Hyaluronidase, an enzyme well known for its role in aesthetic medicine, particularly in the dissolution of hyaluronic acid (HA) dermal fillers, has a range of applications far beyond cosmetic procedures. The enzyme's ability to degrade HA - a major component of the extracellular matrix - makes it invaluable in several medical disciplines. By increasing tissue permeability, hyaluronidase facilitates the dispersion and absorption of injected substances, enhancing the efficacy of many treatments. Explore other uses and applications of hyaluronidase beyond fillers with Creative Enzymes.

Mechanism of Action

Hyaluronidase functions by hydrolyzing HA, a glycosaminoglycan prevalent in connective tissues. By breaking down HA, hyaluronidase reduces the viscosity of the extracellular matrix, thereby increasing tissue permeability. This action enhances the diffusion of co-administered drugs and fluids, making hyaluronidase a valuable adjunct in various therapeutic contexts.

Figure 1. Degradation of dermal hyaluronan by infiltration of hyaluronidase. Dermal fibroblasts play a major role in neo-synthesis of hyaluronan (HA) as an essential component of the extracellular matrix (ECM). The injection of hyaluronidase degrades HA, and subsequently renders the ECM more permeable, resulting in a greater diffusion capacity and bioavailability of injected drugs. In addition, applied hyaluronidase induces the de novo synthesis of HA in dermal fibroblasts to compensate potential transient hyaluronidase-induced HA deficits. (Buhren et al., 2016)

FDA-Approved Indications

• Subcutaneous Fluid Infusion (Hypodermoclysis): Hyaluronidase is approved for subcutaneous fluid administration, particularly in patients requiring hydration therapy. By degrading HA, it increases tissue permeability, allowing for more efficient fluid absorption.
• Enhancing Drug Absorption: Hyaluronidase is used as an adjuvant to accelerate the absorption and distribution of injected drugs. This is particularly beneficial for drugs that require rapid systemic delivery, such as insulin in the treatment of diabetes, immunoglobulins in primary immunodeficiencies, and monoclonal antibodies in the treatment of cancer. For example, when co-administered with insulin, hyaluronidase can reduce the time to peak concentration (C_max), thereby increasing therapeutic efficacy.
• Subcutaneous Urography: In urinary tract angiography, hyaluronidase is used to improve the absorption of radiopaque agents, facilitating clearer imaging.

Figure 2. Three applications of FAD-approved hyaluronidase.

Off-Label Uses

• Dissolving Hyaluronic Acid Fillers: One of the most well-known off-label uses of hyaluronidase is in aesthetic medicine. It is considered the gold standard for dissolving HA-based fillers used in facial contouring and rejuvenation. Complications such as overcorrection, vascular occlusion, and irregular filler distribution can be effectively managed with hyaluronidase. Recent studies have shown that the efficacy of hyaluronidase in dissolving fillers depends on the type of filler, enzyme concentration, and application technique.
• Managing Extravasation: Hyaluronidase is used to treat extravasation of drugs from intravenous lines. By breaking down the surrounding HA, it facilitates the dispersion of the extravasated drug, thereby reducing tissue damage.
• Adjunct in Local Anesthetic Eye Blocks: In ophthalmic surgery, hyaluronidase is added to local anesthetics to enhance their diffusion and effectiveness. This results in improved analgesia and reduced postoperative pain.
• Keloid Scar Treatment: Hyaluronidase is used in combination with cryosurgery, triamcinolone, and 5-fluorouracil to treat keloid scars. The enzyme helps in breaking down the HA-rich scar tissue, promoting scar resolution.
• Treatment of Granulomatous Foreign Body Reactions: Hyaluronidase may be used to treat granulomatous reactions associated with filler injections. It helps dissolve HA deposits and reduce inflammation.
• Enhancing Local Anesthesia: In dermatosurgery and other surgical disciplines, hyaluronidase is added to local anesthetics to increase their diffusion capacity and bioavailability. This improves the anesthetized area and reduces intra- and post-operative pain.

