Durability, Behavior, and Tolerability of 5

Hyaluronidase Products
Gabriela Casabona, MD,* Paula Barreto Marchese, MD,† José Raúl Montes, MD,‡ and
Carl S. Hornfeldt, PhDx

BACKGROUND Hyaluronic acid (HA) dermal fillers are commonly used in cosmetic dermatology. Due to
differences in their physical characteristics, HA fillers demonstrate different sensitivity to degradation by
hyaluronidase because of HA concentration and differences in cross-linking. Similarly, there are differences in
the activity of hyaluronidase products depending on source and concentration.

OBJECTIVE The primary objective was to demonstrate the differences in potency and activity of 5 hyal-
uronidase products when used to degrade 5 different HA products using a human in vivo model.

MATERIALS AND METHODS The study subject was a healthy, consenting adult woman scheduled to
undergo abdominoplasty. Skin to be excised was injected with 0.1 to 0.2 mL of each filler (10 injections each)
leaving a visible lump. Immediately afterward, the HA lumps were injected with 4 IU of each hyaluronidase
product every 2 minutes until the HA lumps were no longer visible or palpable. This procedure was repeated
after 30 days. Injected tissues were excised after abdominoplasty for histological analysis.

RESULTS The 5 hyaluronidase products displayed a wide range of doses and times required to completely
degrade the 5 HA products ranging from <2 to >16 minutes.

CONCLUSION Cosmetic practitioners should familiarize themselves with differences in HA and hyaluroni-
dase products.

Supported by Allergan Produtos Farmacêuticos LTDA, São Paulo-SP, Brazil. The authors have indicated no
significant interest with commercial supporters.

T he number of cosmetic procedures performed in

the United States each year continues to grow.
The top 2 minimally invasive procedures in 2016 were
botulinum toxin Type A (6.7 million) and soft-tissue
fillers (2.4 million).1 Among dermal fillers, the use of
hyaluronic acid (HA) products exceeds that of all
others combined, with more than 1.9 million
procedures performed.1 Also known as hyaluronan,
HA is a versatile filler that provides tissue volume
augmentation for deep wrinkle correction, lip
augmentation, and to improve the appearance of
nasolabial folds, marionette lines, glabellar creases,
and tear trough deformities.2,3 Hyaluronic acid can
also restore volume to local areas such as the cheeks
and temples.4 The versatility of HA filler products is
due to their physical properties such as concentration,
particle size, cross-linking, and the type of cross-linker
used.2 Based on these properties, HA products
demonstrate different physical characteristics such as
elasticity, firmness, viscosity, and persistence.5–8
Although generally safe, a variety of adverse events
can occur during and after the injection of hyaluroni-
dase.9–12 Transient local effects include erythema,
edema, bruising, and pain,11 which generally respond
to symptomatic care. Delayed inflammatory response
consisting of granulomatous reactions occasionally
occurs in some patients.13,14 Hyaluronic acid filler
complications include misplaced injections13 or over-
correction,15 undesirable aesthetic outcomes,16 and

*
Scientific Department, Ocean Clinic, Marbella, Spain; †Clinical and Surgical Dermatology, Sao Paulo, Brazil; ‡Torre
Medica Auxilio Mutuo, San Juan, Puerto Rico; xApothekon, Inc., St. Paul, Minnesota

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
· ·
ISSN: 1076-0512 Dermatol Surg 2018;00:1–9 DOI: 10.1097/DSS.0000000000001562

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 HYALURONIDASE PROPERTIES

TABLE 1. Hyaluronic Acid Filler Products

Product Characteristics Technology

37
Juvéderm Volbella XC Cross-linked hyaluronic acid, 15 mg/mL Vycross
Juvéderm Voluma XC38 Cross-linked hyaluronic acid, 20 mg/mL Vycross
Juvéderm Ultra Plus39 Cross-linked hyaluronic acid, 24 mg/mL Hylacross
Belotero Volume40 Cross-linked hyaluronic acid, 25.5 mg/mL Cohesive Polydensified Matrix (CPM)
Belotero Balance41 Cross-linked hyaluronic acid, 22.5 mg/mL Cohesive Polydensified Matrix (CPM)

