What is Hyaluronidase?
Hyaluronidase is an enzyme that degrades hyaluronic acid in the extracellular matrix, thereby increasing tissue permeability and enhancing the diffusion and absorption of injected substances. 1
Mechanism of Action
Hyaluronidase hydrolyzes hyaluronic acid by splitting the glucosaminidic bond between C1 of an N-acetylglucosamine moiety and C4 of a glucuronic acid moiety, temporarily decreasing the viscosity of cellular cement and promoting dispersion of injected fluids or localized transudates. 2
The enzyme modifies the permeability of connective tissue through hydrolysis of hyaluronic acid, a polysaccharide found in the intercellular ground substance of connective tissue and specialized tissues such as the umbilical cord and vitreous humor. 2
Hyaluronidase cleaves glycosidic bonds of hyaluronic acid and, to a variable degree, some other acid mucopolysaccharides of the connective tissue. 2
Clinical Applications
Enhancement of Drug Absorption and Diffusion
Hyaluronidase is FDA-approved for hypodermoclysis, drug absorption enhancement, and subcutaneous urography. 3
When added to local anesthetics, hyaluronidase enhances diffusion of the anesthetic solution, improving the absorption of extravasated drugs. 1
The enzyme increases the bioavailability of injected drugs by acting as a "spreading factor" that decomplexes hyaluronic acid in the extracellular matrix. 4
Management of Chemotherapy Extravasation
For vinca alkaloid extravasations, hyaluronidase is recommended to prevent skin necrosis, with a dose of 1–6 mL of 150 U/mL solution injected through the existing i.v. line. 1
The usual dose is 1 mL of hyaluronidase solution for 1 mL of extravasated drug. 1
In animal models, local infiltration with hyaluronidase decreased ulcer rate by 50–60% and decreased ulcer size by up to 50% following extravasation. 1
A 1994 study of seven patients with accidental vinca alkaloid extravasation showed no skin necrosis after treatment with local hyaluronidase. 1
Dermatologic and Aesthetic Applications
In aesthetic medicine, hyaluronidase is considered the gold standard for managing hyaluronic acid filler-associated complications, used off-label to dissolve subcutaneous nodules or correct excessive quantities of injected filler. 4, 5
Hyaluronidase can be added to infiltration anesthesia in dermatologic surgery, though benefits remain unclear and no strong recommendations for or against its use can be made at this time. 1
Reports suggest mixing 7.2 IU of hyaluronidase with local anesthetic may minimize tissue distortion during infiltration and enhance ease of tissue undermining, though randomized trials are needed to support these observations. 1
Other Medical Applications
Hyaluronidase is beneficial for treating keloids, managing pain, enhancing distribution of chemotherapeutic agents within tumors, and reducing fibrosis in scleroderma, scleromyxedema, and chronic GVHD. 3
The enzyme is used to reduce synovial fluid viscosity in research settings, ensuring more homogenized synovial fluid before extracellular vesicle separation and characterization. 1
Hyaluronidase promotes resorption of excess fluids and extravasated blood in tissues and increases the effectiveness of local anesthesia. 6
Safety Considerations and Contraindications
Cross-reactivity between bee venom and hyaluronidase exists, and hyaluronidase should not be administered to patients with a history of bee sting allergy. 1
When allergy to hyaluronidase is in question, prick testing may be used for confirmation. 1
Aside from hypersensitivity reactions, adverse events caused by hyaluronidase are infrequent and the drug is considered safe. 1, 3
Repeated injections of relatively large amounts of hyaluronidase preparations may result in the formation of neutralizing antibodies, as hyaluronidase is antigenic. 2
Pharmacokinetics
Knowledge of the mechanisms involved in the disappearance of injected hyaluronidase is limited, though components in blood of mammalian species bring about the inactivation of hyaluronidase. 2
The reconstitution of the dermal barrier removed by intradermal injection of hyaluronidase indicates that at 24 hours restoration is incomplete and inversely related to dosage; at 48 hours, the barrier is completely restored in all treated areas. 2
In the absence of hyaluronidase, material injected subcutaneously disperses very slowly, with the rate and extent of dispersion proportionate to the amount of hyaluronidase and volume of solution. 2