Clinical Considerations

• Enzyme Sources and Variability: Hyaluronidase can be derived from various sources, including animal tissues and recombinant human technologies. Different sources may have varying efficacy and potential for allergic reactions. Recombinant human hyaluronidase is increasingly preferred due to its reduced risk of immunogenicity.
• Duration of Activity: The pharmacokinetics of hyaluronidase indicate that its enzymatic activity persists for several hours after injection. However, in biological tissues, its activity can decrease within 30 minutes, which requires timely intervention in clinical scenarios.
• Adverse Effects: Although generally well tolerated, the use of hyaluronidase may result in side effects such as temporary post-injection pruritus or allergic reactions. Careful patient selection and pre-treatment screening are essential to minimize these risks.

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Case Studies

Case 1: Endovascular hyaluronidase application through superselective angiography to rescue blindness caused by hyaluronic acid injection; Zhang et al., 2020

This study investigates a novel approach to treating blindness caused by hyaluronic acid (HA) filler embolization by direct delivery of hyaluronidase through endovascular cannulation. A multidisciplinary team treated four patients using microcatheters inserted from the femoral artery to the ophthalmic artery to dissolve the HA blockage. Angiography showed partial success in restoring blood flow in three patients, but only one experienced slight visual improvement. The procedure carried significant risks, including stroke in three patients. While the procedure helped reopen blocked vessels, its effectiveness in restoring vision was limited, and the associated risks warrant cautious use.

Figure 3. Pre- and posttreatment ocular fundus angiography of Patient I. (A) Fluorescein filling was delayed in a branch of the central retinal artery in FFA angiography before treatment (red arrow). (B) The choroidal perfusion was partly compromised in ICGA angiography before treatment (red arrow). (C) Fluorescein filling was improved in the embolized artery in FFA angiography 2 days after treatment (red arrow). (D) Partially compromised choroidal perfusion was improved in ICGA angiography 2 days after treatment (red arrow). FFA, fundus fluorescein angiography; ICGA, indocyanine green angiography. (Zhang et al., 2020)

Case 2: Application of pH and hyaluronidase dual-responsive mesoporous carbon nitride nano-drug delivery system for chemodynamic therapy and chemotherapy combination therapy of non-small cell lung cancer; Pei et al., 2024

Chemotherapy remains the mainstay of treatment for non-small cell lung cancer (NSCLC), but it faces limitations such as poor solubility, low targeting efficiency, and significant side effects. To address these issues, researchers developed a novel nano-drug delivery system—PCN-CuO-HA@AZD—that combines chemotherapy and chemodynamic therapy (CDT). This system uses mesoporous carbon nitride loaded with copper oxide and the chemotherapy drug osimertinib (AZD), and is surface-modified with hyaluronic acid (HA) to enable pH- and hyaluronidase-responsive drug release. Copper ions released from the system trigger CDT via the Fenton reaction, generating toxic hydroxyl radicals that induce tumor cell death. Both in vitro and in vivo studies demonstrated effective tumor targeting, potent anticancer activity and minimal systemic toxicity. This dual-action platform shows promising potential as a safer and more effective therapy for NSCLC.

Figure 4. Schematic illustration of synthesis and synergistic therapy of PCN-CuO-HA@AZD. (Pei et al., 2024)

In summary, the versatility of hyaluronidase extends far beyond its cosmetic applications. Its role in enhancing drug delivery, facilitating surgical procedures, managing complications, and aiding reproductive technologies underscores its importance in modern medicine. As research continues to uncover new therapeutic avenues, hyaluronidase remains a valuable tool across multiple medical disciplines.

If you are looking for high quality hyaluronidase for research, Creative Enzymes is here to provide you with reliable, expertly sourced enzyme products. Contact us today with your questions and inquiries.