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Hyaluronidase: An overview of its properties, applications, and side effects

DOI:10.5999/aps.2020.00752
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Hyunwook Jung at Inha University
Hyunwook Jung
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Abstract

Hyaluronidase, an enzyme that breaks down hyaluronic acid, has long been used to increase the absorption of drugs into tissue and to reduce tissue damage in cases of extravasation of a drug. With the increasing popularity of hyaluronic acid filler, hyaluronidase has become an essential drug for the correction of complications and unsatisfactory results after filler injection. For this reason, when performing procedures using hyaluronic acid filler, a sufficient knowledge of hyaluronidase is required. In order for hyaluronidase to dissolve a hyaluronic acid filler, it must interact with its binding sites within the hyaluronic acid. The reaction of a filler to hyaluronidase depends on the hyaluronic acid concentration, the number of crosslinks, and the form of the filler. Hyaluronidase is rapidly degraded and deactivated in the body. Therefore, in order to dissolve a hyaluronic acid filler, a sufficient amount of hyaluronidase must be injected close to the filler. If the filler is placed subcutaneously, injection of hyaluronidase into the filler itself may help, but if the filler is placed within a blood vessel, it is sufficient to inject hyaluronidase in the vicinity of the vessel, instead of into the filler itself. Allergic reactions are a common side effect of hyaluronidase. Most allergic reactions to hyaluronidase are local, but systemic reactions may occur in infrequent cases. Since most allergic responses to hyaluronidase are immediate hypersensitivity reactions, skin tests are recommended before use. However, some patients experience delayed allergic reactions, which skin tests may not predict.
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Review Article
Copyright © 2020 The Korean Society of Plastic and Reconstructive Surgeons
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/
licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
www.e-aps.org
297
INTRODUCTION
Hyaluronidase, which is an enzyme that breaks down hyaluronic
acid, has been used in medical applications for over 60 years.
The US Food and Drug Administration has approved hyaluron-
idase for the following indications: (1) subcutaneous fluid infu-
sion (hypodermoclysis), (2) as an adjuvant to accelerate the ab-
sorption and dispersion of drugs in subcutaneous tissue or to
manage extravasation, and (3) as an adjunct to promote the ab-
sorption of contrast media in urinary tract angiography (subcu-
taneous urography) [1]. In addition, it has been approved and
used for the purpose of increasing hematoma absorption in Eu-
rope [2]. Hyaluronidase has a variety of uses in addition to its
approved indications. Its current off-label uses include dissolving
hyaluronic acid fillers, treating granulomatous foreign body reac-
tions, and treating skin necrosis associated with filler injections.
Although the use of hyaluronidase for these off-label indications
has increased significantly, medical practitioners have few op-
Hyaluronidase: An overview of its properties,
applications, and side effects
Hyunwook Jung
Gangnam L Plastic Surgery Center, Sejong, Korea
Hyaluronidase, an enzyme that breaks down hyaluronic acid, has long been used to increase
the absorption of drugs into tissue and to reduce tissue damage in cases of extravasation of a
drug. With the increasing popularity of hyaluronic acid filler, hyaluronidase has become an
essential drug for the correction of complications and unsatisfactory results after filler injec-
tion. For this reason, when performing procedures using hyaluronic acid filler, a sufficient
knowledge of hyaluronidase is required. In order for hyaluronidase to dissolve a hyaluronic
acid filler, it must interact with its binding sites within the hyaluronic acid. The reaction of a
filler to hyaluronidase depends on the hyaluronic acid concentration, the number of crosslinks,
and the form of the filler. Hyaluronidase is rapidly degraded and deactivated in the body.
Therefore, in order to dissolve a hyaluronic acid filler, a sufficient amount of hyaluronidase
must be injected close to the filler. If the filler is placed subcutaneously, injection of hyal-
uronidase into the filler itself may help, but if the filler is placed within a blood vessel, it is
sufficient to inject hyaluronidase in the vicinity of the vessel, instead of into the filler itself.
