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Clinical Applications of Hyaluronidase

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Therapeutic Enzymes: Function and Clinical Implications

Abstract

Hyaluronidases are enzymes that degrade hyaluronic acid, which constitutes an essential part of the extracellular matrix. Initially discovered in bacteria, hyaluronidases are known to be widely distributed in nature and have been found in many classes including insects, snakes, fish and mammals. In the human, six different hyaluronidases, HYAL1-4, HYAL-P1 and PH-20, have been identified. PH-20 exerts the strongest biologic activity, is found in high concentrations in the testicles and can be localized on the head and the acrosome of human spermatozoa. Today, animal-derived bovine or ovine testicular hyaluronidases as well as synthetic hyaluronidases are clinically applied as adjuncts to increase the bioavailability of drugs, for the therapy of extravasations, or for the management of complications associated with the aesthetic injection of hyaluronic acid-based fillers. Further applications in the fields of surgery, aesthetic medicine, immunology, oncology, and many others can be expected for years to come. Here, we give an overview over the molecular and cellular mode of action of hyaluronidase and the hyaluronic acid metabolism, as well as over current and potential future clinical applications of hyaluronidase.

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Abbreviations

BEL:

Belotero®

BTH:

Bovine testicular hyaluronidase

CHO:

Chinese hamster ovary

CPM:

Cohesive polydensified matrix

DMSO:

Dimethylsulfoxide

ECM:

Extracellular matrix

EMV:

Emervel®

FDA:

Food and Drug Administration

GAG:

Glycosaminoglycan

HA:

Hyaluronan

HAS:

Hyaluronan synthase

HYAL:

Hyaluronidase

Ig:

Immunoglobulin

IGSC:

Subcutaneous immunoglobulins

IU:

International units

JUV:

Juvederm®

kDA:

Kilodalton

l:

Liter

LA:

Local anesthetic

mAb:

Monoclonal antibody

ml:

Milliliter

μm:

Micrometer

OTH:

Ovine testicular hyaluronidase

PEGPH20:

PEGylated recombinant human hyaluronidase

PG:

Proteoglycan

RES:

Restylane®

rHuPH20:

Recombinant human hyaluronidase

S. aureus :

Staphylococcus aureus

References

  • Ahmed S, Ahmed OA (2004) Hyaluronidase revisited-a single injection technique for harvesting split thickness skin grafts under local anaesthesia. Br J Plast Surg 57:589–591

    Article  PubMed  Google Scholar 

  • Albanell J, Baselga J (2000) Systemic therapy emergencies. Semin Oncol 27:347–361

    CAS  PubMed  Google Scholar 

  • Alberts DS, Dorr RT (1991) Case report: topical DMSO for mitomycin-C-induced skin ulceration. Oncol Nurs Forum 18:693–695

    CAS  PubMed  Google Scholar 

  • Allen CH, Etzwiler LS, Miller MK et al (2009) Recombinant human hyaluronidase-enabled subcutaneous pediatric rehydration. Pediatrics 124:e858–e867

    Article  PubMed  Google Scholar 

  • Aruffo A, Stamenkovic I, Melnick M et al (1990) CD44 is the principal cell surface receptor for hyaluronate. Cell 61:1303–1313

    Article  CAS  PubMed  Google Scholar 

  • Atmuri V, Martin DC, Hemming R et al (2008) Hyaluronidase 3 (HYAL3) knockout mice do not display evidence of hyaluronan accumulation. Matrix Biol 27:653–660

    Article  CAS  PubMed  Google Scholar 

  • Attenello NH, Maas CS (2015) Injectable fillers: review of material and properties. Facial Plast Surg 31:29–34

    Article  CAS  PubMed  Google Scholar 

  • Ballin AC, Cazzaniga A, Brandt FS (2013) Long-term efficacy, safety and durability of Juvederm(R) XC. Clin Cosmet Investig Dermatol 6:183–189

    PubMed  PubMed Central  Google Scholar 

  • Barsukov AK, Kozhevnikova OV, Khokhriakova AV (2003) Isolation and purification of bovine testicular hyaluronidase. Prikl Biokhim Mikrobiol 39:625–629

