]
• Pre-existing Conditions: Caution is advised for patients with evidence of venous or lymphatic stasis in the leg to be treated, as the injection could potentially exacerbate these conditions.[3] The safety and efficacy in severely inflamed knee joints have not been established.[3]
• Drug and Material Interactions: A specific and preventable chemical interaction can lead to treatment failure. Disinfectants containing quaternary ammonium salts (e.g., benzalkonium chloride) must not be used for skin preparation prior to injection. These positively charged compounds can cause the negatively charged hyaluronan polymer to precipitate out of solution, destroying its rheological properties and rendering the treatment ineffective.[3]
• Injection Technique: The injection must be administered strictly intra-articularly. Do not inject extra-articularly, into the synovial tissue or capsule, or intravascularly, as improper placement can lead to significant local and systemic adverse events.[3]

Use in Special Populations

The safety and effectiveness of Hylan G-F 20 have not been formally established in the following populations, and its use is therefore not recommended:

• Pregnant women.[1]
• Nursing mothers.[1]
• Pediatric patients (defined as individuals ≤21 years of age).[3]

The table below presents quantitative data on the incidence of common adverse events from the pivotal trial for Synvisc-One®, comparing it against a saline control.

Table 4: Incidence of Common Adverse Events (Synvisc-One® Pivotal Trial)

Adverse Event	Synvisc-One® (N=123) n (%)	Saline Control (N=130) n (%)
Any Treatment-Emergent AE	44 (35.8%)	44 (33.8%)
Arthralgia (Joint Pain)	31 (25.2%)	28 (21.5%)
Joint Stiffness	10 (8.1%)	13 (10.0%)
Joint Effusion	7 (5.7%)	7 (5.4%)
Joint Swelling	5 (4.1%)	7 (5.4%)
Injection Site Pain	1 (0.8%)	1 (0.8%)

Data from source:.[3] Note: The overall incidence of treatment-emergent AEs was similar between the Hylan G-F 20 and saline groups, suggesting many events are related to the injection procedure.

Regulatory and Marketing History

The regulatory journey of Hylan G-F 20 reflects a strategic, phased global launch, followed by a significant product line extension to enhance its market position and clinical utility.

Timeline of Key Regulatory Approvals

• Early Markets: Synvisc® was first marketed internationally before receiving approval in the United States. It has been commercially available in Canada since November 1992 and in Sweden since June 1995. It received CE Mark Approval for use in the European Community in November 1995.[25]
• United States (FDA):
• Synvisc® (3-injection): The original Premarket Approval (PMA) application (P940015) was submitted to the FDA on May 31, 1994. Following a lengthy review process, it was granted FDA approval on August 8, 1997.[23]
• Synvisc-One® (single-injection): Recognizing the clinical need for a more convenient regimen, a PMA supplement (P940015/S012) for the single-injection formulation was submitted on June 19, 2007.[62] The application received a unanimous positive recommendation (5-0) for approval from the FDA's Orthopaedic and Rehabilitation Devices Advisory Committee on December 9, 2008.[64] The FDA granted final marketing approval on February 26, 2009.[22] The nearly 12-year gap between the approvals of the two formulations reflects the time required to conduct the necessary clinical trials to establish the safety and efficacy of the new regimen and navigate the complex regulatory process for a significant modification to the product's administration.
• Australia (TGA):
• Synvisc-One®: Was listed on the Australian Register of Therapeutic Goods (ARTG ID 159219) on February 9, 2009.[24]
• Synvisc®: Is also listed on the ARTG under ID 145345.[26]

Summary of Post-Market Surveillance and Labeling Updates

As with all medical products, Hylan G-F 20 is subject to ongoing post-market surveillance to monitor its real-world safety and performance. This process has led to periodic updates to its labeling to reflect new safety information. For instance, an FDA-approved supplement in November 2022 resulted in the addition of a warning statement regarding the risk of skin necrosis to the physician labeling and an advisory in the patient labeling to report the development of any skin disorders following treatment.[67] Such updates demonstrate the function of a robust pharmacovigilance system and the commitment of regulatory agencies to ensure that the product's known risks are communicated effectively to clinicians and patients.

