Hyaluronic Acid


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Kendra Walker
Brandon Basehore


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Patrick Zito


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Sandeep Sekhon


Updated:
10/7/2019 2:40:45 PM

Indications

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.[1][2][3]

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 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

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.[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.

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.

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

Administration

The hyaluronic acid filler is available in varying sized, preloaded syringes, and the concentration depends on the specific brand chosen.[7][8][9]

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 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 five injections one week apart. No evaluation has taken place on the effectiveness of fewer than three injections. Any joint effusion present should be removed before administration, and strict aseptic technique is necessary during administration. Injection of lidocaine or another local anesthetic is sometimes an option 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 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 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 is preventable with proper aseptic technique and ensures 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 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.

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.

Contraindications

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

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, which is evidenced by bluish discoloration.

Enhancing Healthcare Team Outcomes

Several healthcare professionals use hyaluronic acid gel, including the plastic surgeon, primary care provider,  dermatologist, nurse practitioner, and the internist to enhance cosmesis. 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. Nursing staff can assist during the procedure, offer to counsel following the injection and verify post-procedure compliance with the treating physician's orders. Often, these products are supplied via compounding pharmacies, so it is vital that the pharmacist understand the needs and wishes of the physician and compound the proper formulation for the particular procedure; two-way communication is essential. While not an overly complicated process, it still requires the collaboration of an interprofessional team approach to best direct outcomes successfully. [Level V]

It is essential to educate the patient this dermal filler is not permanent, and its results may last anywhere from 8 to 16 weeks, depending on the type of product.[3][10]


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Hyaluronic Acid - Questions

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A patient presents to the clinic wanting lip augmentation to create a fuller pout with hyaluronic acid injection. However, on physical exam, you note lesions shown in the image. What is the best next step?

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Which medication does not potentiate any possible side effects for a patient seeking hyaluronic acid gel injections?



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A patient presents to the clinic 3 months after receiving hyaluronic acid filler in her nasolabial folds. On physical exam, you find a subcutaneous nodule within the nasolabial fold. You take a biopsy and find on microscopy macrophages with abundant pink cytoplasm with surrounding multinucleated giant cells and lymphocytes. What is this reaction called?



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When used to treat osteoarthritis, which joint has the only FDA approved indication for hyaluronic acid injection?



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Which of the following does not contain naturally occurring hyaluronic acid?



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Patient presents to dermatology clinic 3 weeks after receiving hyaluronic acid gel filler in her nasolabial folds. She complains of bluish discoloration in the area where she had the injection that has not resolved. She currently is afebrile and not complaining of any increased warmth or swelling at the injection sites. What caused this?



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A 45-year-old distance runner has a hyaluronic acid injection to his knee because of degenerative arthritis. He immediately develops a severe rash and a systemic hypersensitivity reaction. This patient most likely is also allergic to which of the following?



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Hyaluronic Acid - References

References

Salsberg J,Andriessen A,Abdulla S,Ahluwalia R,Beecker J,Sander M,Schachter J, A review of protection against exposome factors impacting facial skin barrier function with 89% mineralizing thermal water. Journal of cosmetic dermatology. 2019 Apr 9;     [PubMed]
Alharbi M, Review of sterility of reused stored dermal filler. Journal of cosmetic dermatology. 2019 Apr 9;     [PubMed]
Charlesworth J,Fitzpatrick J,Perera NKP,Orchard J, Osteoarthritis- a systematic review of long-term safety implications for osteoarthritis of the knee. BMC musculoskeletal disorders. 2019 Apr 9;     [PubMed]
Kim JH,Moon MJ,Kim DY,Heo SH,Jeong YY, Hyaluronic Acid-Based Nanomaterials for Cancer Therapy. Polymers. 2018 Oct 12;     [PubMed]
Fallacara A,Baldini E,Manfredini S,Vertuani S, Hyaluronic Acid in the Third Millennium. Polymers. 2018 Jun 25;     [PubMed]
Eberle Heitzmann M,Thumm D,Baudouin C, A review of the efficacy, safety and tolerability of Lacrycon{sup}®{/sup} eye drops for the treatment of dry eye syndrome. Journal francais d'ophtalmologie. 2019 Mar 28;     [PubMed]
Pontes-Quero GM,García-Fernández L,Aguilar MR,San Román J,Pérez Cano J,Vázquez-Lasa B, Active viscosupplements for osteoarthritis treatment. Seminars in arthritis and rheumatism. 2019 Feb 19;     [PubMed]
Han Y,Huang H,Pan J,Lin J,Zeng L,Liang G,Yang W,Liu J, Meta-analysis Comparing Platelet-Rich Plasma vs Hyaluronic Acid Injection in Patients with Knee Osteoarthritis. Pain medicine (Malden, Mass.). 2019 Mar 7;     [PubMed]
Arima H,Motoyama K,Higashi T, [Potential Use of Sacran for Dermal and Oral Preparations]. Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2019;     [PubMed]
Najjarzadeh M,Mohammad Alizadeh Charandabi S,Mohammadi M,Mirghafourvand M, Comparison of the effect of hyaluronic acid and estrogen on atrophic vaginitis in menopausal women: A systematic review. Post reproductive health. 2019 Feb 24;     [PubMed]

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