    CAS  PubMed  Google Scholar 

  • Beleznay K, Carruthers JD, Humphrey S et al (2015) Avoiding and treating blindness from fillers: a review of the world literature. Dermatol Surg 41:1097–1117

    Article  CAS  PubMed  Google Scholar 

  • Bellin MF, Jakobsen JA, Tomassin I et al (2002) Contrast medium extravasation injury: guidelines for prevention and management. Eur Radiol 12:2807–2812

    Article  PubMed  Google Scholar 

  • Belzunegui T, Louis CJ, Torrededia L et al (2011) Extravasation of radiographic contrast material and compartment syndrome in the hand: a case report. Scand J Trauma Resusc Emerg Med 19:9

    Article  PubMed  PubMed Central  Google Scholar 

  • Benditt EP, Schiller S, Matthews MB et al (1951) Evidence that hyaluronidase is not the factor in testicular extract causing increased vascular permeability. Proc Soc Exp Biol Med 77:643–646

    Article  CAS  PubMed  Google Scholar 

  • Bertelli G (1995) Prevention and management of extravasation of cytotoxic drugs. Drug Saf 12:245–255

    Article  CAS  PubMed  Google Scholar 

  • Bertelli G, Dini D, Forno GB et al (1994) Hyaluronidase as an antidote to extravasation of Vinca alkaloids: clinical results. J Cancer Res Clin Oncol 120:505–506

    Article  CAS  PubMed  Google Scholar 

  • Bertelli G, Gozza A, Forno GB et al (1995) Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol 13:2851–2855

    Article  CAS  PubMed  Google Scholar 

  • Bertelli G, Cafferata MA, Ardizzoni A et al (1997) Skin ulceration potential of paclitaxel in a mouse skin model in vivo. Cancer 79:2266–2269

    Article  CAS  PubMed  Google Scholar 

  • Bertolami CN, Donoff RB (1982) Identification, characterization, and partial purification of mammalian skin wound hyaluronidase. J Invest Dermatol 79:417–421

    Article  CAS  PubMed  Google Scholar 

  • Bissell MJ, Hall HG, Parry G (1982) How does the extracellular matrix direct gene expression? J Theor Biol 99:31–68

    Article  CAS  PubMed  Google Scholar 

  • Bohaumilitzky L, Huber AK, Stork EM et al (2017) A trickster in disguise: Hyaluronan’s ambivalent roles in the matrix. Front Oncol 7:242

    Article  PubMed  PubMed Central  Google Scholar 

  • Bookbinder LH, Hofer A, Haller MF et al (2006) A recombinant human enzyme for enhanced interstitial transport of therapeutics. J Control Release 114:230–241

    Article  CAS  PubMed  Google Scholar 

  • Boulanger J, Ducharme A, Dufour A et al (2015) Management of the extravasation of anti-neoplastic agents. Support Care Cancer 23:1459–1471

    Article  CAS  PubMed  Google Scholar 

  • Buhren BA, Schrumpf H, Hoff NP et al (2016) Hyaluronidase: from clinical applications to molecular and cellular mechanisms. Eur J Med Res 21:5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Buhren BA, Schrumpf H, Bolke E et al (2018) Standardized in vitro analysis of the degradability of hyaluronic acid fillers by hyaluronidase. Eur J Med Res 23:37

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Buntrock H, Reuther T, Prager W et al (2013) Efficacy, safety, and patient satisfaction of a monophasic cohesive polydensified matrix versus a biphasic nonanimal stabilized hyaluronic acid filler after single injection in nasolabial folds. Dermatol Surg 39:1097–1105

    Article  CAS  PubMed  Google Scholar 

  • Carne E, Ponsford M, El-Shanawany T et al (2016) Five years of self-administered hyaluronidase facilitated subcutaneous immunoglobulin (fSCIg) home therapy in a patient with primary immunodeficiency. J Clin Pathol 69:87–88

    Article  CAS  PubMed  Google Scholar 

  • Cochran ST, Bomyea K, Kahn M (2002) Treatment of iodinated contrast material extravasation with hyaluronidase. Acad Radiol 9(Suppl 2):S544–S546