Conclusion and Clinical Perspective

Synthesis of Hylan G-F 20's Risk-Benefit Profile

Hylan G-F 20 (Synvisc® and Synvisc-One®) is a well-established viscosupplementation agent that offers a clinically meaningful and durable therapeutic option for the management of pain associated with knee osteoarthritis. Its efficacy is supported by evidence from numerous randomized controlled trials demonstrating superiority over placebo and a distinct therapeutic profile when compared to other common treatments. The primary benefit of Hylan G-F 20 is its ability to provide pain relief and functional improvement that can last for up to six months following a single course of treatment. This prolonged duration of action is attributed to its unique high-molecular-weight, cross-linked structure, which enhances its intra-articular residence time and facilitates a cascade of beneficial biological effects beyond simple mechanical supplementation.

The primary risks associated with Hylan G-F 20 are local, transient, and generally mild-to-moderate inflammatory reactions in the injected knee, such as pain, swelling, and effusion. While severe systemic reactions are rare, the potential for hypersensitivity, particularly in patients with avian allergies, requires careful patient screening. The overall risk-benefit profile is generally considered favorable for appropriately selected patients.

Positioning within the Multimodal Management of Knee Osteoarthritis

Within the comprehensive, multimodal management of knee OA, Hylan G-F 20 is appropriately positioned as a valuable second-line therapy. It is an important option for patients who have failed to achieve adequate symptom control with conservative non-pharmacologic measures and simple analgesics. Its clinical utility is most apparent when viewed through its comparative advantages:

• Versus Intra-Articular Corticosteroids: Hylan G-F 20 offers a significantly longer duration of pain relief, making it a preferred choice for patients seeking sustained, long-term baseline symptom control rather than the rapid, short-lived relief provided by corticosteroids.
• Versus Oral NSAIDs: Hylan G-F 20 provides a superior systemic safety profile. By delivering treatment locally to the affected joint, it avoids the significant gastrointestinal, renal, and cardiovascular risks associated with chronic oral NSAID use, making it a particularly compelling option for elderly patients and those with comorbidities.

The availability of both a multi-injection (Synvisc®) and a single-injection (Synvisc-One®) formulation allows for treatment to be tailored to patient preference, logistical considerations, and physician discretion, enhancing its versatility.

Future Directions and Unresolved Questions

Despite its established role, several questions regarding Hylan G-F 20 and viscosupplementation in general remain. Future research should focus on identifying reliable clinical or biological predictors of patient response to better target therapy to those most likely to benefit. The optimal timing and frequency of repeat treatment cycles for maintaining long-term efficacy require further clarification. Rigorous, real-world cost-effectiveness analyses are needed to better define its economic value relative to less expensive alternatives. Finally, continued investigation into the complex biological and pharmacological mechanisms of action will deepen the scientific understanding of its therapeutic effects and may pave the way for the development of next-generation intra-articular therapies. The prominent and confounding placebo effect observed in this field also warrants dedicated research to disentangle the procedural, psychological, and physiological components of treatment response in knee OA.

