What is "Hyaluronidase," which dissolves hyaluronic acid? Effects, risks, and costs

1. What is Hyaluronidase

In cosmetic and reconstructive medicine,Hyaluronic acidNon-surgical injection therapy (filler injection) using hyaluronic acid (HA) has become extremely popular due to its short downtime and minimally invasive nature. One of the greatest reasons why hyaluronic acid fillers are chosen as the first-line filler worldwide is the existence of hyaluronidase, a "reversal agent (antagonist/dissolving agent)." Hyaluronidase is an enzyme with the ability to break down hyaluronic acid, and it functions as an essential safety measure to dissolve injected hyaluronic acid and return it to its original state in the event of complications after filler injection.

Hyaluronic acid itself is a glycosaminoglycan that naturally exists in the human body, and hypersensitivity reactions from modern hyaluronic acid fillers are said to be extremely rare. However, no matter how safe a substance is, as long as it is a medical procedure, there is no zero risk of complications or unsatisfactory results. In such cases, the characteristic of being able to rapidly dissolve fillers by using hyaluronidase is a decisive advantage that other fillers do not have. In fact, other semi-permanent fillers such as calcium hydroxyapatite (CaHA) do not have a dedicated dissolving agent like hyaluronidase. A group of experts including Kurkjian noted that the absence of an agent equivalent to hyaluronidase to correct failures and unsatisfactory results is a reason for avoiding injectionNose augmentationWe do not recommend the use of calcium hydroxyapatite in this area. In this way, hyaluronidase is not merely a corrective agent, but is positioned as one of the most important elements ensuring the overall safety of procedures using hyaluronic acid fillers.

2. Cases where dissolution is necessary

Cases requiring dissolution of injected filler using hyaluronidase range from minor aesthetic concerns to serious complications requiring urgent intervention. The main indications are as follows.

Overfilling (overcorrection) and misplacement

When excessive filler volume has been injected or filler is accidentally placed in unintended tissue planes or locations, hyaluronidase can be used to break down excess hyaluronic acid. It is also used to correct contour irregularities or mild surface imperfections (imperfections) that develop after treatment.

Formation of nodules and granulomas

After hyaluronic acid filler injection, nodules or granulomas may form in a delayed manner. For these complications, hyaluronidase injection to dissolve hyaluronic acid is recommended alongside other treatment options such as local steroid injection or surgical excision.

Dispersal and dissolution of special filler materials

Hyaluronidase may be used for fillers other than pure hyaluronic acid fillers. For example, Algeness, which has agarose gel as its main component (ArgianesArgianes, a 100% natural biodegradable filler, can in exceptional circumstances promote gel dispersion by injecting hyaluronidase along with warm saline or 250–500 mg/mL vitamin C solution (Karapantzou 2020). Furthermore, in treatment procedures for certain microparticle fillers (such as formulations containing non-crosslinked hyaluronic acid), it has been demonstrated that hyaluronidase can be administered additionally if complications occur.

Vascular occlusion (most severe case)

"Vascular occlusion," where filler is accidentally injected into an artery or blood flow is obstructed by compression from surrounding tissue, is the case most urgently requiring hyaluronidase. Because vascular occlusion can result in irreversible consequences such as skin necrosis or blindness, immediate dissolution with hyaluronidase is essential. (This is detailed in the section "5. Emergency use".)

3. Effects and time required

The greatest characteristic of hyaluronidase is the rapidity of its therapeutic effect.

Dissolution speed and time limit

Once injected, hyaluronidase rapidly breaks down hyaluronic acid. Particularly regarding the prevention of skin necrosis due to vascular occlusion, the passage of time affects the outcome. According to data from animal studies, subcutaneous injection of hyaluronidase within 4 hours of vascular occlusion occurrence has been demonstrated to reversibly prevent potential skin necrosis (DeVictor 2021). Thus, to maximize the effects of hyaluronidase, early detection of signs of complications and immediate administration are required.

Standards regarding dosage and frequency of administration

Currently, there is no medically fully established consensus regarding the "optimal dosage" or "frequency of administration" of hyaluronidase as a reversal agent for hyaluronic acid. However, certain effective guidelines have been indicated through multiple clinical studies and expert guidelines.

• Hyaluronidase can be used at any time during the duration of filler persistence, and multiple injections can be performed as needed.
• In a retrospective study of 5,000 non-surgical rhinoplasty procedures by Harb and Brewster, immediate injection of 1,500 IU of hyaluronidase dissolved in 1 ml of normal saline at the injection site and areas showing skin changes in patients exhibiting signs of ischemia resulted in complete recovery without sequelae such as necrosis. In this study, no patients required re-administration of hyaluronidase (multiple treatments) (Harb 2020).
• In severe cases such as vascular occlusion, administration of "high-dose" hyaluronidase without hesitation is recommended as a management protocol.

4. Risks and side effects

In the provided sources, detailed descriptions of direct adverse effects (such as allergic reactions) caused by hyaluronidase itself are not included; however, strict warnings are issued regarding risks surrounding the use of hyaluronidase and risks when use is delayed.

Lack of consensus on optimal dosage

As mentioned previously, the lack of clear consensus regarding the optimal dosage and frequency of hyaluronidase becomes a risk for medical professionals. If the dosage is insufficient, hyaluronic acid may not be completely dissolved and vascular occlusion may progress; conversely, unnecessary overdosage may trigger unexpected tissue reactions. Therefore, medical professionals must confirm guidelines in their respective countries and approved indications in advance, and use the substance carefully based on their own clinical judgment.