the Tyndall effect.17,18 Although rare, vascular occlu-
sion can cause tissue necrosis19 and blindness.20
Hyaluronidase is a naturally occurring enzyme that
degrades HA. The US Food and Drug Administration
has approved several hyaluronidase products that are
used to hydrolyze HA to increase the absorption,
dispersion, and resorption of subcutaneously admin-
istered fluids and drugs. Other hyaluronidase products
are available in other countries. Hyaluronidase is often
used off-label for applications in aesthetic dermatol-
ogy such as treating the undesirable effects of HA
described above,21,22 including misplaced injections,13
overcorrection,15,23,24 unexpected outcomes,16 the
Tyndall effect,14,17 granulomas and inflammatory
reactions,25,26 and vascular occlusion.19,27,28
Owing to differences in the physical characteristics of
different HA products described above,2,5 available
HA fillers demonstrate different sensitivity to degra-
dation by hyaluronidase.29,30 Similar to HA products,
there are also differences in enzyme activity among
various hyaluronidase products depending on source
(ovine vs. bovine vs. human recombinant) and
concentration.29,31,32
The primary objective of the following study was to
evaluate the differences in potency in terms of required
units and activity of 5 hyaluronidase products used
worldwide, when used to degrade 5 different HA
products having different concentrations, cross-
linking, and matrices using a human in vivo model.
Other objectives were to determine the dose of differ-
ent hyaluronidase products required to dissolve 0.1
mL of 2 different HA products used as volumizers
having different rheological properties and also to
determine any correlation between hyaluronidase
dose and degradation of endogenous HA in human
skin, and differences in hyaluronidase tolerability.
Methods
The 5 different HA products used in the study are listed
in Table 1. The 5 different hyaluronidase products
used in this study and their dilutions are listed in Table
2. This was done to standardize the dose as 0.4 IU of
hyaluronidase in each 0.025 mL of solution. The only
one that required a smaller volume of solution because
of its high concentration was Hyaluronidase 2000 at
0.4 IU per 0.01 mL. A healthy, consenting adult
woman scheduled to undergo abdominoplasty in 6
months was enrolled as the study subject.

TABLE 2. Hyaluronidase Products

Product Where Available Hyaluronidase, USP Dilution Dose

42
Vitrase USA, Canada 200 U/1.2 mL, ovine 5.0 mL* 4 IU/0.025 mL
Hylenex43 USA, Canada 150 U/1.0 mL, recomb. human 1.2 mL* 4 IU/0.025 mL
Hylase Dessau44 USA, Canada, and Europe 150 U/1 mL, bovine 1.0 mL NS 4 IU/0.025 mL
Hyaluronidase 200045 Brazil 2000 U/5.0 mL, bovine 1.0 mL NS 4 IU/0.01 mL
Reductonidase46 Europe 1500 U/10.0 mL, bovine 10.0 mL NS 4 IU/0.025 mL

Vitrase, ISTA Pharmaceuticals, Irvine, CA; Hylenex, Halozyme Therapeutics, San Diego, CA (marketed by Baxter Healthcare Corp.);
Hylase, Dessau, Riemer Pharma, GmbH, Berlin, Germany; Hyaluronidase 2000, Biometil Swiss, Sao Bento do Sul, SC, Brasil; and
Reductonidasa, Mesoestetic Pharma Group, Barcelona, Spain.
*Supplied with product.
NS, normal saline; USP, United States Pharmacopeia.

2 DERMATOLOGIC SURGERY

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 CASABONA ET AL

hyaluronidase product (Table 2) every 2 minutes. A

chronometer was used to measure the time until the
HA lump was no longer visible or palpable. The 2-
minute interval was used because this has been
reported to be the mean duration of hyaluronidase
activity.33 The hyaluronidase injections and time for
HA product dissolution were each performed by the
same investigators. This procedure was repeated after
30 days in another area reserved for this purpose.