Works cited

1. Hylan G-F 20 Uses, Side Effects & Warnings - Drugs.com, accessed November 1, 2025, https://www.drugs.com/mtm/hylan-g-f-20.html
2. HYLAN G-F 20 INJ - VA Formulary Advisor, accessed November 1, 2025, https://www.va.gov/formularyadvisor/drugs/4028692-HYLAN-G-F-20-INJ
3. SYNVISC ONE® HYLAN G-F 20 Prescribing Information - Sanofi U.S., accessed November 1, 2025, https://products.sanofi.us/synviscone/synviscone.html
4. Efficacy and safety of a single intra-articular injection of 6 ml Hylan GF 20 compared to placebo in Chinese patients with symptomatic knee osteoarthritis, accessed November 1, 2025, https://d-nb.info/1240984820/34
5. Efficacy and safety of a single intra-articular injection of 6 ml Hylan G-F 20 compared to placebo in Chinese patients with symptomatic knee osteoarthritis: C-SOUND study, a 26-week multicenter double-blind randomized placebo-controlled trial in China - PMC - PubMed Central, accessed November 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8106861/
6. Synvisc (hylan G-F 20) injection: Uses, Side Effects, Dosage & More - GoodRx, accessed November 1, 2025, https://www.goodrx.com/synvisc/what-is
7. What is Synvisc-One®? | Synvisc-One® Official Site, accessed November 1, 2025, https://www.synviscone.com/what-is-synvisc-one/
8. Hylan G-F 20 Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed November 1, 2025, https://www.drugs.com/dosage/hylan-g-f-20.html
9. SYNVISC® HYLAN G-F 20 Prescribing Information - Sanofi U.S., accessed November 1, 2025, https://products.sanofi.us/synvisc/synvisc.html
10. Synvisc (Hylan G-F 20): Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed November 1, 2025, https://www.rxlist.com/synvisc-drug.htm
11. Osteoarthritis Knee Pain Relief Treatment | Synvisc-One® Official Site, accessed November 1, 2025, https://www.synviscone.com/
12. Osteoarthritis Knee Pain Relief | Synvisc‐One® (Hylan G‐F 20) | For HCPs, accessed November 1, 2025, https://www.synvisconehcp.com/
13. Reimbursement Tools and Information - Synvisc‐One, accessed November 1, 2025, https://www.synvisconehcp.com/reimbursement
14. Synvisc-One® Frequestly Asked Questions, accessed November 1, 2025, https://www.synviscone.com/what-is-synvisc-one/synvisc-faqs
15. Synvisc - SPECIALTY GUIDELINE MANAGEMENT, accessed November 1, 2025, https://www.shpnc.gov/documents/files/synvisc/open
16. Hylan G-F 20: Review of its Safety and Efficacy in the Management of Joint Pain in Osteoarthritis - ResearchGate, accessed November 1, 2025, https://www.researchgate.net/publication/49677555_Hylan_G-F_20_Review_of_its_Safety_and_Efficacy_in_the_Management_of_Joint_Pain_in_Osteoarthritis
17. Full article: Managing joint pain in osteoarthritis: safety and efficacy of hylan G-F 20, accessed November 1, 2025, https://www.tandfonline.com/doi/full/10.2147/jpr.s4732
18. Synviscone.ca: Home, accessed November 1, 2025, https://www.synviscone.ca/
19. About SYNVISC, accessed November 1, 2025, https://tcomn.com/wp-content/uploads/2015/10/Kelly_Synvisc-Patient-handout_1015.pdf
20. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial | Annals of the Rheumatic Diseases, accessed November 1, 2025, https://ard.bmj.com/content/69/01/113
21. Orthovisc, Synvisc (hyaluronic-acid-and-derivatives) dosing, indications, interactions, adverse effects, and more - Medscape Reference, accessed November 1, 2025, https://reference.medscape.com/drug/orthovisc-synvisc-hyaluronic-acid-and-derivatives-999526
22. New Drugs/Drug News - PMC - NIH, accessed November 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2697092/
23. FDA Approves Genzyme's Synvisc-One for Osteoarthritis of the Knee | Fierce Biotech, accessed November 1, 2025, https://www.fiercebiotech.com/biotech/fda-approves-genzyme-s-synvisc-one-for-osteoarthritis-of-knee
24. Sanofi-Aventis Australia Pty Ltd - SYNVISC-ONE (Hylan G-F 20 ..., accessed November 1, 2025, https://www.tga.gov.au/resources/artg/159219
25. Synvisc - accessdata.fda.gov, accessed November 1, 2025, https://www.accessdata.fda.gov/cdrh_docs/pdf/P940015b.pdf