Allergic reactions are a common side effect of hyaluronidase. Most allergic reactions to hyal-
uronidase are local, but systemic reactions may occur in infrequent cases. Since most allergic
responses to hyaluronidase are immediate hypersensitivity reactions, skin tests are recom-
mended before use. However, some patients experience delayed allergic reactions, which skin
tests may not predict.
Keywords Hyaluronidase / Hyaluronic acid / Filler
Correspondence: Hyunwook Jung
Gangnam L Plastic Surgery Center,
SaeromCity Building, 273 Hannuri-
daero, Sejong 30127, Korea
Tel: +82-44-863-1412
Fax: +82-44-864-1413
E-mail: hyunwookj83@gmail.com
This review article was prepared by the
Botulinum Toxin-Filler-Thread Academic
Association for the Korean Plastic &
Reconstructive Surgeon.
Received: April 21, 2020 • Revised: July 1, 2020 • Accepted: July 1, 2020
pISSN: 2234-6163 • eISSN: 2234-6171 • https://doi.org/10.5999/aps.2020.00752 • Arch Plast Surg 2020;47:297-300
Jung H Overview of hyaluronidase
298
portunities to study hyaluronidase. This article presents the
types and characteristics of hyaluronidase, and also introduces
research results that will be helpful for using hyaluronidase.
ACTION OF HYALURONIDASE
Hyaluronic acid is a glycosaminoglycan, a major component of
the extracellular matrix, and is also a component of fillers that
are frequently used for cosmetic purposes. As shown in Fig. 1,
which depicts the structure of hyaluronic acid, D-glucuronic
acid and D-N-acetylglucosamine are polymers composed of di-
saccharides linked by β-1,4 and β-1,3 glycosidic bonds. Hyal-
uronic acid fillers are made by cross-linking hyaluronic acid
molecules with a plasticizing agent such as 1,4-butanediol digly-
cidyl (BDDE) to stabilize and slow decomposition [3].
Hyaluronidase is an endoglycosidase that breaks down hyal-
uronic acid into monosaccharides by cleaving its glycosidic
bonds; additionally, to some extent, it also breaks down other
acid mucopolysaccharides in the connective tissue [4].
TYPES OF HYALURONIDASE
Human hyaluronidase is present both in organs (testis, spleen,
skin, eyes, liver, kidneys, uterus, and placenta) and in body fluids
(tears, blood, and semen) [5]. There are six known types (hyal-
uronidase 1–4, PH-20, and HYALP1). Hyaluronidase 1, which
is encoded by the HYAL1 gene, is present in major organs such
as the liver, kidney, spleen, and heart, as well as in serum and
urine. It acts as a major hyaluronidase in plasma and is activated
at an acidic pH. Hyaluronidase 2 exerts weaker enzymatic activ-
ity than hyaluronidase 1 and only breaks down high-molecular-
weight hyaluronic acid. Hyaluronidase 3 is found only in the
testis and bone marrow, and its role is unknown. Testicular PH-
20 hyaluronidase is found on the surface of human sperm and
inner acrosomal membrane and serves to degrade hyaluronic
acid in the ovum during fertilization [6].
Meyer classified hyaluronidases into three categories accord-
ing to its mechanism of action. First, mammalian hyaluronidases
are endo-β-N-acetylhexosaminidases that break down β-1,4 gly-
cosidic linkages to form tetrasaccharides. Second, leech/hook-
worm hyaluronidases are endo-β-D-glucuronidases that break
down β-1,3 glycosidic bonds to form pentasaccharides and hex-
asaccharides. Finally, microbial hyaluronidases are classified as
hyaluronate lyases. Unlike other hyaluronidases, they do not
catalyze hydrolysis reactions; instead, they produce unsaturated
disaccharides through a β-elimination reaction at β-1,4 glyco-
sidic linkages (Fig. 1) [2].
Hyaluronidases can also be classified into two types according
to the pH at which they are most active. Acid-active hyaluroni-
dases are activated at a pH of 3 to 4. Neutral-active hyaluroni-
dases—which includes the hyaluronidase enzymes found in
snake and bee venom—are activated at a pH of 5 to 8 [2].