Two days (48 hours) before abdominoplasty, 1 mL

Figure 1. Grids consisting of 10 squares for each of the 5
HA products were drawn on the skin to be later excised
during abdominoplasty. Each square was injected with 0.1
or 0.2 mL of HA filler (5 squares each) leaving a small
visible lump. HA, hyaluronic acid.
Grids consisting of 20 squares for each of the 5 HA
products were drawn on the skin to be later excised
(Table 1). These 1 cm2 squares were superficially
injected (retrograde injection with a 4-mm needle from
the subdermis to the dermis) using 0.1 or 0.2 mL of
a filler (10 squares each) into the intradermal and
subdermal layers per manufacturer recommendations,
leaving a small visible lump (Figure 1). Immediately
after injection, the 0.1 and 0.2 mL lumps of each
injected HA product were injected with 4 IU of each
volumes of 2 fillers (Belotero Volume and Juvéderm
Voluma) were injected in each of six 1 cm2 squares.
Immediately after injection, the 0.1 mL lump of each
injected HA product was injected with 0 (control),
50, 150, 300, 600, 1200, and 2000 IU of the same
hyaluronidase product (Vitrase). This range of
Vitrase doses is what would normally be used clin-
ically to correct misplaced HA injections. Other
injected tissues were excised following the abdom-
inoplasty procedure. The injected areas were
examined immediately after injection and again
after 24 and 48 hours for signs of local reactions.
The skin was then excised during abdominoplasty,
and a histological examination was performed to
determine the threshold dose for complete

TABLE 3. Dose of Hyaluronidase and Time to Hyaluronic Acid Filler Disappearance Immediately After
Filler Injection

Hyaluronidase
Reductonidasa Vitrase Hylenex Hylase 2000

Dose Dose Dose Dose Dose

Fillers and Dose (IU) Time (IU) Time (IU) Time (IU) Time (IU) Time
Juvederm Volbella 0.1 mL 16 4925$ 8 2944$ 12 0930$ 12 3909$ 12 4920$
Juvederm Volbella 0.2 mL 16 4938$ 8 2927$ 16 2930$ 16 6935$ 16 6912$
Juvederm Voluma 0.1 mL 16 4918$ 8 2927$ 20 16935 16 390$ 8 390$
$
Juvederm Voluma 0.2 mL 16 4929$ 8 2927$ 28 17920 16 390$ 8 390$
$
Juvederm Ultra Plus XC 0.1 4 2924$ 4 1916$ 08 0911$ 4 0905$ 4 0950$
mL
Juvederm Ultra Plus XC 0.2 8 2934$ 4 196$ 08 1943$ 8 2925$ 8 3940$
mL
Belotero Balance 0.1 mL 4 1911$ 4 0924$ 08 093$ 8 0960$ 4 0940$
Belotero Balance 0.2 mL 4 1924$ 4 1958$ 08 3945$ 8 0960$ 8 1930$
Belotero Volume 0.1 mL 16 2927$ 8 1956$ 16 2916$ 16 1940$ 16 9930$
Belotero Volume 0.2 mL 8 2952$ 8 1949$ 16 390$ 4 0960$ 20 1390$

00:00:MONTH 2018 3

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 HYALURONIDASE PROPERTIES

TABLE 4. Dose of Hyaluronidase and Time to Disappearance 35 Days After Filler Injection

Hyaluronidase
Reductonidasa Vitrase Hylenex Hylase 2000

Dose Dose Dose Dose Dose

Filler and Dose (IU) Time (IU) Time (IU) Time (IU) Time (IU) Time
Juvederm Volbella 0.1 mL 16 2906$ 8 193$ 16 394$ 16 890$ 12 5934$
Juvederm Volbella 02 mL 12 296$ 8 1956$ 16 493$ 20 894$ 12 6908$
Juvederm Voluma 0.1 mL 12 0934$ 8 0933$ 24 13923 4 0944$ 12 0919$
$
Juvederm Voluma 0.2 mL 12 1932$ 8 0933$ 24 1490$ 12 2945$ 16 6921$
Juvederm Ultra Plus XC 0.1 4 1927$ 4 192$ 20 1094$ 8 3956$ 4 093$
mL
Juvederm Ultra Plus XC 0.2 4 1927$ 4 190$ 20 1094$ 8 3956$ 4 093$
mL
Belotero Balance 0.1 mL 4 0916$ 4 0914$ 6 1090$ 4 0909$ 4 0908$
Belotero Balance 0.2 mL 4 0917$ 4 0914$ 6 0915$ 16 4927$ 4 0908$
Belotero Volume 0.1 mL 4 1907$ 4 0936$ 8 0938$ 4 194$ 4 2907$
Belotero Volume 0.2 mL 8 2956$ 4 0937$ 8 192$ 4 096$ 8 2928$

dissolution of 0.1 mL of Belotero Volume and Results

Juvéderm Voluma. Histology studies were per-
formed using hematoxylin and eosin and colloidal
iron staining. To further determine the response of
normal human HA to hyaluronidase, a pinch test
was performed on each injected area immediately
before and 1 day after treatment to determine
changes in resistance.
Hyaluronidase Activity, Day 1
The 5 hyaluronidase products displayed a wide range
of doses and times required to completely degrade the
5 HA products (Table 3). Vitrase was the fastest of 3
products (60%), and Hylenex was the fastest of 2
products (40%), although the differences in many