Risks when hyaluronidase is not used (or use is delayed)

The risks when appropriate treatment is not performed in situations where hyaluronidase should be used are extremely serious. Injection of hyaluronic acid filler can cause early complications such as erythema, edema, ecchymosis, nodule formation, and infection, as well as late complications such as granuloma formation, filler migration, and delayed-type hypersensitivity. However, the most frightening is vascular occlusion, and if overlooked and left untreated without hyaluronidase administration, it causes skin necrosis or irreversible blindness due to retinal artery occlusion or embolism (DeVictor 2021) (Williams 2020).

Some physicians attempt to prevent accidental intravascular injection through "aspiration" of the syringe before injection; however, in animal model experiments, the reliability of the aspiration test is only approximately 53%, and the absence of blood backflow in the syringe does not completely exclude the possibility of intravascular injection (Trevidic 2022). Therefore, injecting hyaluronic acid filler without having hyaluronidase prepared on hand is itself an act that exposes patients to serious risk.

5. Emergency use (vascular occlusion)

The most critical situation demanding emergency use of hyaluronidase is "Vascular Occlusion (Vascular Compromise)." Vascular occlusion is caused by embolism from filler being directly injected into an artery, or by external vascular compression due to excessive injection volume or edema.

Incidence of vascular occlusion

A systematic review by DeVictor et al. of 8,604 patients reported transient vascular occlusion in 30 cases (0.35%), skin necrosis in 7 cases (0.08%), and vision loss in 8 cases (0.09%) (DeVictor 2021). Additionally, Williams et al.'s review identified 65 vascular complications following filler injection to the nose, of which 30 cases involved nasal skin necrosis and 33 cases were associated with visual and ophthalmologic symptoms including retinal artery occlusion and blindness (Williams 2020). While these are extremely rare events, the consequences are devastating when they occur, making immediate intervention with hyaluronidase essential.

Symptoms and early detection of vascular occlusion

Symptoms suggesting vascular occlusion include skin blanching, mottling discoloration, severe localized pain, eye or tooth pain, visual abnormalities, and headache (Harb 2020). If any of these symptoms appear, injection must be stopped immediately and management to prevent ischemia must take priority.

Specific management protocol for vascular occlusion

When vascular occlusion due to hyaluronic acid is suspected, the following protocol is recommended.

• Administration of high-dose hyaluronidase: High-dose hyaluronidase is immediately infiltrated into the affected area and surrounding tissue.
• Warm compresses and massage: To promote blood flow, the local area is warmed and massaged vigorously (Harb 2020).
• Use of vasodilators: Vasodilators such as nitroglycerin paste are applied to improve blood flow.
• Hyperbaric oxygen therapy: If ischemic symptoms progress, hyperbaric oxygen therapy is also considered.

Clinical success cases from emergency administration

Literature reports numerous success cases in which rapid emergency administration of hyaluronidase prevented serious sequelae.

• In Harb et al.'s report, of 5,000 treatments, 24 patients (0.48%) showed immediate signs of vascular compromise. When hyaluronidase was immediately infiltrated in 10 of these patients, all achieved complete recovery with no cases progressing to necrosis. In another case, gray discoloration of the nasal tip and epidermal sloughing occurred 2 days after treatment, but rapid recovery was achieved through treatment with hyaluronidase and oral antibiotics (Harb 2020).
• Sun et al.'s research reported 15 cases at risk of skin necrosis followinghyaluronic acid injectionto the nose. Hyaluronidase was used in 13 of these cases, and in 11 patients, progression of nasal skin necrosis was effectively prevented (Williams 2020).
• Regarding visual complications, there are reports of 2 cases in which hyaluronidase was used and both achieved complete recovery of visual symptoms (Williams 2020).

This clinical data strongly suggests that early local hyaluronidase administration is an extremely effective treatment for vascular complications from hyaluronic acid. Particularly since injection to the nasal dorsum is a high-risk area with relatively high embolism event rates, hyaluronidase must always be prepared within reach during procedures and kept immediately accessible (Trevidic 2022).

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6. Summary

Hyaluronidase is an extremely important medication that fundamentally underpins safety in non-surgical aesthetic medicine using hyaluronic acid fillers. While hyaluronic acid filler itself is an excellent filling agent with predictable effects and high safety, it inherently carries the risk of a rare yet devastating complication—vascular occlusion. The very fact that hyaluronidase exists and can rapidly dissolve filler in an emergency is the primary reason why hyaluronic acid is widely supported as a safe option (the safest filler) compared to other filler agents such as calcium hydroxyapatite.

When symptoms of vascular occlusion (skin blanching, severe pain, visual abnormalities, etc.) occur, there is no room for delay. Numerous clinical cases have demonstrated that prompt and appropriate administration of high-dose hyaluronidase prevents irreversible outcomes such as skin necrosis and blindness, leading to complete patient recovery (Harb 2020) (Williams 2020).

However, hyaluronidase is ultimately a "last safety net" and should not be relied upon excessively. To prevent complications, it is a prerequisite that the physician has deep knowledge of the complex vascular anatomy of the face and nose. Furthermore, strict adherence to safe injection techniques is required—targeting deep layers such as the periosteum or perichondrium, maintaining the midline, and injecting small amounts of filler (0.1 ml or less per injection) slowly at low pressure (Trevidic 2022). Only when both hyaluronidase availability and advanced anatomical knowledge and injection technique are in place can safe and reproducible aesthetic medical care be provided to patients.

Author of this article

Hiromitsu NakamuraPhysician

Zetith Beauty Clinic Ginza, Osaka, Fukuoka

With a track record of research presentations at domestic and international conferences, he is involved in technical instruction and education across Zetith Beauty Clinic. He specializes in precise aesthetic medicine based on anatomical evidence and pursues natural results tailored to each individual's skeletal structure and tissue.