    Article  PubMed  Google Scholar 

  • Connolly AA, Meyer LC, Tate JJ (1994) Local anaesthetic agents in surgery for ingrown toenail. Br J Surg 81:425–426

    Article  CAS  PubMed  Google Scholar 

  • Connolly S, Korzemba H, Harb G et al (2011) Techniques for hyaluronidase-facilitated subcutaneous fluid administration with recombinant human hyaluronidase: the increased flow utilizing subcutaneously enabled administration technique (INFUSE AT) study. J Infus Nurs 34:300–307

    Article  PubMed  Google Scholar 

  • Courtiss EH, Ransil BJ, Russo J (1995) The effects of hyaluronidase on local anesthesia: a prospective, randomized, controlled, double-blind study. Plast Reconstr Surg 95:876–883

    Article  CAS  PubMed  Google Scholar 

  • Cowman MK (2017) Hyaluronan and hyaluronan fragments. Adv Carbohydr Chem Biochem 74:1–59

    Article  PubMed  Google Scholar 

  • Crawford M, Kerr WJ (1994) The effect of hyaluronidase on peribulbar block. Anaesthesia 49:907–908

    Article  CAS  PubMed  Google Scholar 

  • Csoka TB, Frost GI, Stern R (1997) Hyaluronidases in tissue invasion. Invasion Metastasis 17:297–311

    CAS  PubMed  Google Scholar 

  • Dai G, Freudenberger T, Zipper P et al (2007) Chronic ultraviolet B irradiation causes loss of hyaluronic acid from mouse dermis because of down-regulation of hyaluronic acid synthases. Am J Pathol 171:1451–1461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dayan SH, Bassichis BA (2008) Facial dermal fillers: selection of appropriate products and techniques. Aesthet Surg J 28:335–347

    Article  PubMed  Google Scholar 

  • De Boulle K, Glogau R, Kono T et al (2013) A review of the metabolism of 1,4-butanediol diglycidyl ether-crosslinked hyaluronic acid dermal fillers. Dermatol Surg 39:1758–1766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Delorenzi C (2013) Complications of injectable fillers, part I. Aesthet Surg J 33:561–575

    Article  PubMed  Google Scholar 

  • Dempsey GA, Barrett PJ, Kirby J (1996) The effect of hyaluronidase on peribulbar block. Anaesthesia 51:515

    Article  CAS  PubMed  Google Scholar 

  • Dempsey GA, Barrett PJ, Kirby IJ (1997) Hyaluronidase and peribulbar block. Br J Anaesth 78:671–674

    Article  CAS  PubMed  Google Scholar 

  • Dieleman M, Bettink-Remeijer MW, Jansen J et al (2012) High incidence of adverse reactions to locoregional anaesthesia containing hyaluronidase after uneventful ophthalmic surgery. Acta Ophthalmol 90:e245–e246

    Article  PubMed  Google Scholar 

  • Doellman D, Hadaway L, Bowe-Geddes LA et al (2009) Infiltration and extravasation: update on prevention and management. J Infus Nurs 32:203–211

    Article  PubMed  Google Scholar 

  • Doherty GJ, Tempero M, Corrie PG (2018) HALO-109-301: a phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. Future Oncol 14:13–22

    Article  CAS  PubMed  Google Scholar 

  • Dorr RT (1990) Antidotes to vesicant chemotherapy extravasations. Blood Rev 4:41–60

    Article  CAS  PubMed  Google Scholar 

  • Dougherty L (2008) IV therapy: recognizing the differences between infiltration and extravasation. Br J Nurs 17:896. 898–901

    Article  PubMed  Google Scholar 

  • Dubois A, Fehr M, Bochtler H et al (1996) Clinical course and management of paclitaxel extravasation. Oncol Rep 3:973–974

    Article  CAS  PubMed  Google Scholar 

  • Dunagin WG (1982) Clinical toxicity of chemotherapeutic agents: dermatologic toxicity. Semin Oncol 9:14–22

    CAS  PubMed  Google Scholar 

  • Dunn AL, Heavner JE, Racz G et al (2010) Hyaluronidase: a review of approved formulations, indications and off-label use in chronic pain management. Expert Opin Biol Ther 10:127–131

