With the increasing use of hyaluronic acid (HA) dermal fillers in the non-surgical aesthetic industry,1 we inevitably will come across more and more patients that require filler removal.
This is either due to incorrect placement, poor results, lumps and bumps or simply through changes in aesthetic trends. Removal due to trends and more complications in general are certainly what I am seeing in my practice.
In this article, I will discuss the use of hyaluronidase, what happens physically and anatomically when HA is dissolved, considerations around when to re-treat and best practice guidance. It’s important to note that emergency reversal is not covered and is outside the scope of this article.
What is hyaluronidase?
Hyaluronidases are a family of enzymes widely used as off-label drugs by aesthetic practitioners to prevent complications such as necrosis, treat nodules and remove unwanted or overcorrected HA. They are also naturally occurring enzymes found in the human body. 2
Hyaluronidases have been used widely in medicine for a number of years as a diffusing agent.2 Some examples of its use have been in treatment of vitreous haemorrhage, prevention of tissue damage in extravasation of substances and in fertility treatments to remove the cumulus-corona-oocyte complex formed during intracytoplasmic sperm injection.2 Hyaluronidase is derived from ovine/bovine testicles, recombinant human hyaluronidase, leech/hook worm or microbial.2
In the UK, we have access to Hyalase, a 1500 unit ampoule of freeze-dried powder for reconstitution which is of ovine origin.3 It is reported that those with an allergy to bee stings (or other stinging insects) would also be highly likely to be allergic to this form of hyaluronidase due to some cross allergenicity with the hyaluronidase in bee venom.4,5,6
Other brands of hyaluronidase include Vitrase and Hylenex however, for the purpose of this article, I will focus on Hyalase due to having most experience using this particular product.
Recombinant human hyaluronidase (Hylenex for example) has a purity 100 times higher than other formulations and is a non-foreign protein, so is proven through a number of multiple clinical studies to have a lower incidence of allergic reactions.4,7
How does it work?
Hyaluronidase acts by hydrolysing HA in tissues, increasing cell membrane permeability, reducing viscosity and leaving tissues more pervious to injected fluids.8 The effects of hyaluronidase on skin tissue is very poorly studied at present with very little literature on it.
Often patients ask me if using hyaluronidase can impact their natural collagen. According to a study by Cavallini et al., which tested human fibroblast and human skin cultures in a lab setting, hyaluronidases did not affect fibroblast proliferation or human skin viability at low dosages of around 14 units.9 Buhren et al., also suggest in their in vitro experimental data that any degradation of the human body’s own HA by injection of hyaluronidase will be immediately replaced by de novosynthesis of HA in fibroblasts.10 Large dose studies are yet to be conducted.
A consensus opinion in the literature review conducted by King et al.,4 on behalf of the Aesthetic Complications Expert (ACE) Group, states five units of Hyalase is needed to break down 0.1ml of 20mg/ml HA. The group has also broken this down by providing guidelines on hyaluronidase units per region (Figure 1) which in my opinion isn’t clear given that each practitioner and every face is unique, therefore require different quantities of filler.
We should note that there aren’t any recommendations for the lips specifically.4 However, the ACE Group states that in the event of a suspected vascular obstruction, a high-dose protocol, between 450-1,500 units, should be adopted.4
In my practice, I often dissolve and correct poor lip filler treatment and superficially-placed tear trough filler.
While I am not aware of recommendations for dosages in the lips, I personally find that there is a need for higher doses than the recommended amounts for other areas for a number of reasons:
- Most patients have had numerous previous treatments in this area
- Practitioners, in my opinion, tend to select a higher viscosity and cross-linked product and so it can be more difficult to breakdown11
- I personally find intramuscular deposits of filler are harder to remove due to spreadability from muscle movement
- To avoid the need to repeat hyaluronidase treatment and reduce allergen potential
Case Study 1
This 29-year-old patient had HA dermal filler injected in her lips by another practitioner. She felt that after a few months the filler appeared to have been placed incorrectly giving her a ‘duck lip’, had migrated and that the upper lip was too projected and stiff. The patient wanted to dissolve the old filler and start fresh with my own technique.
