Continuing Education Activity

Hyaluronic acid is a high-molecular-weight polysaccharide, which is widely distributed in the connective tissue extracellular matrix. Several hyaluronic acid preparations have become widely available for subcutaneous/intradermal, intraarticular, topical, and ocular use. This activity outlines the indications, mechanism of action, administration, significant adverse effects, and contraindications of various hyaluronic acid preparations to increase practitioners' knowledge regarding how to approach this substance and use it in practice for its indicated purposes.

Objectives:

• Identify the mechanism of action of hyaluronic acid.
• Outline some of the conditions where hyaluronic acid is useful and indicated.
• Explain the potential adverse effects of hyaluronic acid.
• Summarize interprofessional team strategies for improving care coordination and communication to advance improved outcomes using hyaluronic acid when indicated.

Indications

Several preparations of hyaluronic acid are available for many FDA-approved indications. The most common application indications are for cosmetics and intra-articular use, although many other ophthalmic and topical forms are also available.

Hyaluronic acid gel fillers are injected to restore volume lost due to age or disease, provide facial contour, and help maintain a youthful appearance. Filler injection has become one of the most commonly performed procedures in a dermatology cosmetic practice. Many different types of hyaluronic acid gel fillers differ in their hyaluronic acid concentration, particle size, cross-linking density, duration, and presence of lidocaine. High-density, large-particle fillers are recommended for deep dermal injections, while the low-density, small-particle fillers are recommended for fine lines. Hyaluronic acid filler has become popular because of its low allergic response, ease of injection, rapid recovery, reproducibility, and immediate results.[1][2][3] Common injection sites are glabella, nasolabial folds, melolabial folds, lips, malar hollows, infraorbital hollows, perioral rhytids, and chin.

Intraarticular injections of hyaluronic acid are also widely used, especially for pain relief in patients with osteoarthritis of the knees. They have become popular as a non-surgical treatment modality, especially with the concern most clinicians have with repeating intraarticular corticosteroid injections. Several preparations are available, including various commercially available injections of sodium hyaluronate, hylan polymers A and B, and hyaluronan.

United States Food and Drug Administration (FDA) Labeled Indications

Intraarticular injection:

• For pain relief in patients with mild to moderate osteoarthritis (OA) of the knees, who have not responded to conservative non-pharmacological measures and/or analgesics. The FDA has not evaluated nor approved this treatment for any other joints.

Intradermal injection:

• Injection into the mid-to-deep dermis for correction of facial wrinkles or folds and perioral rhytids. Patients must be over the age of 21.

Subcutaneous injection:

• Volume deficit correction for dorsal hands in patients over the age of 21.
• Correction of age-related volume loss and for cheek augmentation in mid-face in patients over the age of 21.

Subperiosteal injection:

• Correction of age-related volume loss and for cheek augmentation in mid-face in patients over the age of 21.

Submucosal injection:

• Injection into the lips for lip augmentation in patients over the age of 21.

Topical cream/gel:

• Management of wounds, skin ulcers
• Relief of symptoms (burning, itching, and pain) in dermatoses such as atopic dermatitis, radiodermatitis, and allergic contact dermatitis.

Ophthalmic:

• Surgical aid cataract extraction, intraocular lens implantation, corneal transplant, glaucoma filtration, retinal attachment surgery, and anterior segment surgery.

Non-FDA-Labeled Indications

• Injection to provide a scaffold for regenerative endodontic procedures
• Injection into vocal folds to treat glottal insufficiency
• Injection into the areola to enhance nipple projection after breast reconstructive surgery
• Refractory interstitial cystitis

Mechanism of Action

Hyaluronic acid, a naturally occurring chemical, is a glycosaminoglycan polysaccharide composed of alternating residues of the monosaccharides d-glucuronic acid and N-acetyl-d-glucosamine, which form a linear polysaccharide chain. In its pure form, hyaluronic acid is the same in all organisms and is not species or tissue-specific. Therefore, hyaluronic acid theoretically should not cause an immune response.[4][5][6]

Hyaluronic acid, a chief component of the extracellular matrix, is found throughout various human tissues such as the skin, eyes, connective tissue, and synovium. Due to hyaluronic acid's highly anionic proprieties, it can attract water to swell and create volume and provide structural support. Aging leads to decreased production of hyaluronic acid and collagen in the skin. Once the skin has lost its viscoelastic properties, overlying wrinkles begin to form. Hyaluronic acid dermal fillers work to counteract aging by replacing lost volume. In addition to this, hyaluronic acid fillers have also been shown to increase collagen production and affect fibroblast morphology.