    Article  CAS  PubMed  Google Scholar 

  • Duran-Reynals F (1942) TISSUE PERMEABILITY AND THE SPREADING FACTORS IN INFECTION: a contribution to the host: parasite problem. Bacteriol Rev 6:197–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edsman K, Nord LI, Ohrlund A et al (2012) Gel properties of hyaluronic acid dermal fillers. Dermatol Surg 38:1170–1179

    Article  CAS  PubMed  Google Scholar 

  • Elam EA, Dorr RT, Lagel KE et al (1991) Cutaneous ulceration due to contrast extravasation. Experimental assessment of injury and potential antidotes. Investig Radiol 26:13–16

    Article  CAS  Google Scholar 

  • El-Saghir N, Otrock Z, Mufarrij A et al (2004) Dexrazoxane for anthracycline extravasation and GM-CSF for skin ulceration and wound healing. Lancet Oncol 5:320–321

    Article  CAS  PubMed  Google Scholar 

  • Fanning GL (2001) Hyaluronidase in ophthalmic anesthesia. Anesth Analg 92:560

    Article  CAS  PubMed  Google Scholar 

  • Farr C, Menzel J, Seeberger J et al (1997) Clinical pharmacology and possible applications of hyaluronidase with reference to Hylase “Dessau”. Wien Med Wochenschr 147:347–355

    CAS  PubMed  Google Scholar 

  • Federle MP, Chang PJ, Confer S et al (1998) Frequency and effects of extravasation of ionic and nonionic CT contrast media during rapid bolus injection. Radiology 206:637–640

    Article  CAS  PubMed  Google Scholar 

  • Flynn TC, Sarazin D, Bezzola A et al (2011) Comparative histology of intradermal implantation of mono and biphasic hyaluronic acid fillers. Dermatol Surg 37:637–643

    Article  CAS  PubMed  Google Scholar 

  • Fox AN, Villanueva R, Miller JL (2017) Management of amiodarone extravasation with intradermal hyaluronidase. Am J Health Syst Pharm 74:1545–1548

    Article  PubMed  Google Scholar 

  • Fraser JR, Laurent TC, Pertoft H et al (1981) Plasma clearance, tissue distribution and metabolism of hyaluronic acid injected intravenously in the rabbit. Biochem J 200:415–424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fraser JR, Laurent TC, Laurent UB (1997) Hyaluronan: its nature, distribution, functions and turnover. J Intern Med 242:27–33

    Article  CAS  PubMed  Google Scholar 

  • Fronza M, Caetano GF, Leite MN et al (2014) Hyaluronidase modulates inflammatory response and accelerates the cutaneous wound healing. PLoS One 9:e112297

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Frost GI (2007) Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opin Drug Deliv 4:427–440

    Article  CAS  PubMed  Google Scholar 

  • Garg SK, Buse JB, Skyler JS et al (2014) Subcutaneous injection of hyaluronidase with recombinant human insulin compared with insulin lispro in type 1 diabetes. Diabetes Obes Metab 16:1065–1069

    Article  CAS  PubMed  Google Scholar 

  • Garvin JH Jr, Chipman DM (1974) Subunit structure of testicular hyaluronidase. FEBS Lett 39:157–159

    Article  CAS  PubMed  Google Scholar 

  • Glogau RG (1997) Physiologic and structural changes associated with aging skin. Dermatol Clin 15:555–559

    Article  CAS  PubMed  Google Scholar 

  • Goolsby TV, Lombardo FA (2006) Extravasation of chemotherapeutic agents: prevention and treatment. Semin Oncol 33:139–143

    Article  CAS  PubMed  Google Scholar 

  • Guedan S, Rojas JJ, Gros A et al (2010) Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth. Mol Ther 18:1275–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gul A, Can E, Niyaz L et al (2015) Hyaluronidase in ophthalmic evisceration surgery. Trop Dr 45:100–104

    Google Scholar 

  • Hamizi S, Freyer G, Bakrin N et al (2013) Subcutaneous trastuzumab: development of a new formulation for treatment of HER2-positive early breast cancer. Onco Targets Ther 6:89–94

