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

Jung, Hyunwook Korean Society of Plastic and Reconstructive Surge 2020 Archives of Plastic Surgery Vol.47 No.4

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.

Acute urticaria caused by the injection of goat-derived hyaluronidase

Joo-Hee Kim,Gil-Soon Choi,Young-Min Ye,Dong-Ho Nahm,Hae-Sim Park 대한천식알레르기학회 2009 Allergy, Asthma & Immunology Research Vol.1 No.1

Hyaluronidase is a goat testicular protein that hydrolyzes hyaluronic acid, a structural component of the intercellular matrix. It is commonly used as a spreading factor to improve the diffusion of drugs, including local anesthetics and chemotherapeutics. We experienced a 55-yr-old female with generalized urticaria that developed within 1 hr after the epidural injection of hyaluronidase. She had a history of allergic rhinitis, and had suffered from post-herpetic neuralgia and a herniated disc for several years. To relieve her pain, she had been given epidural injections consisting of mepivacaine hydrochloride, triamcinolone acetonide, and morphine sulfate biweekly for one year. Hyaluronidase had been administered several times with these drugs before this episode of generalized urticaria. Skin prick testing showed a positive response to 1,500 IU/mL of hyaluronidase extract, as compared to histamine. The patient’s serum hyaluronidase-specific IgE level, determined using an enzyme-linked immunosorbent assay (ELISA), was markedly elevated, as compared to unexposed healthy controls. An IgE immunoblot analysis using hyaluronidase extract and the patient’s serum showed IgE binding components at 31 and 21 kDa, whereas no corresponding IgE binding component was found in healthy controls. An ELISA inhibition test showed significant, dose-dependent inhibition with the serial addition of hyaluronidase extract. This is the first case of an IgE-medicated allergic reaction to goat (Naemorhedus goral raddenus) hyaluronidase, demonstrated by skin testing and a specific IgE and immunoblot assay.

Calcium gluconate의 혈관외 누출시 피부괴사에 대한 hyaluronidase의 효과 : 용량과 치료시간 지연에 따른 반응

이홍기,백무현,김승홍,김승한 大韓成形外科學會 1998 Archives of Plastic Surgery Vol.25 No.5

Extravasation necrosis due to intravenously administered fluids and drugs is an increasing problem in hospital practice. The incidence of extravasation is variable but skin necrosis is a potentially devastating complication of intravenous therapy. Local injection of hyaluronidase has been recommended for several types of infusion extravasations. The previous studies found hyaluronidase to be effective in the prevention of necrosis following intradermal nafcillin, 12% dextrose, sodium bicarbonate, aminophylline or vince alkaloids. The objectives of the study are to determine the dosage of hyaluronidase which is effective in reducing extravasation necrosis caused by 10% calcium-gluconate and to establish how soon after this extravasation it must be given to retain its effectiveness. Study I evaluated control versus only normal saline group and normal saline with hyaluronidase groups (dose:75,150,300,450 units; all in volume 2 ml, treatment delay:immediate, 15-minutes delay, half hour delay, one hour delay, three hour delay). Size and rate of eschar were compared between groups. Study Ⅱ was undertaken to examine the evolution of calcium-gluconate induced soft tissue injury in the rabbit. The histologic findings of extravasation sites were compared between groups. A statistically significant protective effect was found in the treated group versus the nontreated group within 15 minutes to 30 minutes. The most effective protection was achieved by the immediate injection of 300 units dosage of hyaluronidase. In conclusion, in the 10% calcium gluconate-induced extravasation, the given data suggest that one can expect the most protective effect with a 300 units dosage of hyaluronidase and within half-hour delay in the treatment group

Case Report : Allergic reactions to hyaluronidase in pain management

( Tae Wan Kim ),( Jae Hoon Lee ),( Kyung Bong Yoon ),( Duck Mi Yoon ) 대한마취과학회 2011 Korean Journal of Anesthesiology Vol.60 No.1

Hyaluronidase has been gaining interest because it reduces tissue edema and fibrosis. Although rare, hyaluronidase has been shown to cause allergic reactions. A few cases of allergic reactions following hyaluronidase administration have been reported. Most of the described patients presented allergic reactions after peribulbar anesthesia for eye surgery. In this report, we describe three patients who experienced with allergic reactions to hyaluronidase following pain management. Two of the patients had a history of uneventful injection with hyaluronidase. All patients were afebrile and blood tests results were normal. Intradermal skin tests were positive. These clinical findings were helpful in establishing the differential diagnosis of infection. Although allergic reaction to hyaluronidase is rare and mostly benign, this must be considered before treating patients. (Korean J Anesthesiol 2011; 60: 57-59)

