Hyaluronidase — what it can reverse and what it cannot

Every hyaluronidase preparation used in Korea comes in a 1,500 IU presentation. In July 2024 a recombinant product received its first Korean marketing approval, so animal-derived and recombinant are now both options here.

“Dissolving filler” is not among the approved indications. The wording on the Korean label is two things — “increased penetration on subcutaneous or intramuscular injection, with local anaesthetics and on subcutaneous infusion” and “promoting the reabsorption of fluid and blood present in excess within tissue”. Dissolving filler is not in there. Every aesthetic use is therefore outside the label (off-label). The same is true in the UK · the US · the EU. A UK consensus guideline states explicitly that this fact should be disclosed to the patient as part of the consent process; we did not find an equivalent explicit guideline in Korea.

The dosage section of the Korean label is a single line — dissolve 1,500 IU in 1 mL of water for injection or normal saline. Every per-area · per-situation dose we look at below is a number generated outside that label.

The column that matters in this table is the right-hand one. Whether “it does not dissolve” rests on an actual experiment or on an inference from the mechanism differs from family to family.

Hyaluronidase cleaves only particular bonds in hyaluronic acid. So there is no reason for it to act on polycaprolactone · polylactic acid · polynucleotide · acellular dermal matrix. That inference is very likely to be correct. But we did not find literature that tested it directly, and so we have not written that it “has been confirmed by experiment”.

CaHA is the exception — there are failed experiments

For CaHA alone, “it does not dissolve” is not an inference. In an experiment in which CaHA was injected into cadaveric facial arteries and then soaked for 24 hours in sodium thiosulfate at three concentrations, and in combination with 300 IU of hyaluronidase, the CaHA remained inside the artery under every condition. The authors' own sentence runs like this — “Adverse events caused by intraarterial administration of CaHA-based fillers still lack a suitable antidote.”

In another preclinical study in pigs, no sign of degradation by sodium thiosulfate was observed either in vitro or in vivo, and the action was consistent with dispersing rather than degrading. On top of that, necrosis and haemorrhage appeared at the treated site, which the authors recorded as an obstacle to use. That said, there is a separate study reporting that “sodium thiosulfate dissolved CaHA”, so this part is still disputed.

The accurate statement is this. There is still room to try something on CaHA that has clumped within tissue, as in a nodule, but when a vessel is occluded there is currently no drug that works. So for the CaHA family, the accurate information for a patient is not “it does not dissolve” but “if it goes wrong, only time and physical measures are left”. For non-hyaluronic-acid preparations the alternatives the literature offers are intralesional steroid, 5-FU, incision · excision — all of which can leave a scar.

“It is hyaluronic acid, so it dissolves” is correct as far as it goes. But how fast, and how much you need, differs greatly from product to product. There is measured material in which 16 products were broken down to completion under identical conditions (37 degrees, the same amount of enzyme added every 5 minutes).

The authors' conclusion was that “the manufacturing technology, rather than whether the product is cross-linked, is the most important factor”. In fact there is separate measured material in which a stabilised non-cross-linked preparation was firmer than two cross-linked products and held out longer against the enzyme — elastic modulus 523 Pa against 376 Pa · 158 Pa, resistance time 39.2 minutes against 14.6 · 21.8 minutes.

So the conversion “5 units dissolves 0.1 mL of hyaluronic acid” is hard to use as it stands. It is the most widely cited number, and the source guideline itself attaches the caveat that “there is considerable variation in the literature”, but it collides head-on with the 12.5-fold difference the measurements above showed. One international consensus guideline declared outright that “no standard concentration or standard dose is described in the literature”.

One more thing — a “unit” is not equivalent between products. The products used in the overseas literature include some at 150 U per vial and some at 1,500 IU. Because a unit is defined by a potency assay and not by mass, you cannot carry “300 units” from an overseas paper straight across to a Korean 1,500 IU product.

For the same total amount, splitting the dose was faster. When the enzyme was put into the most resistant formulation five times at 5-minute intervals, 90% degradation took 26.2 minutes; when the same total amount went in all at once, it took 46.9 minutes — 43% shorter. With the animal-derived enzyme split into three doses, the degradation at 120 minutes was also ahead, 90.7% against 77.2%.

The mechanism has been worked out. The rate of degradation by the enzyme peaks within 5 minutes of administration and falls off afterwards, becoming negligible past 60 minutes. The authors attribute this to the enzyme gradually inactivating. In other words, a good part of the enzyme poured in all at once dies before it does any work. This is the only measured basis on which the question “why not dissolve it all in one go?” can be answered.

The clinical implication the authors stated was that “dividing into small doses to reduce the total amount can maintain the optimal degradation range while reducing side effects”. That said, this material is from laboratory conditions, and it has not yet been confirmed that the same proportional benefit appears in people.