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harb G, Lebel F, Battikha J et al (2010) Safety and pharmacokinetics of subcutaneous ceftriaxone administered with or without recombinant human hyaluronidase (rHuPH20) versus intravenous ceftriaxone administration in adult volunteers. Curr Med Res Opin 26:279–288

    Article  CAS  PubMed  Google Scholar 

  • Harman D (1992) Role of free radicals in aging and disease. Ann N Y Acad Sci 673:126–141

    Article  CAS  PubMed  Google Scholar 

  • Hascall V, Esko JD (2015) Hyaluronan. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, Darvill AG, Kinoshita T, Packer NH, Prestegard JH, Schnaar RL, Seeberger PH (eds) Essentials of glycobiology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

  • Henson PM (1971a) The immunologic release of constituents from neutrophil leukocytes. II. Mechanisms of release during phagocytosis, and adherence to nonphagocytosable surfaces. J Immunol 107:1547–1557

    CAS  PubMed  Google Scholar 

  • Henson PM (1971b) The immunologic release of constituents from neutrophil leukocytes. I. The role of antibody and complement on nonphagocytosable surfaces or phagocytosable particles. J Immunol 107:1535–1546

    CAS  PubMed  Google Scholar 

  • Herman IM, Castellot JJ Jr (1987) Regulation of vascular smooth muscle cell growth by endothelial-synthesized extracellular matrices. Arteriosclerosis 7:463–469

    Article  CAS  PubMed  Google Scholar 

  • Hilton S, Schrumpf H, Buhren BA et al (2014) Hyaluronidase injection for the treatment of eyelid edema: a retrospective analysis of 20 patients. Eur J Med Res 19:30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hirsch RJ, Brody HJ, Carruthers JD (2007a) Hyaluronidase in the office: a necessity for every dermasurgeon that injects hyaluronic acid. J Cosmet Laser Ther 9:182–185

    Article  PubMed  Google Scholar 

  • Hirsch RJ, Cohen JL, Carruthers JD (2007b) Successful management of an unusual presentation of impending necrosis following a hyaluronic acid injection embolus and a proposed algorithm for management with hyaluronidase. Dermatol Surg 33:357–360

    CAS  PubMed  Google Scholar 

  • Hompesch M, Muchmore DB, Morrow L et al (2011) Accelerated insulin pharmacokinetics and improved postprandial glycemic control in patients with type 1 diabetes after coadministration of prandial insulins with hyaluronidase. Diabetes Care 34:666–668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang E, Song YS (2017) Quantitative correlation between hyaluronic acid filler and hyaluronidase. J Craniofac Surg 28:838–841

    Article  PubMed  Google Scholar 

  • Hyde CE, Old RW (1999) Expression pattern of a novel hyaluronidase during Xenopus embryogenesis. Mech Dev 82:213–217

    Article  CAS  PubMed  Google Scholar 

  • Jahn K, Homey B, Gerber PA (2014) Management of complications after aesthetic hyaluronic acid injections. Hautarzt 65:851–853

    Article  CAS  PubMed  Google Scholar 

  • Jones D, Tezel A, Borrell M (2010) In vitro resistance to degradation of hyaluronic acid dermal fillers by ovine testicular hyaluronidase. Dermatol Surg 36:804–809

    Article  CAS  Google Scholar 

  • Juhasz MLW, Levin MK, Marmur ES (2017) The kinetics of reversible hyaluronic acid filler injection treated with hyaluronidase. Dermatol Surg 43:841–847

    Article  CAS  PubMed  Google Scholar 

  • Juhlin L (1997) Hyaluronan in skin. J Intern Med 242:61–66

    Article  CAS  PubMed  Google Scholar 

  • Kagan L, Mager DE (2013) Mechanisms of subcutaneous absorption of rituximab in rats. Drug Metab Dispos 41:248–255

    Article  CAS  PubMed  Google Scholar 

  • Kassner E (2000) Evaluation and treatment of chemotherapy extravasation injuries. J Pediatr Oncol Nurs 17:135–148

    Article  CAS  PubMed  Google Scholar 

  • Kenne L, Gohil S, Nilsson EM et al (2013) Modification and cross-linking parameters in hyaluronic acid hydrogels – definitions and analytical methods. Carbohydr Polym 91:410–418

