Hyaluronidase is a versatile enzyme with a wide range of medical applications, from enhancing drug absorption to treating complications arising from cosmetic procedures. This comprehensive guide delves into the uses, effects, and precautions associated with hyaluronidase injections, drawing on trusted sources to provide an in-depth understanding of this important medical tool.

What is Hyaluronidase?

Hyaluronidase is a naturally occurring enzyme that breaks down hyaluronic acid, a substance found in the body's connective tissues. It is derived from animal sources (such as cows or pigs) or produced recombinantly in laboratories using human albumin. The enzyme works by temporarily degrading hyaluronic acid, which facilitates the spread and absorption of fluids and medications in the body.

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Medical Uses of Hyaluronidase Injections

• Enhancing Drug Absorption: Hyaluronidase is often used to improve the absorption and distribution of other medications administered subcutaneously. This is particularly useful when intravenous administration is not possible. For example, it is used in subcutaneous urography to enhance the absorption of radioactive contrast media.

Figure 1. Hyaluronidase increases the bioavailability of injected drugs. Hyaluronidase can catalyze the degradation of hyaluronan in the extracellular matrix, thereby enabling enhanced tissue permeability and increasing the bioavailability of injected drugs, e.g. local infiltration anesthetics. (a–c) The efficacy of conventional local infiltration anesthesia is limited by the fact that the dense extracellular matrix constrains a rapid dispersion of the drug within the tissue. (d–f) Hyaluronidase is co-injected with the local anesthetic to promote dispersion of the drug as a "spreading factor". In the case of local infiltration anesthetics this results in (f) a faster and more widespread anesthesia and hence a higher efficacy. (Weber et al., 2019)

• Treating Dehydration: In cases of severe dehydration, hyaluronidase can be used alongside fluids to facilitate their absorption into the body. This application is especially valuable in emergency situations where rapid rehydration is critical.
• Reversing Hyaluronic Acid Fillers: Hyaluronidase plays a critical role in cosmetic medicine by dissolving hyaluronic acid-based dermal fillers. This is especially important in cases of complications such as vascular occlusion, filler migration, or allergic reactions. Ultrasound-guided hyaluronidase injections have been shown to improve accuracy and reduce the amount of enzyme required.

Figure 2. Hyaluronidase effectively degrades hyaluronan-based dermal fillers. The injection of hyaluronidase results in rapid degradation of the complex network of hyaluronan (HA)-fillers into HA fragments. (Buhren et al., 2016)

• Diagnostic Imaging: The enzyme is also used to enhance the visibility of contrast dyes in certain imaging procedures, such as subcutaneous urography, by improving their distribution and absorption.
• Treatment of Microstomia: In rare cases, hyaluronidase has been used to treat microstomia (a condition characterized by a reduced oral aperture) caused by localized scleroderma. Injections help to break down fibrous tissue, improving mouth mobility

Administration and Dosage

For Enhancing Drug Absorption

Hyaluronidase is often used to increase the absorption and distribution of injected drugs or fluids by breaking down hyaluronic acid in connective tissues. It is commonly administered at a concentration of 150 units/mL, depending on the specific drug and medical condition being treated. This use is particularly beneficial in:

• Subcutaneous fluid administration (hypodermoclysis) for patients requiring hydration.
• Local anesthesia augmentation, where hyaluronidase helps anesthetics spread more effectively.
• Ophthalmic surgery, to improve drug diffusion around the eye.

For Dissolving Dermal Fillers

Hyaluronidase is commonly used in aesthetic medicine to dissolve unwanted or misplaced hyaluronic acid-based dermal fillers. The dosage required varies depending on the type, amount and location of the filler, but typically ranges from 5 to 300 units. It is injected directly into the treated area to dissolve the filler for correction or reversal of cosmetic procedures.

A 2024 study by Hong and Yi reviewed historical dosage recommendations, which suggested that 5-15 units of hyaluronidase could dissolve 0.1 mL of HA filler, making 150 units sufficient for 1 mL. However, modern HA fillers, which are designed with greater cross-linking for increased volume, often require higher doses. Softer HA fillers used for wrinkle treatment typically require 200-300 units per 1 mL, while volumizing fillers may require over 500 units per 1 mL for effective dissolution.

Administration and Safety Measures

Before receiving hyaluronidase, a skin test may be performed to identify potential allergic reactions, especially in patients with a history of sensitivity. Injections are usually administered by a trained healthcare professional in a clinical setting to ensure proper dosing and minimize risks.

Side Effects and Risks

Although hyaluronidase is generally considered safe, it can cause side effects ranging from mild irritation to severe allergic reactions.

• Common Reactions
  • Pain, swelling, redness, or itching at the injection site.
  • Temporary bruising or mild discomfort after the procedure.
• Allergic Reactions (Rare but Serious)
  • Anaphylaxis, a life-threatening reaction with symptoms such as hives, difficulty breathing, and swelling of the face or throat.
  • Immediate medical attention is required if severe allergic symptoms occur.
• Overdose Symptoms
  • Blurred vision
  • Dizziness
  • Nausea
  • Irregular heartbeat

Precautions

• Allergies: Patients with a known allergy to hyaluronidase or animal-derived products should avoid its use. Individuals with bee venom allergies may have an increased risk of allergic reactions.
• Pregnancy and Breastfeeding: There is limited research on the safety of hyaluronidase during pregnancy or lactation. It should be used only when the potential benefits outweigh the risks and under the supervision of a health care professional.
• Drug Interactions: Hyaluronidase may interact with live vaccines, potentially altering their effectiveness. It may also increase the spread of local anesthetics, requiring careful dosage adjustments. Patients should inform their physician of all medications they are currently taking to avoid adverse interactions.