TABLE 5. Effect of Hyaluronidase Dose on Hyaluronic Acid Filler Degradation

Vitrase (IU) Eosinophils* Belotero Volume† Human HA

0 2 + Normal
50 + + Normal
150 + 2 Diminished
300 ++ 2 Diminished
600 +++ 2 Diminished
1200 ++++ 2 Diminished
2000 ++++ 2 Diminished

Vitrase (IU) Eosinophils Voluma Volume Human HA

150 + + Normal
300 ++ + Diminished
600 +++ 2 Diminished
1200 ++++ 2 Diminished
2000 ++++ 2 Diminished

*Classification, +/++++ based on eosinophil concentration.

†Classification, + product present, 2 product absent.
HA, hyaluronic acid.

4 DERMATOLOGIC SURGERY

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 CASABONA ET AL

Figure 2. 0.1 mL of Voluma was injected with 300 U of Vitrase (left) or 600 U of Vitrase (right). Blue stain indicates the
presence of hyaluronic acid.

cases were small. Belotero Balance 0.1 and 0.2 mL
were completely degraded by Reductonidasa 4 IU in
less than 2 minutes, and Juvederm Ultra Plus 0.1 and
0.2 mL were both completely dissolved by Vitrase 4 U
in less than 2 minutes. By contrast, Juvederm Voluma
0.1 and 0.2 mL required more than 16 minutes after
injection with Hylenex 20 and 28 U, respectively.
Volbella was more efficiently dissolved by Vitrase.
Hyaluronidase Activity, Day 30
Overall, times to HA degradation were generally
shorter 35 days after filler injection (Table 4). Belotero
Balance 0.1 and 0.2 mL was completely degraded in
less than 1 minute by 4 U of either Reductonidasa or
Vitrase. Juvederm Voluma 0.1 and 0.2 mL again
required the largest dose of Hylenex (24 U), requiring
more than 13 minutes to degrade the product.

Figure 3. 0.1 mL of Belotero Volume was injected with 50 U of Vitrase (left) or 150 U of Vitrase (right). Blue staining
indicates the presence of hyaluronic acid.

00:00:MONTH 2018 5

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 HYALURONIDASE PROPERTIES

Histology

Histology results revealed the 2 HA products treated with

hyaluronidase displayed dose-related increases in eosi-
nophils and required different doses to achieve total dis-
solution (Table 5, Figures 2 and 3). Clinically,
depressions in areas treated with more than 50 U of
hyaluronidase (Vitrase) could be observed and also noted
by the change in resistance to pinching. These changes
returned to normal in 48 hours (Figure 4). Unfortunately,
based on a qualitative comparison of biopsies (Figure 5),
no difference could be detected because the hematoxylin–
eosin and colloidal iron stains were not sensitive enough
to detect any changes in HA; however, hyaluronidase
produced dose-related decreases in HA because the pre-
and post-treatment pinch test of each injected area dem-
onstrated dose-related changes in tissue resistance.

Tolerability

Bovine-derived hyaluronidase (Reductonidasa and

Figure 4. After 24 hours, there was a slight depression in
areas treated with more than 50 U of hyaluronidase
(Vitrase, top), returning to normal after 48 hours
(bottom).
Hylase) produced severe erythema and burning
immediately after injection (Table 6). Mild erythema
persisted after 24 hours, and mild edema was also
observed. Hylase also caused moderate erythema
immediately after injection of which little remained

TABLE 6. Skin Reactions Immediately After Injection and After 24 Hours Following 20 IU of Injections

Immediately After Injection

Hyaluronidase Product Erythema Edema Burning Pruritus

Reductonidase ++++ 2 ++++ 2
Vitrase 2 2 2 2
Hylase +++ 2 2 2
Hylenex 2 2 2 2
Hyaluronidase 2000 +++ 2 +++ 2

24 Hours After Injection

Hyaluronidase Product Erythema Edema Burning Pruritus

Reductonidase ++ ++ 2 +
Vitrase + 2 2 2
Hylase + 2 2 2
Hylenex 2 2 2 2
Hyaluronidase 2000 + 2 2 2

Classification: 2 none/+ very little/++ mild/+++ moderate/++++ severe.

