Hyaluronic Acid

Article Author:
Kendra Walker
Article Editor:
Patrick Zito
2/2/2019 8:36:08 AM
PubMed Link:
Hyaluronic Acid


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. There exist many different types of hyaluronic acid gel fillers that 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. 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.

Common Injection Sites

  • Glabella
  • Nasolabial folds
  • Melolabial folds
  • Lips
  • Malar hollows
  • Infraorbital hollows
  • Perioral rhytids
  • Chin

 FDA-Labeled Indications

  • Injection into the mid-to-deep dermis for correction of facial wrinkles, folds, and defects. Patients must be over the age of 21
  • Injection into the lips for lip augmentation. Patients must be over the age of 21
  • Injection into the knee joint as a treatment for mild to moderate osteoarthritis (OA) of the knee that has not responded to conservative non-pharmacological measures and/or analgesics. The FDA has not evaluated nor approved this treatment for any other joints.

Non-FDA-Labeled Indications

  • Injection to provide 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

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 filler theoretically should not cause an immune response.

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

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 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.

When used to treat OA of the knee, the mechanism of action is that of an intra-articular lubricant and "shock absorber."


The hyaluronic acid filler is supplied in varying sized, preloaded syringes and the concentration depends on the specific brand chosen. 

Preparation of site should include removal of any makeup and cleansing with an antiseptic agent typically isopropyl alcohol or chlorhexidine. In order to prevent biofilm, the technique should be as aseptic as possible. Reduction of pain at the injection site can be achieved 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 specific problem being addressed. Lip augmentation requires 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 orthopedically, injection is performed directly into the joint space of the knee; it is typically given as a series of 5 injections one week apart. No evaluation has been made on the effectiveness of fewer than 3 injections. Any joint effusion present should be removed before administration, and strict aseptic technique must be followed during administration. Injection of lidocaine or another local anesthetic is sometimes performed before 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.

Adverse Effects

The most common adverse effects associated with hyaluronic acid filler are a pain, bruising, redness, itching, and swelling. These side effects are self-limited and typically last no more than 7 days. They can be reduced by applying an ice pack on 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 can be prevented with proper aseptic technique and ensure 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 as well as 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 seen 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 important to be aware 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 reactivation of the virus. This can be prevented and treated with oral acyclovir.

In intra-articular use for knee OA, the primary adverse event is transient swelling and pain. Intra-articular hyaluronic acid is not known to interact with any other medications.


All of the following are contraindications for the use of hyaluronic acid filler:

  • History of severe allergies manifested by anaphylaxis
  • Allergy to gram-positive proteins
  • Bleeding disorder
  • Injection into spaces other than the dermis or submucosa for lip augmentation

For intra-articular use, the contraindications for the use of hyaluronic acid are:

  • History of severe allergies to sodium hyaluronate preparations
  • Infections or skin diseases in the vicinity of the injection site


The effects of hyaluronic acid filler can be reversed with hyaluronidase, an enzyme that breaks down both native and injected hyaluronic acid. Hyaluronidase is particularly useful when it is deemed that the filler injection was too superficial which is evidenced by bluish discoloration.


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