The hyaluronic acid filler can classify as animal-derived or non-animal derived. Animal-derived fillers come from a rooster comb, and non-animal derived hyaluronic acid production occurs through biofermentation of Streptococcus. The hyaluronic acid filler can further be classified based on whether it is processed through particulate or non-particulate manufacturing. The particulate size determines the longevity of particulate manufactured hyaluronic acid filler, whereas cross-linking density determines the longevity of non-particulate manufactured hyaluronic acid filler.

The hyaluronic acid filler contains modified hyaluronic acid particles that are cross-linked, which allows for the production of a more concentrated hyaluronic acid that has greater resistance to chemical and physical degradation. During the degradation and breakdown of hyaluronic acid filler, water slowly takes its place, resulting in a less concentrated hyaluronic gel yet occupying the same amount of volume. This action is termed “isovolumetric degradation.” The effects of hyaluronic acid filler are last up to 4 to 6 months depending on location, a specific brand of filler used, and injection technique.

The mechanism of action of hyaluronic acid when used intra-articularly is similar. Hyaluronic acid is a naturally occurring part of the synovial fluid and cartilage, and in osteoarthritis, the concentration of hyaluronic acid decreases along with a decrease in the size of individual hyaluronic acid molecules, thus decreasing the viscosity of the synovial fluid. When injected into the joint, hyaluronic acid is cleared within several hours, with half-lives ranging from 17 hours to 1.5 days.[7] The half-life is longer for purified or synthesized hyaluronic acid preparations with a large molecular weight. 

Despite such a short half-life, the clinical benefit, including pain relief from intraarticular hyaluronic injections, lasts several months. Several mechanisms have been proposed for this long-lasting efficacy of intraarticular hyaluronic acid injections. Injection of hyaluronic acid may stimulate the native synovial sites that produce hyaluronic acid. Anti-inflammatory and anti-nociceptive effects of hyaluronic acid have been demonstrated as well.[8] Several meta-analyses have been done to evaluate the efficacy of different hyaluronic acid preparations for osteoarthritis management, with varying results.[9][10][11] The overall consensus is that of small but significant symptomatic and long-lasting effects following a series of intraarticular hyaluronic acid injections. 

Administration

The hyaluronic acid filler is available in varying sized, preloaded syringes, and the concentration depends on the specific brand chosen.[12][13][14] Preparation of the site should include removal of any makeup and cleansing with an antiseptic agent, typically isopropyl alcohol or chlorhexidine. The technique should be as aseptic as possible to prevent biofilm. Reduction of pain at the injection site is achievable through topical or injectable anesthetics, nerve blocks, ice packs, and distraction techniques. The hyaluronic acid filler is injected into the mid to deep dermis, and techniques include serial puncture, linear threading, fanning, and cross-hatching. The technique used depends on the injection site and the specific problem addressed. Lip augmentation requires an injection into the submucosa. Common injection sites are lips, nasolabial folds, glabellar lines, and periorbital and generalized facial wrinkles. Once the injections are complete, the patient should have a cool ice pack applied to minimize bruising and swelling, as well as be advised to avoid manipulating the treatment area.

When administered intraarticularly, injection is performed directly into the joint space of the knee. It is recommended to aspirate any joint effusion if present. Strict aseptic technique is necessary during the administration. Injection of lidocaine or another local anesthetic is optional before the intra-articular injection of hyaluronic acid. The patient should refrain from vigorous or prolonged weight-bearing physical activity for at least 48 hours post-injection. Several preparations are available, each with differences in the number of injections in each series, molecular weight, origin (avian or bacterial), viscosity, ad presence or absence of cross-linkage. 

For topical use, it is recommended to clean the wound with normal saline and debride the wound if needed before applying hyaluronic acid preparation. A thin layer shall be applied to the ulcer or wound, and excessive rubbing shall be avoided. After application, the wound shall be covered with a sterile non-stick gauze pad or dressing. For use in dermatoses, hyaluronic acid preparation can be applied directly to the affected area.

Adverse Effects

The most common adverse effects associated with hyaluronic acid filler are pain, bruising, redness, itching, and swelling. These side effects are self-limited and typically last no more than seven days. The patient can mitigate them by applying an ice pack to the injection site, remaining upright, and, 1 week before the procedure, stopping medications or supplements that increase the risk of bleeding, for example, aspirin, nonsteroidal anti-inflammatory medications, vitamin E, fish oils, St. John’s wort, and ginkgo biloba.