The first stage was to dissolve. I used 350 units of Hyalase 1,500 ampoule which brought the lips back to their near original state. Some filler remained in her lower lip but it wasn’t unsightly and so I decided not to dissolve any further.
The patient returned two weeks later and I re-filled with 1ml of HA dermal filler in both her upper and lower lip using a combination of needle and cannula. I generally try to leave it two weeks (a week longer than necessary) to allow for any side effects such as bruising and swelling to have completely resolved before re-treating. I usually advise patients to take an antihistamine for any swelling and avoid heavy exercise for one to two days, by which time most of the swelling has resolved.
Typically if a patient has had more than 1ml (which is more than likely for the lips), I use around 200-500 units, sometimes more, to remove an entire lip in one or two sittings. I make this decision based on the above listed reasons but after carrying out a full, in-depth consultation. It’s important to note that one size does not fit all and dosage is patient dependent. In tear troughs, it is usually the complete opposite.
I find very low doses are more than adequate to remove filler and largely due to the opposite reasons of the first three listed. In my experience, I inject 10-20 units on average. I like to use small fine 0.3ml micro-syringes with pre-attached needles to allow for better precision in the tear trough.
Re-treating a patient
When injected, hyaluronidase has an immediate working effect on HA in tissue. It is known to have a half-life of around two minutes, however, its duration of action is longer at around 48 hours.4,7
It is thought the reasons behind this are:
- Low number of units required to have a clinically significant effect and so its action continues despite degradation
- Initial breakdown of HA crosslinking leaves free HA in the skin, which is known to have a half-life of 24-48 hours4
A small study on murine conducted by Kim HJ et al., concluded that six hours after reinjection of a monophasic filler following hyaluronidase, the filler materials restored almost its original volume and there were no significant differences from the positive control.12
Considering the above and evidence of free HA in the skin post hyaluronidase, I would support re-treatment no earlier than 48 hours to avoid breakdown of any consecutive re-treatment with HA filler. I personally only re-treat after two weeks to allow for any bruising and swelling to have completely resolved.
There may also be an argument for patch testing for hyaluronidase before a patient has filler for the first time. This is particularly important, in my opinion, due to the lack of available human hyaluronidase in the UK market at present and the rise in patients having filler removed.13
Case Study 2
This 34-year-old patient had undergone numerous treatments prior to presenting in my clinic; however, the original anatomy wasn’t respected by the treating practitioner. Upon clinical examination, I observed that too much filler had been placed in the border of the lip.
After repeated treatment, this had migrated into the orbicularis muscle. Overall, the lip was highly volumous and, in my opinion, looked distorted. She reached out to me to try and improve the size and overall shape.
I dissolved the filler using 1,000 units of hyaluronidase after knowing the patient’s previous history and products used. Following treatment there was still some filler remaining in the lower lip.
As it was still in the correct tissue plane and the patient preferred volume in the lips, I decided to leave it there. We refilled after two weeks with the aim of providing good volume, however respecting the natural anatomy and keeping in line with her lip borders. In total, 1.5ml of dermal filler was used to create this.
Case Study 3
This 40-year-old patient had her tear troughs injected some months prior by an inexperienced practitioner who unfortunately placed most of the filler superficially, creating pooling and a Tyndall effect (blue appearance).
She asked for her existing filler to be dissolved and for a re-treatment to help improve the hollows under her eyes. After the usual patch testing I placed 15 units per trough superficially using a 0.3ml micro-syringe with a pre-attached needle and massaged for 60 seconds to help with spread.
This helped to dissolve the filler, restoring the area to the original state. I re-treated two weeks later to allow for any side effects to settle with a low-density HA filler, placing it deeper to help avoid the problem repeating again.