    Article  CAS  PubMed  Google Scholar 

  • Khandwala M, Ahmed S, Goel S et al (2008) The effect of hyaluronidase on ultrasound-measured dispersal of local anaesthetic following sub-Tenon injection. Eye (Lond) 22:1065–1068

    Article  CAS  Google Scholar 

  • Khorlin AY, Vikha IV, Milishnikov AN (1973) Subunit structure of testicular hyaluronidase. FEBS Lett 31:107–110

    Article  CAS  PubMed  Google Scholar 

  • Kim DW, Yoon ES, Ji YH et al (2011) Vascular complications of hyaluronic acid fillers and the role of hyaluronidase in management. J Plast Reconstr Aesthet Surg 64:1590–1595

    Article  PubMed  Google Scholar 

  • Kind LS, Roffler S (1961) Allergic reactions to hyaluronidase. Proc Soc Exp Biol Med 106:734–735

    Article  CAS  PubMed  Google Scholar 

  • Kontis TC (2013) Contemporary review of injectable facial fillers. JAMA Facial Plast Surg 15:58–64

    Article  PubMed  Google Scholar 

  • Kreil G (1995) Hyaluronidases – a group of neglected enzymes. Protein Sci 4:1666–1669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuppermann BD, Thomas EL, De Smet MD et al (2005) Pooled efficacy results from two multinational randomized controlled clinical trials of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol 140:573–584

    Article  CAS  PubMed  Google Scholar 

  • Landau M (2015) Hyaluronidase caveats in treating filler complications. Dermatol Surg 41(Suppl 1):S347–S353

    Article  PubMed  Google Scholar 

  • Landsman L, Mandy SH (1991) Adjuncts to scalp reduction surgery. Intraoperative tissue expanders and hyaluronidase. J Dermatol Surg Oncol 17:670–672

    Article  CAS  PubMed  Google Scholar 

  • Langer SW, Sehested M, Jensen PB (2000) Treatment of anthracycline extravasation with dexrazoxane. Clin Cancer Res 6:3680–3686

    CAS  PubMed  Google Scholar 

  • Laurent TC, Fraser JR (1992) Hyaluronan. FASEB J 6:2397–2404

    Article  CAS  PubMed  Google Scholar 

  • Lee A, Grummer SE, Kriegel D et al (2010) Hyaluronidase. Dermatol Surg 36:1071–1077

    Article  CAS  PubMed  Google Scholar 

  • Lewis-Smith PA (1986) Adjunctive use of hyaluronidase in local anaesthesia. Br J Plast Surg 39:554–558

    Article  CAS  PubMed  Google Scholar 

  • Lindley-Jones MF (2000) Topical anaesthesia for phacoemulsification surgery. Clin Exp Ophthalmol 28:287–289

    Article  CAS  PubMed  Google Scholar 

  • Lokeshwar VB, Selzer MG (2008) Hyalurondiase: both a tumor promoter and suppressor. Semin Cancer Biol 18:281–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lokeshwar VB, Rubinowicz D, Schroeder GL et al (2001) Stromal and epithelial expression of tumor markers hyaluronic acid and HYAL1 hyaluronidase in prostate cancer. J Biol Chem 276:11922–11932

    Article  CAS  PubMed  Google Scholar 

  • Lorenc ZP, Fagien S, Flynn TC et al (2013) Review of key Belotero Balance safety and efficacy trials. Plast Reconstr Surg 132:33S–40S

    Article  CAS  PubMed  Google Scholar 

  • Lv SH, Rong SF, Cai BG et al (2015) Property and current clinical applications of mammal hyaluronidase. Eur Rev Med Pharmacol Sci 19:3968–3976

    PubMed  Google Scholar 

  • Maccara ME (1983) Extravasation: a hazard of intravenous therapy. Drug Intell Clin Pharm 17:713–717

    CAS  PubMed  Google Scholar 

  • Martin-Deleon PA (2011) Germ-cell hyaluronidases: their roles in sperm function. Int J Androl 34:e306–e318

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Quintanilla J, He D, Wakimoto H et al (2015) Encapsulated stem cells loaded with hyaluronidase-expressing oncolytic virus for brain tumor therapy. Mol Ther 23:108–118