In the past, medical hyaluronidase was extracted from bovine
or sheep testicles and used without purification. However, the
mammalian hyaluronidase obtained in this way was low in puri-
ty and contained components that could cause an immune re-
sponse. Subsequently, purification of mammalian hyaluronidase
was implemented as a processing step, and microbial hyaluroni-
dase obtained from Streptococcus agalactiae bacteria was also
used to reduce side effects.
D-Glucuronic acid and D-N-acetylglucosamine are linked by β-1,3 bonds (blue) to form a disaccharide. Multiple disaccharides are linked by β-1,4
bonds (red) to form hyaluronic acid. Mammalian and microbial hyaluronidases cleave β-1,4 bonds (red), and leech/hookworm hyaluronidases de-
grade β-1,3 bonds (blue).
Fig. 1. Structure of hyaluronic acid
Vol. 47 / No. 4 / July 2020
299
HYALURONIDASE IN THE BODY
When hyaluronidase is injected into the body, its activity gradu-
ally decreases over time as a result of dilution, diffusion, and de-
activation [7]. Deactivation is caused by anti-hyaluronidase ac-
tivity, which proceeds at different rates in subcutaneous tissue
and the plasma. In an experiment using rodents, the half-life of
hyaluronidase in subcutaneous tissue was less than 30 minutes
[8,9], and its activity was partially maintained until 1 hour de-
pending on the experiment [10]. In plasma, the half-life was 2
to 3 minutes when hyaluronidase was injected intravenously in
humans, and even repeated injections did not result in a sus-
tained elevation of serum levels of hyaluronidase [2,5,8]. The
reasons for the short half-life of hyaluronidase in human plasma
are the presence of numerous hyaluronidase inhibitors in the
plasma and the metabolism of hyaluronidase in the kidneys and
liver [2].
Hyaluronidase in the body is affected by various drugs. Hyal-
uronidase antagonists include anti-inflammatory agents (e.g., in-
domethacin, dexamethasone, and salicylates), numerous plant-
based compounds (e.g., flavonoids and antioxidants), antihista-
mines, mast cell stabilizers, heparin, vitamin C, dicumarene, and
radiographic contrast media [2,5].
Levels of hyaluronidase inhibitors may increase depending on
an individual’s physical condition. In acute-phase responses
such as burns, septicemia, and shock, hyaluronidase inhibitor
levels increase to prevent circulatory collapse by reducing the
turnover rate of hyaluronic acid [11].
HYALURONIC ACID FILLERS AND
HYALURONIDASE
In order for hyaluronidase to dissolve a hyaluronic acid filler, it
must be able to access the intramolecular bonds within hyal-
uronic acid. The factors that interfere with access include the
number of crosslinks between hyaluronic acid molecules and
the concentration of hyaluronic acid. The more cross-linking,
the more difficult it is for hyaluronidase to access its binding
sites inside the hyaluronic acid filler. For this reason, fillers with
extensive cross-linking require a long time to dissolve with hyal-
uronidase [12]. In addition, the higher the concentration of hy-
aluronic acid, the slower it will be dissolved by hyaluronidase
[13]. Monophasic fillers are less soluble in hyaluronidase be-
cause they are less exposed to hyaluronidase than polyphasic
fillers [3].
As the side effects of fillers on blood vessels are known, many
attempts have been made to effectively dissolve fillers inside
blood vessels. DeLorenzi [3] concluded in a 2014 paper that
hyaluronidase could be injected subcutaneously without the
need for intravascular injections to treat filler-induced vascular
embolism. In an animal experiment, Wang et al. [14] also found
that subcutaneous injections of hyaluronidase were more effec-
tive than intravascular injections for preventing skin necrosis
caused by hyaluronic acid filler embolism. The amount of hyal-
uronidase is important when injecting hyaluronidase in the vi-
cinity of a blood vessel to dissolve filler inside the vessel. Lee et
al. [15] reported that it was effective to inject 30–50 IU or more
in one place in an animal test in 2020, and recommended inject-
ing 100 IU or more at each location for a clear effect.