It is important to be aware of the consideration associated with not only dissolving filler but re-treating too. If re-treated too soon after dissolution, you may also dissolve the new filler placed, which may require further treatment and dissatisfaction, as well as increased cost, for the patient.
As well as this, one of the key considerations is that sometimes we are unaware of what filler was used or how much for that matter, making it difficult to determine effective dosing. In this case I would advise to always over-dose, for the reasons explained above.
Before proceeding to treat with hyaluronidase it is safe and expected practice that a patch test is performed, unless in an emergency situation, according to the ACE Group.14 This is usually with eight to 20 units of hyaluronidase injected intradermally on the patient’s forearm and observe.14
A positive reaction consists of a wheal with pseudopods (arm-like projections) appearing within five minutes and persisting for 20 to 30 minutes, accompanied by localised itching. Transient vasodilation (i.e. erythema) at the site of the test is not generally regarded as a positive reaction.4 Note also that false negative patch tests do occur so I would advise that you make sure your clinic is fully equipped with anaphylaxis kits.
As our industry expands it is just as important for practitioners to maintain good knowledge about how to reverse and correct treatments as well as performing them in the first place.
Although literature around this topic is limited, it seems promising that there is no indication so far of long-term damage to skin or fibroblast activity. Of course more research surrounding this is necessary.
I would recommend that practitioners always patch test and aren’t afraid to help patients achieve their desired aesthetic outcome through dissolution of HA dermal filler and re-treatment. As always, ensure that a full medical history is taken and you are competent and experienced in the specific indication.
- LaingBuisson, The UK cosmetic surgery market, October 2018 <https://www.laingbuissonevents.com/wp-content/uploads/2018/10/Liz-Heath.pdf>
- Cavallini M, Gazzola R et al., The Role of Hyaluronidase in the Treatment of Complications From Hyaluronic Acid Dermal Fillers, Aesthetic surgery journal, 2013
- Medsafe.govt.nz, Product Summary, Hyalase <https://medsafe.govt.nz/Profs/Datasheet/h/Hyalaseinj.pdf>
- King M, Convery C, Davies E, This month’s guideline: The use of Hyaluronidase in Aesthetic Practice, Journal of Clinical and Aesthetic Dermatology, June 2018 <https://europepmc.org/articles/pmc6011868>
- Ewan P, Venom allergy, British Medical Journal, May 1998 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1113072/>
- Bailey S, Cohen J et al., Etiology, Prevention and Treatment of Dermal Filler Complications, Aesthetic Surgery Journal, January 2011 <https://academic.oup.com/asj/article/31/1/110/273423>
- ScienceDirect, Recombinant Hyaluronidase < https://www.sciencedirect.com/topics/neuroscience/recombinant-hyaluronidase>
- Girish K, The magic glue hyaluronan and eraser hyaluronidase: A biological overview, Life Sciences, May 2007 <https://www.sciencedirect.com/science/article/pii/S002432050700210X#aep-section-id29>
- Cavallini M, Antonioli B et al., Hyaluronidases for treating complications by hyaluronic acid dermal fillers: evaluation of the effects on cell cultures and human skin, European journal of plastic surgery, August 2013
- Buhren B, Schrumpf et al.,Hyaluronidase: from clinic application to molecular and cellular mechanisms, European Journal of Medical Research, February 2016
- Funt D, Pavicic T, Dermal fillers in aesthetics: an overview of adverse events and treatment approaches, Clinical, Cosmetic and Investigational Dermatology, December 2013 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865975/>
- Kim H, Kwon S et al., The duration of hyaluronidase and optimal timing of hyaluronic acid (HA) filler reinjection after hyaluronidase injection, Journal of Cosmetic Laser Therapy, February 2018
- Cherrington R, Lip Filler Removal Guide: From How Hyaluronidase Works to Picking A Safe Practitioner, Huffington Post, January 2017
- ACE Group, The Use of Hyaluronidase in Aesthetic Practice, February 2014 <http://acegroup.online/wp-content/uploads/2016/01/ACE-Group-Hyaluronidase-v1.2.pdf>