    Article  CAS  PubMed  Google Scholar 

  • Mcclean D (1941) Studies on diffusing factors: the hyaluronidase activity of testicular extracts, bacterial culture filtrates and other agents that increase tissue permeability. Biochem J 35:159–183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Menzel EJ, Farr C (1998) Hyaluronidase and its substrate hyaluronan: biochemistry, biological activities and therapeutic uses. Cancer Lett 131:3–11

    Article  CAS  PubMed  Google Scholar 

  • Menzinger S, Kaya A, Saurat JH et al (2016) Injected hyaluronidase reduces the volume of exogenous hyaluronate fillers in mice and results in clinical improvement in a patient with pretibial myxedema. Dermatopathology (Basel) 3:61–67

    Article  Google Scholar 

  • Meyer AW (1937) The hunters in embryology: part III. Cal West Med 46:38–40

    CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer K (1947) The biological significance of hyaluronic acid and hyaluronidase. Physiol Rev 27:335–359

    Article  CAS  PubMed  Google Scholar 

  • Meyer LJ, Stern R (1994) Age-dependent changes of hyaluronan in human skin. J Invest Dermatol 102:385–389

    Article  CAS  PubMed  Google Scholar 

  • Montgomery LA, Budreau GK (1996) Implementing a clinical practice guideline to improve pediatric intravenous infiltration outcomes. AACN Clin Issues 7:411–424

    Article  CAS  PubMed  Google Scholar 

  • Morcos PN, Zhang X, Mcintyre C et al (2013) Pharmacokinetics and pharmacodynamics of single subcutaneous doses of tocilizumab administered with or without rHuPH20. Int J Clin Pharmacol Ther 51:537–548

    Article  CAS  PubMed  Google Scholar 

  • Muchmore DB, Vaughn DE (2010) Review of the mechanism of action and clinical efficacy of recombinant human hyaluronidase coadministration with current prandial insulin formulations. J Diabetes Sci Technol 4:419–428

    Article  PubMed  PubMed Central  Google Scholar 

  • Myung Y, Yim S, Jeong JH et al (2017) The classification and prognosis of periocular complications related to blindness following cosmetic filler injection. Plast Reconstr Surg 140:61–64

    Article  CAS  PubMed  Google Scholar 

  • Narayanan R, Kuppermann BD (2009) Hyaluronidase for pharmacologic vitreolysis. Dev Ophthalmol 44:20–25

    Article  CAS  PubMed  Google Scholar 

  • Narins RS, Bowman PH (2005) Injectable skin fillers. Clin Plast Surg 32:151–162

    Article  PubMed  Google Scholar 

  • Narins RS, Coleman WP 3rd, Donofrio LM et al (2010) Improvement in nasolabial folds with a hyaluronic acid filler using a cohesive polydensified matrix technology: results from an 18-month open-label extension trial. Dermatol Surg 36(Suppl 3):1800–1808

    Article  CAS  PubMed  Google Scholar 

  • Narins RS, Brandt FS, Dayan SH et al (2011) Persistence of nasolabial fold correction with a hyaluronic acid dermal filler with retreatment: results of an 18-month extension study. Dermatol Surg 37:644–650

    Article  CAS  PubMed  Google Scholar 

  • Olver IN, Aisner J, Hament A et al (1988) A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol 6:1732–1735

    Article  CAS  PubMed  Google Scholar 

  • Ozturk CN, Li Y, Tung R et al (2013) Complications following injection of soft-tissue fillers. Aesthet Surg J 33:862–877

    Article  PubMed  Google Scholar 

  • Papakonstantinou E, Roth M, Karakiulakis G (2012) Hyaluronic acid: a key molecule in skin aging. Dermatoendocrinology 4:253–258

    Article  CAS  Google Scholar 

  • Perrault M, Housset E (1952) Hyaluronidase and its therapeutic applications. Therapie 7:196–206

    CAS  PubMed  Google Scholar 

  • Pirrello RD, Ting Chen C, Thomas SH (2007) Initial experiences with subcutaneous recombinant human hyaluronidase. J Palliat Med 10:861–864