Applications in Cosmetic Medicine

• Reversing Dermal Fillers: Hyaluronidase is the gold standard for dissolving hyaluronic acid fillers in cases of complications such as vascular occlusion, nodules, or overfilling. Ultrasound guidance has improved the precision of these injections, reducing the risk of adverse effects.
• Managing Vascular Complications: Vascular occlusion is a rare but serious complication of filler injections. Hyaluronidase can dissolve the filler and restore blood flow, preventing tissue necrosis and blindness. Early intervention is critical for successful outcomes.
• Reducing Swelling and Bruising: In some cases, hyaluronidase is used to minimize swelling and bruising after filler injections, improving patient satisfaction.

Ultrasound-Guided Hyaluronidase Injections

Ultrasound imaging has revolutionized the use of hyaluronidase in aesthetic medicine. It allows clinicians to:

• Accurately locate filler deposits.
• Guide hyaluronidase injections to the target area.
• Minimize the amount of enzyme required, thereby reducing the risk of side effects.

Studies have shown that ultrasound-guided injections are particularly effective in the treatment of vascular complications because they allow precise targeting of the affected area.

Patient Considerations

• Pre-Treatment Assessment: Before receiving hyaluronidase, patients should undergo a thorough medical evaluation, including a review of allergies, medications, and medical history. A skin test may be performed to assess the risk of allergic reactions.
• Post-Treatment Care: After hyaluronidase injection, patients should:
  • Avoid rubbing or massaging the treated area.
  • Monitor for signs of allergic reactions or infection.
  • Follow up with their healthcare provider as recommended.
• Contraindications: Hyaluronidase should not be used in patients with:
  • Known hypersensitivity to the enzyme.
  • Active infections at the injection site.
  • Certain medical conditions that may increase the risk of complications.

Case Studies

Case 1: Human Recombinant Hyaluronidase Injections for Upper Limb Muscle Stiffness in Individuals with Cerebral Injury: A Case Series; Raghavan et al., 2016

Hyaluronan accumulation in muscles contributes to stiffness after neurological injury. Hyaluronidase injections effectively reduce this stiffness and improve both passive and active movement without causing muscle weakness or significant side effects. In a study of 20 patients with unilateral upper limb spasticity, multiple intramuscular injections of human recombinant hyaluronidase resulted in sustained improvements in movement and reduced muscle stiffness for up to five months. Four-time assessments confirmed increased joint mobility and decreased Ashworth scores. The treatment is safe and shows promise as an effective option for treating muscle stiffness in neurologically impaired individuals, warranting further validation in placebo-controlled trials.

Figure 3. Muscles injected with Human Recombinant Hyaluronidase. (Raghavan et al., 2016)

Case 2: A Scoping Review of Hyaluronidase Use in Managing the Complications of Aesthetic Interventions; Farahani et al., 2024

Hyaluronidase is widely used to treat complications of hyaluronic acid (HA) filler injections, including necrosis, blindness, hypersensitivity, delayed nodules, and unsatisfactory aesthetic results. To evaluate its efficacy, a systematic review was conducted using PubMed, Medline, Embase, and Cochrane databases and identified five randomized clinical trials (RCTs) from the United States. These trials, which included 53 subjects, demonstrated the efficacy of hyaluronidase in the removal of uncomplicated HA nodules from the forearm, upper arm, and back skin, with follow-up ranging from 14 days to four years. A dose-dependent response was observed, with single-injection doses ranging from 1.25 to 37.5 units per 0.1 mL of HA filler, while lower doses (0.375-2.25 units) were effective when administered weekly for three consecutive weeks. Importantly, no serious adverse events were reported.

However, the review highlighted a significant gap in the clinical evidence regarding the use of hyaluronidase for facial HA filler complications, such as inflammatory nodules, overcorrection, and tissue ischemia or necrosis. The lack of RCTs, clinical trials, or retrospective case-control studies in these areas underscores the need for further research. While existing studies support the efficacy of the enzyme in specific non-facial areas, additional well-powered studies are needed to determine the optimal dosing and treatment protocols for HA filler reversal and complication management in facial applications.

In summary, hyaluronidase is a valuable tool in both medical and cosmetic settings, offering solutions for drug delivery, dehydration and filler complications. While generally safe, its use requires careful consideration of potential risks and precautions. With advances such as ultrasound-guided injections, the precision and efficacy of hyaluronidase treatments continue to improve, enhancing patient outcomes and safety. By understanding the uses, effects, and precautions associated with hyaluronidase injections, healthcare providers and patients can make informed decisions about its use, ensuring optimal outcomes and minimizing risks.

At Creative Enzymes, we provide high-quality hyaluronidase products that meet the needs of healthcare professionals and aesthetic practitioners. Contact us today to learn more about our hyaluronidase offerings.