“Hyaluronidase in large amounts” is a widely spread principle for when filler has occluded a vessel. But the paper that became the starting point for this principle is a case series summarising one author's two years of clinical experience, not a randomised controlled trial. The author himself wrote that “further research is needed to determine the optimal parameters”.

The systematic review and pilot meta-analysis (15 studies · 223 patients) that came afterwards came out like this.

This result does not let us say “a low dose is better”. It is not significant. But it does let us say “there is no evidence that a high dose is better either”. What is certain in this field right now is starting early, not putting in a lot.

Seeing the target on ultrasound cuts the dose sharply

In a meta-analysis pooling cases in which the occluded site was identified on ultrasound before injecting (4 studies · 55 people), complete recovery was 94.6%. Flooding the area broadly without looking was about 77.8%. The dose is the more striking part — the actual doses under ultrasound guidance cited by the same international guideline average 35–60 units, while the conventional approach the same document recommends is 1,500 units.

Divide the two figures and the gap is 25- to 43-fold. That is, the high-dose protocol may be another way of saying “we do not know where it is, so we soak everything”. That said, the ultrasound-guided material is still small at 4 studies and 55 people, and the authors themselves wrote that better-powered studies are needed.

Allergic reactions are reported in the range of 0.05–0.7%, and one international guideline puts it at about 0.1%. That figure lumps mild local reactions in with delayed reactions, and immediate anaphylaxis is far lower than that — in the aesthetic field, three case reports (four patients) are all that has been reported. This may of course be because of under-reporting.

The higher number turned out to be somewhere else. As one international guideline sets it out, the allergy rate for benzyl alcohol, the preservative in saline, is 1.3% — more than ten times higher than the enzyme itself (about 0.1%). That is, a good share of what has been reported so far as “hyaluronidase allergy” may have been a reaction to the preservative. What the drug is reconstituted with can govern the actual risk, and this point is barely discussed.

If you have ever had a severe reaction to a bee or wasp sting, please be sure to tell us. Bee venom also contains hyaluronidase, cross-reactivity is known, and international guidelines treat this history as a relative contraindication. Beyond that, taking an ACE inhibitor or a beta blocker, or having hereditary angioedema, also puts you in the risk group for a severe reaction.

There is material showing that about 5% of the general population carry antibodies that react to the recombinant enzyme, but no adverse events arising from this have been reported yet. Which of animal-derived and recombinant dissolves better has not been settled — the laboratory studies conflict with one another.

On this item it is not that the evidence is split — the guidelines collide head-on. We write it down as it is, without hiding it.

Actual practice is split too. In a survey of 264 injectors, 29% never did it · 25% always did · 38% did it sometimes depending on history, and interestingly the experts who sat on consensus panels did it less (sometimes, 20% against 65% of general injectors).

There is a point in Korea that is particularly ambiguous. The Korean label says it is “desirable”, while the most recent international consensus says it is “not valid”. And as we saw above, in Korea this procedure is already outside the label, so it is not even clear whether there is an obligation to follow the label wording as written. Still, if something goes wrong, the label wording remains. We do not hide this tension, and we take the approach of taking the history first and planning differently for people in the risk group.

People commonly say “dissolve, then re-inject two weeks later”. What that two weeks actually is gets blurred in almost every consultation.

It is not because enzyme is left over. As the international guidelines describe it, no activity remains by 48 hours, so cross-linked hyaluronic acid put in after that will not be dissolved. So what is the two weeks — it is the time you wait for the swelling to settle so that the result can be predicted. That is, it is a convention of observational convenience, not a pharmacokinetically required waiting time.

The interval before re-treating a nodule is a matter of divided practice too — in the same survey, 1–2 weeks was 56% and 24–48 hours was 34%. Two practices more than twice apart coexist without evidence. We tried to find the primary literature for this item but could not reach the original text, and so we do not present it as a “confirmed number”.

This is not settled either. The volume reduction is greatest in the first hour after administration and enzyme activity lasts about 6 hours, yet the widely used guideline says to assess at 48 hours. Meanwhile a formulation that has clumped into a single mass can take 24 hours to clear completely.

That “when do you assess” is unsettled is dangerous in practice. It leads to judging that it has not dissolved enough yet and continuing to add more. We take as our default not trying to finish it on the day, but leaving an interval and looking again — and as we saw above, splitting the dose was faster in the measurements too.

The one line this piece is meant to leave. The words “this can be reversed” apply only to the hyaluronic acid family, and even inside it what is required differs greatly by product. And when you choose a family that cannot be reversed, knowing that in advance should be part of designing the procedure. Not being reversible does not mean “permanent”; it means “if it goes wrong, only time and physical measures are left”.

Written and reviewed by Lee Chi-Hak, MD, medical director of Miso Clinic in Daegu, South Korea. Every study cited above is given together with its design, its size and the limitations the authors themselves recorded, and where we could not find data, we have said that we could not find any.