SIDE EFFECTS OF HYALURONIDASE
Local injections of hyaluronidase can cause side effects such as
local pruritus and allergic reactions. The incidence of allergic re-
actions is reported to be 0.05% to 0.69%, and urticaria and angio-
edema have also been reported to occur at a low frequency (less
than 0.1%) [2,16]. Allergic reactions are more likely to occur
when the hyaluronidase dose is more than 100,000 IU through
an intravenous injection, and the occurrence of allergic compli-
cations rises to 31.3% if the dose increases to 200,000 IU [2].
Most allergic reactions of hyaluronidase are immediate hyper-
sensitivity reactions (type I, immunoglobulin E–mediated), but
delayed hypersensitivity reactions (type IV, T-cell–mediated)
may also occur [17]. Immediate hypersensitivity reactions
caused by hyaluronidase manifest as erythematous edema after
1 to 2 hours, and there is no response to antibiotic treatment. In
such cases, systemic steroids, antihistamines, and steroid cream
application are helpful [17]. Delayed hypersensitivity reactions
caused by hyaluronidase can occur even after 24 hours, and in
such cases, a skin test will not produce a positive reaction within
20 minutes, resulting in a negative diagnosis [18].
The skin test is performed with 3 IU of hyaluronidase; al-
though is recommended to perform a skin test before using hy-
aluronidase, doing so can often be difficult in general clinics
[17]. There is usually no link between the patient’s history of al-
lergies and the response to hyaluronidase. However, depending
on the origin of hyaluronidase, injection of hyaluronidase
should be avoided because cross-reactions may occur in patients
who are allergic to bovine collagen and bee stings [1].
CONCLUSIONS
Hyaluronidase use has become more diverse and widespread in
clinical practice. In particular, it is used to address patients’ dis-
satisfaction after hyaluronic acid filler treatment and to treat side
effects. As its use becomes more common, it is increasingly im-
Jung H Overview of hyaluronidase
300
portant for clinicians to have a sufficient knowledge of hyal-
uronidase. Hyaluronidase can serve as an appropriate treatment
in a variety of situations if it is used with a thorough understand-
ing of its mechanism of action, metabolism, and side effects.
NOTES
Conflict of interest
No potential conflict of interest relevant to this article was re-
ported.
ORCID
Hyunwook Jung https://orcid.org/0000-0002-1186-7510
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Introduction and Aims: In our previous studies we found that exercise partially prevents chronic kidney disease (CKD)-induced muscle atrophy. Effective therapeutic strategies to treat Chronic Kidney Disease (CKD)-induced muscle atrophy are urgently needed. Low frequency electrical stimulation (LFES) induces muscle contraction which mimics acupuncture and exercise, and may be effective in preventing muscle atrophy. Methods: CKD was induced in 20-25g mice by 5/6th nephrectomy. CKD and control mice were treated with LFES for 15 days. Results: LFES prevented soleus and EDL muscle weight loss in CKD mice (p<0.05, LFES/CKD vs. CKD) as well as loss of hind-limb muscle grip. LFES countered the CKD-induced decline in the IGF-1 signaling pathway, leading to increased protein synthesis, decreased protein degradation and increased myogenesis markers. There is an acute (immediate) response phase during which inflammation cytokines (IFN and IL-6) increased. M1 macrophage markers (pro-inflammation: IL-1β) were also increased acutely, but M2 markers (anti-inflammation: arg-1, IL-10 and IL-4) were increased 2-days after initiation of LFES. In addition, microRNA-1 and -206 were decreased in the acute phase after starting LFES. Conclusions: We conclude that LFES ameliorates CKD-induced skeletal muscle atrophy by up-regulation of the IGF-1 signaling pathway which improves protein metabolism and promotes myogenesis. The potential mechanisms leading to upregulation of IGF are 1) decrease of microRNA-1 and -206 in the early phase of LEFS resulting in reversal of the inhibition of IGF-1 production by these microRNAs or 2) direct secretion of IGF-1 by M2 macrophages in the later phase inflammatory response.