26. Public submissions on scheduling matters referred to the ACMS #22, ACCS #21 and Joint ACMS-ACCS #17 meetings held in November 20 - Therapeutic Goods Administration (TGA), accessed November 1, 2025, https://www.tga.gov.au/sites/default/files/public-submissions-scheduling-matters-referred-acms-22-accs-21-and-joint-acms-accs-17-meetings-held-november-2017-sanofi.pdf
27. SUMMARY OF SAFETY AND EFEFCTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Hyaluronic Acid, Intraarticular Devi - accessdata.fda.gov, accessed November 1, 2025, https://www.accessdata.fda.gov/cdrh_docs/pdf/p940015s012b.pdf
28. Premarket Approval (PMA) - FDA, accessed November 1, 2025, https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?ID=P940015
29. Hyaluronan or hylans for knee osteoarthritis? - Drug and Therapeutics Bulletin, accessed November 1, 2025, https://dtb.bmj.com/content/37/9/71
30. Viscosupplementation for knee osteoarthritis: a focus on Hylan G-F ..., accessed November 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6376458/
31. Hylan GF-20 Viscosupplementation in the Treatment of Symptomatic Osteoarthritis of the Knee: Clinical Effect Survivorship at 5 Years - ResearchGate, accessed November 1, 2025, https://www.researchgate.net/publication/317083040_Hylan_GF-20_Viscosupplementation_in_the_Treatment_of_Symptomatic_Osteoarthritis_of_the_Knee_Clinical_Effect_Survivorship_at_5_Years
32. Hylan G-F 20: Review of its Safety and Efficacy in the Management ..., accessed November 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2998981/
33. SYNVISC ® Dosing and Administration, accessed November 1, 2025, https://www.synvisconehcp.com/dosing-and-administration
34. Hylan polymers a and b (injection route, intra-articular route) - Side ..., accessed November 1, 2025, https://www.mayoclinic.org/drugs-supplements/hylan-polymers-a-and-b-injection-route-intra-articular-route/description/drg-20074573
35. Knee Pain Assessment Guide | Synvisc-One® Official Site, accessed November 1, 2025, https://www.synviscone.com/treatment-with-synvisc-one/prepare-for-your-doctor-visit
36. Synvisc-One Injection: Uses, Dosage, Side Effects - Drugs.com, accessed November 1, 2025, https://www.drugs.com/synvisc-one.html
37. Frequently Asked Questions | Synvisc-One® Official Site, accessed November 1, 2025, https://www.synviscone.com/what-is-synvisc-one/synvisc-one-faqs
38. Synvisc Intra-Articular: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed November 1, 2025, https://www.webmd.com/drugs/2/drug-4822/synvisc-intra-articular/details
39. Instructions for Use Synvisc-One DESCRIPTION Synvisc-One (hylan G-F 20) is a sterile, nonpyrogenic, elastoviscous fluid containi - Sanofi, accessed November 1, 2025, https://www.sanofi.com/assets/countries/canada/docs/products/prescription-products/synvisc-one-en.pdf
40. Synvisc-One® (Hylan GF 20) | Sanofi Campus, accessed November 1, 2025, https://www.campus.sanofi/dam/jcr:d5965653-63ac-416c-af18-1352c925c8b5/Synvisc%20one%20PI-%20July%202014.pdf
41. Premarket Approval (PMA) - FDA, accessed November 1, 2025, https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P940015S034
42. synvisc, synvisc-one - Devices@FDA, accessed November 1, 2025, https://www.accessdata.fda.gov/SCRIPTS/cdrh/devicesatfda/index.cfm?db=pma&id=352884
43. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee - Annals of the Rheumatic Diseases, accessed November 1, 2025, https://ard.bmj.com/content/annrheumdis/69/01/113.full.pdf
44. Hylan G-F 20: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed November 1, 2025, https://www.rxlist.com/hylan_g-f_20/generic-drug.htm
45. Hylan G-F 20 Intra-Articular: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed November 1, 2025, https://www.webmd.com/drugs/2/drug-91601/hylan-g-f-20-intra-articular/details
46. SYNVSIC POST INJECTION INSTRUCTIONS, accessed November 1, 2025, https://www.ehealthendeavors.com/SynviscPostInjectionInstructions.pdf
47. After Your Appointment - Synviscone.ca, accessed November 1, 2025, https://www.synviscone.ca/en/find-a-doctor/after-your-appointment
48. What To Do After A Synvisc-One Injection, accessed November 1, 2025, https://www.synviscone.com/treatment-with-synvisc-one/after-a-synvisc-one-injection
49. SYNVISC ® Clinical Efficacy, accessed November 1, 2025, https://www.synvisconehcp.com/clinical-efficacy
