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Paap et al. Plast Aesthet Res 2020;7:36 I http://dx.doi.org/10.20517/2347-9264.2020.121 Page 9 of 11

50 microliters of filler was combined with a fluorescent linker dye and exposed to 10 units (U/ml) of
hyaluronidase, with degradation measured by recorded changes in fluorescence intensity. This can be
[15]
contrasted with the work of Flynn et al. , who used a different experimental design (chromatography) but
the same ratio of hyaluronidase to filler (16 U per 0.08 mg) to show Belotero was more resistant to ovine
hyaluronidase than Juvéderm Ultra 3. When compared directly, these studies may suggest that Belotero is
more susceptible than Juvéderm to ovine hyaluronidase than bovine hyaluronidase.

[17]
However, Buhren et al. notably observed no effective degradation of Juvéderm Ultra 3 by bovine
[12]
hyaluronidase, even after 24 h. Sall et al. did observe degradation of Juvéderm Ultra 3 at a lower
concentration of bovine hyaluronidase than Burhen et al. Though Sall et al. did not study Belotero, this
difference in results with the same Juvéderm variety using the same enzyme suggests that the Burhen
experiment may have had some confounding feature either in measurement methodology or other
experimental factors such as pH or temperature. More studies are needed to clarify whether Belotero is less
responsive to bovine hyaluronidase than ovine hyaluronidase.

CONCLUSION
Overall, the literature suggests that different varieties of hyaluronidase and HA fillers vary in their
interactions. Factors associated with higher resistance to degradation include increased concentration
of HA, increased crosslinking, and monophasic formulation. Unsurprisingly, filler varieties that are
monophasic, highly concentrated, and exhibit a high density of crosslinking (such as Juvéderm Ultra
Plus) are less responsive to hyaluronidase and require a larger quantity of enzyme to achieve complete
dissolution.

Clinically, these differences should be considered when following established guidelines for the quantity
of hyaluronidase required for filler dissolution. This amount needed depends on the nature of the
complication. In cases of suboptimal injection placement or overcorrection, 5-10 U of hyaluronidase has
[36]
been cited as the appropriate dose . This recommendation is not specific to the volume of filler, which
must be considered. Additionally, this recommendation established using Restylane, may not be appropriate
for other fillers. In the treatment of ischemic complications as opposed to misplacement, higher doses
of hyaluronidase are required, with 5 units suggested per 0.1 mL of Restylane and 10 units per 0.1 mL of
[34]
Juvéderm . Thus, for any given 1 mL of filler injected, the suggested starting dose of hyaluronidase varies
from 5 to 100 U depending on the type and volume of filler injected and the nature of the complication.
The general principles of degradation susceptibility outlined above in conjunction with clinical context and
volume of filler injected should provide injectors with an estimated starting reversal dose.

In addition to presenting the accepted knowledge to date, this review highlights the information that
remains uncertain and in need of further investigation. While members of the Restylane family appear to
respond best to all varieties of hyaluronidase and members of the Juvéderm family appear to be the most
resistant, experimental results are less consistent for Belotero Balance. There are no clear trends established
across multiple studies to support the claim that any one type of hyaluronidase is better at dissolving a
specific variety of HA filler.

More research is needed to substantiate these results and explore individual efficacy. Such experiments
might include an in vitro study that examines all major HA fillers and all varieties of hyaluronidase under
uniform volumetric, temperature, and time exposure conditions. Once a preliminary set of individual
relationships between filler types and hyaluronidases is established, further studies in animals and human
subjects can determine whether these trends remain valid in vivo. In definitively establishing these
relationships, clarification of this issue will prepare injector clinicians to better address filler complications
that arise from the use of a given HA product.