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“Comparative Effectiveness of Different Interventions of Perivascular Hyaluronidase”
Article
Background: Soft tissue necrosis caused by vascular compromise is a frequent and troublesome complication of hyaluronic acid (HA) filler injection. Hyaluronidase has been proposed as a treatment for this condition. This study aimed to determine the effective dose and administration interval of hyaluronidase injection in a skin necrosis animal model. Methods: New Zealand rabbits were used to simulate the HA-associated vascular occlusion model. HA filler (0.1 ml) was injected into the central auricular artery to create an occlusion. Three rabbit auricular flaps were injected with hyaluronidase 500 IU once (Group A); three with hyaluronidase 250 IU twice, with a 15-min interval (Group B); three with hyaluronidase 125 IU four times, with a 15-min interval (Group C); three with hyaluronidase 100 IU five times, with a 15-min interval (Group D); and three with hyaluronidase 75 IU seven times, with a 15-min interval (Group E), all at 24 h after occlusion. No intervention was administered after occlusion in the controls. Flap fluorescence angiography was performed immediately after hyaluronidase injection and on postoperative day 2, 4, and 7. Analysis of flap necrotic area was performed. Results: All control and experimental flaps demonstrated total occlusion after HA injection. The average total survival rate (positive area/total area ×100%) of control flaps was 37.61%. For experimental groups, the average total survival rates were 74.83%, 81.49%, 88.26%, 56.48%, and 60.69% in groups A-E, respectively. Conclusions: A better prognosis can be obtained by administering repeated doses rather than a single high dose of hyaluronidase.
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New High Dose Pulsed Hyaluronidase Protocol for Hyaluronic Acid Filler Vascular Adverse Events
Article
  • Mar 2017
The purpose of this article is to update the changes to the author’s protocols used to manage acute filler related vascular events from those previously published in this journal. For lack of a better term, this new protocol has been called the High Dose Pulsed Hyaluronidase (HDPH) protocol for vascular embolic events with hyaluronic acid (HA) fillers. The initial protocol used involved many different modalities of treatment. The current protocol is exceedingly simple and involves solely the use of hyaluronidase in repeated high doses. Despite the simplicity of the treatment, it has proven itself to be very successful over the past two years of clinical use. There has been no partial or complete skin loss associated with this protocol since its implementation if the protocol was implemented within 2 days of the ischemic event onset. The protocol involves diagnosis and repeated administration of relatively high doses hyaluronidase (HYAL) into the ischemic tissue repeated hourly until resolution (as detected clinically through capillary refill, skin color, and absence of pain). The dosage of HYAL varies as the amount of ischemic tissue, consistent with the new underlying hypothesis that we must flood the occluded vessels with a sufficient concentration of HYAL for a sufficient period of time in order to dissolve the HA obstruction to the point where the products of hydrolysis can pass through the capillary beds. Although vascular embolic events are rare, it is important to note that the face has higher risk and lower risk areas for filler treatment, but there are no “zero risk” areas with respect to filler treatments. Even with good anatomic knowledge and correct technique, there is still some nonzero risk of vascular embolic events (including highly skilled, experienced injectors). However, with careful low pressure, low volume injection technique, and adequate preparation for treatment of acute vascular events, the risk is quite manageable and the vast majority of adverse events are very treatable with an excellent prognosis, with a few exceptions. This new protocol offers excellent results, but requires further research to determine optimal parameters for various HA fillers.
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The Duration of Hyaluronidase and Optimal Timing of Hyaluronic Acid (HA) filler Reinjection after Hyaluronidase Injection
Article
  • Feb 2017
Background: Hyaluronidase injection is commonly performed treatment method for overcorrection or misplacement of HA filler. Many patients often wants the HA filler reinjection after the use of hyaluronidase, though the optimal timing of reinjection of HA filler still remains unknown. Objectives: To provide the optimal time interval between hyaluronidase injections and HA filler reinjections. Methods: The backs of 6 Sprague-Dawley rats were injected with single monophasic HA filler. 1 week after injection, the injection sites were treated with hyaluronidase. Then,.HA fillers were reinjected sequentially with differing time intervals from 30 minutes to 14 days. 1 hour after the reinjection of the last HA filler, all injection sites were excised for histologic evaluation. Results: 3 hours after reinjection of HA filler, the appearance of filler material became reevident, retaining its shape and volume. 6 hours after reinjection, the filler materials restored almost its original volume and there were no significant differences from the positive control. Conclusions: Our data suggests that the hyaluronidase loses its effect in dermis and subcutaneous tissue within 3 to 6 hours after the injection and successful engraftment of reinjected HA filler can be accomplished 6 hours after the injection.