Characterization of Recombinant Bovine Sperm Hyaluronidase and Identification of an Important Asn-X-Ser/Thr Motif for Its Activity

( Chaeri Park ),( Young-hyun Kim ),( Sang-rae Lee ),( Soojin Park ),( Yena Jung ),( Youngjeon Lee ),( Ji-su Kim ),( Taekil Eom ),( Ju-sung Kim ),( Dong-mok Lee ),( Bong-suk Song ),( Bo-woong Sim ),( S 한국미생물생명공학회(구 한국산업미생물학회) 2018 Journal of microbiology and biotechnology Vol.28 No.9

Hyaluronidases are a family of enzymes that catalyse the breakdown of hyaluronic acid, which is abundant in the extracellular matrix and cumulus oocyte complex. To investigate the activity of recombinant bovine sperm hyaluronidase 1 (SPAM1) and determine the effect of the Asn-X-Ser/Thr motif on its activity, the bovine SPAM1 open reading frame was cloned into the mammalian expression vector pCXN2 and then transfected to the HEK293 cell line. Expression of recombinant bovine hyaluronidase was estimated using a hyaluronidase activity assay with gel electrophoresis. Recombinant hyaluronidase could resolve highly polymeric hyaluronic acid and also caused dispersal of the cumulus cell layer. Comparative analysis with respect to enzyme activity was carried out for the glycosylated and deglycosylated bovine sperm hyaluronidase by N-glycosidase F treatment. Finally, mutagenesis analysis revealed that among the five potential N-linked glycosylation sites, only three contributed to significant inhibition of hyaluronic activity. Recombinant bovine SPAM1 has hyaluronan degradation and cumulus oocyte complex dispersion ability, and the N-linked oligosaccharides are important for enzyme activity, providing a foundation for the commercialization of hyaluronidase.

Optimization and Evaluation of HA filler reinjection after hyaluronidase injection in a rat model

( Sun Bum Kwon ),( Ga Hee Jung ),( Kyung O Kim ),( Hyun Jo Kim ),( Young Lip Park ),( Sung Yul Lee ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.2

Background: In recent years, hyaluronic acid (HA)-based fillers have become the popular material for use in soft tissue and dermal correction. HA fillers are generally accepted today to have replaced collagen fillers as the material of choice and its uses have subsequently grown extensively. Objectives: We investigated the duration of effect of hyaluronidase in vivo to provide the optimal time interval between hyaluronidase injections and HA filler reinjections. Methods: This study is comprised of 6 male Sprague-Dawley rats and used single monophasic HA filler and single hyaluronidase. Sequential reinjection of HA filler with different time interval. After 1 week, 600 IU of hyaluronidase was injected subdermally. All injection site were completely excised and taken biopsy sample simultaneously. Biopsy specimens were stained with hematoxylin-eosin stain and alcian blue stain to highlight the HA within the sections. All specimens were reviewed by a board-certified pathologist. Results: In 6 h intervention group, reinjected HA filler showed almost its original volume and was no significant difference from positive control group in macroscopically and microscopically. Conclusion: Our data suggest that the hyaluronidase lose its effect in dermis and subcutaneous tissue within 3 to 6 hours after injection and proper engraftment of reinjected HA filler can be accomplished after 6 hours.

생쥐 난자의 단위발생에 관한 연구 I. Ethanol 및 hyaluronidase처리에 의한 단위발생유기

이효종,하대식,강태영,최민철,Lee, Hyo-jong,Ha, Dae-sik,Kang, Tae-young,Choi, Min-cheol 대한수의학회 1992 大韓獸醫學會誌 Vol.32 No.4

This experiment was carried out to find out the best condition for the parthenogenetic activation of mouse eggs by treating ethanol and hyaluronidase. For the parthenogenetic activation of eggs with ethanol, cumulus cell enclosed or denuded eggs were treated with 7% ethanol in D-PBS for 5, 7 or 9 minutes. For the activation of eggs with hyaluronidase, the eggs with cumulus masses were released into D-PBS with 100 unit hyaluronidase and treated for 10, 12 or 13 minutes. All of the treated eggs were incubated in BMOC-3 solution for 5 hours at $37^{\circ}C$ at an atmosphere of 5% $CO_2$ in air. The types of parthenogenetic eggs were morphologically classified into haploid, diploid, immediate cleavage eggs under an inverted microscope. The results obtained in this experiment were summarized as follows ; 1. High activation rate(99%) had been achieved by treating the eggs with 7% ethanol for 7 minutes. 2. With 100 IU hyaluronidase, high activation rate (94%) had been achieved by treating for 12 minutes. 3. The most frequent type of parthenogenetic eggs activated with ethanol or hyaluronidase was haploid (p<0.05). 4. The eggs collected from 18 to 22 hours post HCG injection showed higher activation rate than the eggs collected at 16 hours post HCG injection. 5. No significant difference (p>0.05) in activation rate was shown in strain of mouse and in presence of cumulus cells.