6 DERMATOLOGIC SURGERY

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Figure 5. Hyaluronidase produced dose-related decreases in normal skin hyaluronic acid that returned to normal levels in
48 hours.
after 24 hours. As hypothesized, the human recombi-
nant hyaluronidase did not produce any inflammatory
response (Table 5).
Discussion
Differences among HA-containing dermal filler gel
products include HA particle size, total HA concen-
tration, the extent of HA cross-linking, and the degree
of hydration, resulting in gels with different elasticity
and viscosity.5 These properties will affect the way
they behave in the skin including the amount of
structural support or lift they provide. In addition to
affecting the performance and durability of each
product, these factors will also affect their suscepti-
bility to degradation by hyaluronidase.30,34
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CASABONA ET AL
Few studies have assessed the stability of HA products
when exposed to hyaluronidase. One in vitro study
assessed the stability of HA products exposed to
hyaluronidase by measuring the formation or con-
centration of N-acetyl-D-glucosamine, one of the
components of the HA disaccharide units.35 The
results showed that the sensitivity of HA gels to
the effect of enzyme degradation decreased as a func-
tion of the extent of HA cross-linking. Another in vitro
study demonstrated degradation times for several HA
filler products increased with increasing HA molecular
weights.36
The study demonstrates that Voluma (Vycross) is not
an easily dissolvable product, probably requiring the
greatest concentration of hyaluronidase and longer
00:00:MONTH 2018 7
 HYALURONIDASE PROPERTIES
time for dissolution. Clinical implication suggesting
that injections should be conservative in the amount
injected at 1 setting. This suggests that small bolus not
larger than 0.2 mL should be applied. Juvederm Ultra
Plus (Hylacross) and Boletero Balance (Cohesive Pol-
ydensified Matrix) have comparable sensitivity to
hyaluronidase, but Belotero Volume is more durable
because it is a volumizer and has greater cross-linking.
The results of this study demonstrate the wide range in
sensitivity of HA products to the action of hyaluroni-
dase. Similarly, there is a wide range in enzyme activity
among hyaluronidase products. Overall, the ovine
hyaluronidase product Vitrase displayed the greatest
activity against the range of HA products. Dermatol-
ogists who routinely use these products should famil-
iarize themselves with their different characteristics.
These differences may avoid errors in treating HA-
related adverse events across various HA products
because there may be a 3-fold difference in the amount
of hyaluronidase required to degrade the same volume
of HA. Different hyaluronidase products demonstrate
different activity because the extent of cross-linking
and the molecular weight of HA of each product have
a significant effect on resistance to degradation.
A safety issue is the tolerability of hyaluronidase.
Vitrase proved to be the most potent and effective
hyaluronidase, but eosinophilic reactions may be
expected at doses greater than 150 IU. Dose higher
than 300 U may induce inflammation and eosinophil
recruitment, thereby increasing the risk of Type-1
hypersensitivity reactions such as urticaria and
angioedema.33 It would be prudent to observe at-risk
patients at risk of at least 2 hours after treatment with
hyaluronidase. Endogenous HA becomes diminished
at Vitrase doses greater than 300 IU.
Conclusion
Differences in HA particle size, total HA concentra-
tion, the extent of HA cross-linking, and the degree of
hydration result in HA dermal filler gel products with
different degrees of elasticity and viscosity. These
properties also determine the sensitivity of these
products to degradation by hyaluronidase. There are
also substantial differences in the activity of available
8 DERMATOLOGIC SURGERY
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hyaluronidase products. Dermatologists should
familiarize themselves with these product differences.
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Address correspondence and reprint requests to: Gabriela
Casabona, MD, Director of Scientific Department, Ocean
Clinic, Av Ramón y Cajal 7, 2nd floor, Marbella, Spain
29601, or e-mail: grcasabona@uol.com.br
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