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Efficacy of Retrobulbar Hyaluronidase Injection for Vision Loss Resulting from Hyaluronic Acid Filler Embolization
Article
  • Jan 2017
Background Vision loss is a rare but serious complication of facial hyaluronic acid (HA) filler injection, for which there is no proven rescue therapy. Retrobulbar hyaluronidase injection is advocated by many plastic surgeons as an emergency treatment, but has not been carefully assessed for its efficacy. Objectives To evaluate the efficacy of retrobulbar hyaluronidase injection as a rescue treatment for vision loss caused by HA filler embolization. Methods Patients with vision loss caused by HA filler embolization were treated with retrobulbar hyaluronidase injection. Their visual acuity and fundoscopic images before and after treatment were analyzed for efficacy assessment. Results One patient with branch retinal artery occlusion (BRAO), one patient with posterior ischemic optic neuropathy (PION), one patient with ophthalmic artery occlusion, and one patient with both BRAO and PION were treated with one or two retrobulbar injections of 1500 or 3000 units hyaluronidase. No patients demonstrated substantial retinal artery recanalization or vision acuity improvement after treatment. Conclusions One or two retrobulbar injections of 1500 to 3000 IU hyaluronidase are unable to recanalize retinal artery occlusion or improve the visual outcome of patients who presented with vision loss caused by HA filler embolization at least four hours after onset. Level of Evidence: 4
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Comparison of Intra-arterial and Subcutaneous Testicular Hyaluronidase Injection Treatments and the Vascular Complications of Hyaluronic Acid Filler
Article
  • Dec 2016
Background: Hyaluronidase is a key preventative treatment against vascular complications of hyaluronic acid (HA) filler injection, but the degradation profile of HA to hyaluronidase is limited, and the comparison between intra-arterial and subcutaneous injections of hyaluronidase has not been studied. Objective: To evaluate HA degradation to hyaluronidase and compare different treatments between intra-arterial and subcutaneous testicular hyaluronidase injections. Materials and methods: The authors observed HA degradation to hyaluronidase in vitro via microscopic examination and particle analysis. Rabbit ears were used for the in vivo study. There were 2 control groups receiving ligation or HA-induced embolism in the arteries, respectively, and 2 intervention groups receiving hyaluronidase treatments in different regions. The laser Doppler blood perfusion monitoring measurements were made at defined time points, and biopsies were taken on Day 2. Results: Nearly, all of the HAs degraded in vitro at the 1-hour time point. Subcutaneous hyaluronidase treatment showed better recovery of blood perfusion. Histology showed severe inflammation in the embolism group and mild inflammation in the intervention groups. Conclusion: A complete enzymatic degradation of HA filler to hyaluronidase needs a certain time, and subcutaneous hyaluronidase treatment may be the better option.
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Allergic reaction to hyaluronidase use after hyaluronic acid filler injection
Article
  • Jan 2015
ABSTRACT Hyaluronic acid(HA) is biocompatible, easy to use and reversible. HA fillers are considered to be safe, although some complications can occur. At this time, hyaluronidase is used off-label for correction. A 41-year-old woman presented to our clinic for focal erythematous plaque on hyaluronidase injection site. She got the injection for correction of HA filler excess. The skin lesion continued for 7 days. Histopathologic findings were nonspecific. On intradermal skin test, allergic reaction to hyaluronidase were confirmed. Adverse effects of this hyaluronidase are uncommon with local injection site reactions most frequently reported. Allergy to hyaluronidase should be included in the differential diagnosis when focal erythema and swelling occur after hyaluronidase injection.