Brief Report : Delayed Allergic Reaction to Secondary Administrated Epidural Hyaluronidase

( A Reum Park ),( Woong Mo Kim ),( Bong Ha Heo ) 대한통증학회 2015 The Korean Journal of Pain Vol.28 No.2

We are reporting a rare case of a delayed hypersensitivity reaction caused by hyaluronidase allergy following a lumbar transforaminal epidural block. Using an intradermal skin test, we have provided evidence that the systemic allergic reaction resulted from hypersensitivity to hyaluronidase. To our knowledge, this is a rare case of a delayed hypersensitivity reaction to epidural hyaluronidase, comprised of an initial exposure to hyaluronidase with no subsequent allergic response in prior block followed by a subsequent delayed reaction to hyaluronidase during a second epidural block. (Korean J Pain 2015; 28: 153-155)

Clinical and molecular biological aspect of the hyaluronidases: basis and clinical overview for oriental medical application

Kim, Cheorl-Ho,Lee, Dong-Gyu,Jang, Jun-Hyouk,Kim, Jong-De,Nam, Kyung-Soo,Kim, Jeong-Joong,Park, Jong-Kun,Choo, Young-Kug,Kim, Hyung-Min,Lee, Young-Choon Kyung Hee Oriental Medicine Research Center 2000 International journal of oriental medicine Vol.1 No.1

Components of extracellular matrix and the matrix-degrading enzymes are some of the key regulators of tumor metastasis and angiogenesis. Hyaluronic acid (HA), a matrix glycosaminoglycan, is known to promote tumor adhesion and migration, and its small fragments are angiogenic. Until now, we have compared levels of hyaluronidase, an enzyme that degrade HA, in normal adult prostate, benign prostate hyperplasia and prostate cancer tissues and in conditioned media from epithelial explant cultures, using a substrate (HA)-gel assay and ELISA-like assay (Kim et al., unpublished results). The present review described an overall characterization of hyaluronidases and its application to human diseases. The hyaluronidases are a family of enzymes that have, until recently, deed thorough explication. The substrate for these enzymes, hyaluronan, is becoming increasingly important, recognized now as a major participant in basic processes such as cell motility, wound healing, embryogenesis, and implicated in cancer progression. And in those lower life forms that torment human beings, hyaluronidase is associated with mechanisms of entry and spread, e.g. as a virulence factor for bacteria, for tissue dissection in gas gangrene, as a means of treponema spread in syphilis, and for penetration of skin and gut by nematode parasites. Hyaluronidase also comprises a component of the venom of a wide variety of organisms, including bees, wasps, hornets, spiders, scorpions, sh, snakes and lizards. Of particular interest is the homology between some of these venom hyaluronidases and the enzyme found in the plasma membrane of mammalian spermatozoa, attesting to the ancient nature of the conserved sequence, a 36% identity in a 300 amino acid stretch of the enzyme protein. Clearly, hyaluronidase is of biological interest, being involved in the pathophysiology of so many important' human disorders. Greater effort should be made in studying this family of enzymes that have, until recently, been overlooked. Also, oriental medical application of the hyaluronidase will be discussed with respect to inhibition and suppression of inflammation and malignacy.

Acute allergic reaction caused by hyaluronidase used in the pain management: a case report and literature review -A case report-

송윤강,Yeon Dong Kim,Jae-Hong Kim 대한마취통증의학회 2014 Anesthesia and pain medicine Vol.9 No.3

Hyaluronidase is a protein enzyme extracted from goat or ovinetestis. It breaks down hyaluronic acid in connective tissues, therebyreducing swelling and edema and increasing drug penetration intotissues after injection. Because of these properties, it is beingincreasingly used in the field of pain management. The mostfrequently reported hyaluronidase-induced complications are allergicreactions, and are usually reported in cases involving eye surgery. However, there are only a few cases of allergic reactions reportedin the field of pain management. Here, we report a case involvinga 52-year-old patient diagnosed with an allergic reaction afterreceiving epidural administration of hyaluronidase. A literaturereview and comparison of our case with similar cases suggestedthe potential mechanisms underlying these allergic reactions andemphasized the importance of considering the possibility of thesereactions in patients receiving hyaluronidase during the course ofpain management procedures.