50. Osteoarthritis Clinical Trials & Studies | Synvisc‐One® (Hylan G‐F 20) | For HCPs, accessed November 1, 2025, https://www.synvisconehcp.com/synvisc-studies
51. Are intra-articular injections of Hylan G-F 20 efficacious in painful osteoarthritis of the knee? A systematic review and meta-analysis - NCBI, accessed November 1, 2025, https://www.ncbi.nlm.nih.gov/books/NBK219488/
52. Hyaluronic Acid vs. Steroid Injection for Knee Osteoarthritis, accessed November 1, 2025, https://www.jwatch.org/na41533/2016/06/09/hyaluronic-acid-vs-steroid-injection-knee-osteoarthritis
53. Prospective Randomized Trial Comparing the Efficacy of Single 6-ml Injection of Hylan GF 20 and Hyaluronic Acid for Primary Knee Arthritis: A Preliminary Study - Journal of the Medical Association of Thailand, accessed November 1, 2025, http://www.jmatonline.com/PDF/S92-S97-PB-95-S10.pdf
54. Efficacy and Safety of Hylan G-F 20 Versus Intra-Articular Corticosteroids in People with Knee Osteoarthritis: A Systematic Review and Network Meta-Analysis - PubMed, accessed November 1, 2025, https://pubmed.ncbi.nlm.nih.gov/33281462/
55. Corticosteroid injections for knee osteoarthritis offer clinical benefits similar to hyaluronic acid and lower than platelet-rich plasma: a systematic review and meta-analysis in, accessed November 1, 2025, https://eor.bioscientifica.com/view/journals/eor/9/9/EOR-23-0198.xml
56. A double-blind, placebo-controlled comparison of hylan G-F 20 ..., accessed November 1, 2025, https://www.researchgate.net/publication/283464398_A_double-blind_placebo-controlled_comparison_of_hylan_G-F_20_against_diclofenac_in_knee_osteoarthritis
57. Trial Treatment of Osteoarthritis of the Knee: A Prospective, Randomized Corticosteroid Compared with Hyaluronic Acid Injections - UW Orthopaedic Surgery and Sports Medicine, accessed November 1, 2025, https://orthop.washington.edu/sites/default/files/Portals/21/www/Research/Publications/The%20Journal%20of%20Bone%20and%20Joint%20Surgery%20(JBJS)/Corticosteroid%20compared%20with%20Hyaluronic%20Acid%20Injections%20(Seth%20Leopold).pdf
58. Corticosteroid compared with hyaluronic acid injections for the treatment of osteoarthritis of the knee. A prospective, randomized trial - PubMed, accessed November 1, 2025, https://pubmed.ncbi.nlm.nih.gov/12851342/
59. One-year efficacy and safety of single or one to three weekly ..., accessed November 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8121739/
60. Comparison between Four Types of Single-Dose Hyaluronic Acid Injection in Patients with Knee Osteoarthritis : A Randomized Control Trial, accessed November 1, 2025, https://www.semanticscholar.org/paper/Comparison-between-Four-Types-of-Single-Dose-Acid-%3A/3c080b9348941bb12560d9e3169dc9ab21a0ab59
61. Full article: Pain relief and improved physical function in knee osteoarthritis patients receiving ongoing hylan G-F 20, a high-molecular-weight hyaluronan, versus other treatment options: data from a large real-world longitudinal cohort in Canada - Taylor & Francis Online, accessed November 1, 2025, https://www.tandfonline.com/doi/full/10.2147/DDDT.S88473
62. Premarket Approval (PMA) - FDA, accessed November 1, 2025, https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?ID=P940015S012
63. Genzyme Corporation Files for Approval of Single-Treatment Synvisc-One(TM) - BioSpace, accessed November 1, 2025, https://www.biospace.com/genzyme-corporation-files-for-approval-of-single-treatment-synvisc-one-tm
64. FDA Advisory Committee Unanimously Recommends Approval of Genzyme's Synvisc-One, accessed November 1, 2025, https://www.fiercebiotech.com/biotech/fda-advisory-committee-unanimously-recommends-approval-of-genzyme-s-synvisc-one
65. FDA Approves Genzyme Corporation's Synvisc-One for Osteoarthritis of the Knee, accessed November 1, 2025, https://www.biospace.com/fda-approves-genzyme-corporation-s-synvisc-one-for-osteoarthritis-of-the-knee
66. Synvisc-One - Healthdirect, accessed November 1, 2025, https://www.healthdirect.gov.au/medicines/brand/amt,1118961000168101/synvisc-one
67. Devices@FDA, accessed November 1, 2025, https://www.accessdata.fda.gov/SCRIPTS/cdrh/devicesatfda/index.cfm?db=pma&id=514540