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Reversing Facial Fillers: Interactions Between Hyaluronidase and Commercially Available Hyaluronic-Acid Based Fillers
Article
  • Sep 2014
Hyaluronidase (HA) degrades hyaluronic acid, allowing flexibility in the use of hyaluronic acid-based fillers commonly used in facial correction. Potentially differing properties of available hyaluronidases and fillers may influence their interaction, leading to important differences in ultimate cosmetic results. This study examines the physical properties of various fillers after exposure to commonly available hyaluronidases in vitro to better inform their in vivo clinical use. METHODS: Four commonly used HA fillers were exposed to varying concentrations of Vitrase (ovine testicular hyaluronidase) and Hylenex (human recombinant hyaluronidase) in vitro. The gross properties of these fillers were then observed to evaluate time- and dose-response; photographs were obtained to allow visual comparison at 1 minute and 5 minutes post-exposure. RESULTS: At a concentration of 0.1 mL Vitrase to 0.2 mL filler, Restylane dissipated most followed by Juvéderm; Belotero most retained its form. Hylenex at the same concentration showed similar results, again affecting Restylane most and Belotero least. Response to treatment with both hyaluronidases increased substantially over time, increasing progressively from exposure to 5 minutes post-exposure. When exposed to Hylenex at 15 U and 30 U to 0.2 mL filler, Belotero retained its form most, followed by Juvéderm, Juvéderm Voluma, and then Restylane. The effects on filler structure increased with 30 U concentration vs 15 U concentration of Hylenex. DISCUSSION: Available hyaluronidases and HA fillers appear to have differing physical properties that influence their interaction in a time and dose-dependent manner. Knowledge of the ways in which specific fillers interact with different hyaluronidases may help achieve desired cosmesis when aiming to adjust delicate facial fillers. J Drugs Dermatol . 2014;13(9):1053-1056.
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Transarterial Degradation of Hyaluronic Acid Filler by Hyaluronidase
Article
  • Jul 2014
Background: Hyaluronidase (HYAL) has been recommended in the emergency treatment of ischemia caused by accidental intra-arterial injection of hyaluronic acid (HA) dermal fillers. To date, there have been no published studies showing that HYAL can pass through intact arterial wall to hydrolyze HA emboli. Objective: The goal of this study was to study whether or not HYAL could cross intact human facial arterial wall to hydrolyze HA filler. Materials and methods: Short tied-off segments of fresh human cadaver-sourced facial artery specimens, overfilled with a monophasic dermal filler (dermal filler "sausages"), were immersed in either HYAL or normal saline as controls. At 4 and 24 hours, the vessels were removed from the preparations, and one end of each vessel was cut open. Results: Only the HYAL-immersed specimens showed degradation of filler gel. Conclusion: In conclusion, cross-linked HA is susceptible to hydrolysis by HYAL when contained within the intact facial artery in a cadaver model, indicating that direct intra-arterial injection of HYAL is likely not necessary to help restore the circulation of ischemic tissues. This bench study provides support for the current recommended treatment of accidental intra-arterial injection with HYAL injection diffusely into ischemic tissues.
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Overview of recombinant human hyaluronidase-facilitated subcutaneous infusion of IgG in primary immunodeficiencies
Article
  • May 2014
Subcutaneous administration of immunoglobulin (IGSC) in a home setting, compared with intravenous administration, can improve patient quality of life. During IGSC, however, the subcutaneous extracellular matrix inhibits flow and fluid entry into the vascular compartment, which limits the amount of drug delivered. Recombinant human hyaluronidase (rHuPH20) increases the absorption and dispersion of infused fluids and drugs. Results from a Phase III, prospective, open-label, noncontrolled study of patients with primary immunodeficiencies indicated that IGSC infusion, facilitated by rHuPH20, is well tolerated and delivers infusion volumes at treatment intervals and rates equivalent to intravenous administration. This drug evaluation provides an overview of rHuPH20 and results of clinical studies of IGSC infusion facilitated by rHuPH20 in patients with primary immunodeficiencies.
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