Extremely rare side effects of hyaluronic acid gel injection include infection, tissue necrosis, granulomatous foreign body, and activation of herpes labialis. Infection is due to bacterial inoculation through the injection site, which is preventable with proper aseptic technique and ensuring that there is no active infection near the injection site. Tissue necrosis can result from vascular occlusion due to intra-arterial injection of hyaluronic acid filler and highlights the importance of understanding facial anatomy and performing a blood aspiration test before injecting. If this adverse complication is suspected, hyaluronidase should be applied immediately, which will dissolve the hyaluronic acid gel particles. Granulomatous foreign body reaction has been a very rare documented reaction to hyaluronic acid filler injection and is thought to be caused by a reaction to bacterial impurities remaining from the production process. On histology, multinucleated giant cells can be visible at the injection site where the granulomatous foreign body reaction is occurring. The purification process of hyaluronic acid filler has improved significantly, resulting in fewer cases of hypersensitivity reactions. When performing lip injections, it is crucial to be aware of whether the patient has a history of herpes simplex virus infection or has a history of herpes simplex virus reactivation after a previous filler injection. The trauma caused by injection can lead to the reactivation of the virus; this is preventable and treated with oral acyclovir.

Adverse effects of intra-articular injections of hyaluronic acid are usually mild and self-limiting. Local injection site reactions or irritation are the most common side effects. Up to 2% of patients can experience a post-injection flare with more pain, swelling, redness, and warmth, which is usually self-limited and can resolve with icing, rest, and anti-inflammatory medications. Synovial fluid analysis in such cases reveals aseptic fluid with no crystals. Intra-articular infections have not been reported in clinical trials and are extremely rare in clinical practice. Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported. Systemic adverse effects such as rash, arthralgia, myalgia, muscle cramps, and nausea have been reported in about 2% of cases in clinical trials.

Contraindications

Contraindications for the use of hyaluronic acid filler include:

• Hypersensitivity to hyaluronic acid or any of the formulation components.
• History of severe allergic reaction or anaphylaxis to hyaluronic acid.
• Hypersensitivity reaction to gram-positive bacterial proteins (for products derived from bacterial source).
• Hypersensitivity reaction to lidocaine (for products containing lidocaine).
• Bleeding disorder.
• Injection into sites other than the labeling recommended sites.

Contraindications for the use of intraarticular hyaluronic acid include:

• Hypersensitivity to hyaluronic acid or any of the formulation components.
• History of severe allergic reaction or anaphylaxis to hyaluronic acid.
• Hypersensitivity reaction to gram-positive bacterial proteins (for products derived from bacterial source).
• Infections or skin diseases in the vicinity of the injection site or injection into a septic joint.

The safety and efficacy of hyaluronic acid injections in pregnant females, lactating females, and the pediatric population have not been established. 

Toxicity

The effects of hyaluronic acid filler are reversible with hyaluronidase, an enzyme that breaks down both native and injected hyaluronic acid. Hyaluronidase is particularly useful when the determination is that the filler injection was too superficial, as evidenced by bluish discoloration. 

Enhancing Healthcare Team Outcomes

Several healthcare professionals use hyaluronic acid, including the plastic surgeon, primary care clinicians (including PAs and NPs), dermatologists, and internists, to enhance cosmesis. The hyaluronic acid filler can only be injected by the prescription of a licensed health care provider. Hyaluronic acid filler has become popular because of its low allergic response, ease of injection, rapid recovery, reproducibility, and immediate results. It is also frequently used for symptoms relief from knee osteoarthritis by several healthcare professionals, including orthopedics, rheumatologists, physical medicine and rehabilitation providers, and primary care providers. 

It is essential to educate the patient that hyaluronic acid treatment is not permanent, and results may last anywhere from 8 to 16 weeks for the dermal filler and up to 6 months for intraarticular injection, depending on the type of product.[3][15] Nursing staff can assist during the procedure, offer to counsel following the injection, verify post-procedure compliance with the treating clinician's orders, and assist patients with any post-procedural complication recognition. Often, these products are supplied via compounding pharmacies, so the pharmacist must understand the needs and wishes of the clinician and compound the proper formulation for the particular procedure; close communication is essential. While not an overly complicated process, it still requires the collaboration of an interprofessional team approach to successfully direct outcomes. [Level 5]