    Article  PubMed  Google Scholar 

  • Rao V, Chi S, Woodward J (2014) Reversing facial fillers: interactions between hyaluronidase and commercially available hyaluronic-acid based fillers. J Drugs Dermatol 13:1053–1056

    CAS  PubMed  Google Scholar 

  • Rees MD, Hawkins CL, Davies MJ (2004) Hypochlorite and superoxide radicals can act synergistically to induce fragmentation of hyaluronan and chondroitin sulphates. Biochem J 381:175–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Remy M, Pinter F, Nentwich MM et al (2008) Efficacy and safety of hyaluronidase 75 IU as an adjuvant to mepivacaine for retrobulbar anesthesia in cataract surgery. J Cataract Refract Surg 34:1966–1969

    Article  PubMed  Google Scholar 

  • Reynolds PM, Maclaren R, Mueller SW et al (2014) Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy 34:617–632

    Article  CAS  PubMed  Google Scholar 

  • Ridenour S, Reader A, Beck M et al (2001) Anesthetic efficacy of a combination of hyaluronidase and lidocaine with epinephrine in inferior alveolar nerve blocks. Anesth Prog 48:9–15

    CAS  PubMed  PubMed Central  Google Scholar 

  • Romagnoli M, Belmontesi M (2008) Hyaluronic acid-based fillers: theory and practice. Clin Dermatol 26:123–159

    Article  PubMed  Google Scholar 

  • Rowlett J (2012) Extravasation of contrast media managed with recombinant human hyaluronidase. Am J Emerg Med 30:2102 e1–2102 e3

    Article  Google Scholar 

  • Sall I, Ferard G (2007) Comparison of the sensitivity of 11 crosslinked hyaluronic acid gels to bovine testis hyaluronidase. Polym Degrad Stab 92:915–919

    Article  CAS  Google Scholar 

  • Sbitany H, Koltz PF, Mays C et al (2010) CT contrast extravasation in the upper extremity: strategies for management. Int J Surg 8:384–386

    Article  PubMed  Google Scholar 

  • Schonenberg H (1952) Therapeutic use of hyaluronidase in pediatrics. Kinderarztl Prax 20:223–228

    CAS  PubMed  Google Scholar 

  • Schoog M (1951) Therapeutic use of hyaluronidase. Dermatol Wochenschr 124:1033–1037

    CAS  PubMed  Google Scholar 

  • Schrijvers DL (2003) Extravasation: a dreaded complication of chemotherapy. Ann Oncol 14(Suppl 3):iii26–iii30

    Article  PubMed  Google Scholar 

  • Schummer W, Schummer C, Muller A et al (2003) Extravasation: a rare complication of central venous cannulation? Case report of an imminent erosion of the common carotid artery. Anaesthesist 52:711–717

    Article  CAS  PubMed  Google Scholar 

  • Schwartz DM, Shuster S, Jumper MD et al (1996) Human vitreous hyaluronidase: isolation and characterization. Curr Eye Res 15:1156–1162

    Article  CAS  PubMed  Google Scholar 

  • Schwartzman J (1951) Hyaluronidase in pediatrics. N Y State J Med 51:215–221

    CAS  PubMed  Google Scholar 

  • Selek H, Ozer H, Aygencel G et al (2007) Compartment syndrome in the hand due to extravasation of contrast material. Arch Orthop Trauma Surg 127:425–427

    Article  PubMed  Google Scholar 

  • Shpilberg O, Jackisch C (2013) Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase. Br J Cancer 109:1556–1561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silverstein SM, Greenbaum S, Stern R (2012) Hyaluronidase in ophthalmology. J Appl Res 12(1):1–13

    CAS  Google Scholar 

  • Smith KJ, Skelton HG, Turiansky G et al (1997) Hyaluronidase enhances the therapeutic effect of vinblastine in intralesional treatment of Kaposi’s sarcoma. Military Medical Consortium for the Advancement of Retroviral Research (MMCARR). J Am Acad Dermatol 36:239–242

    Article  CAS  PubMed  Google Scholar 

  • Soldi A (1951) Hyaluronidase and its therapeutic applications. Farmacol Sci Tec 6:765–791

    CAS  Google Scholar 

  • Soltes L, Mendichi R, Kogan G et al (2006) Degradative action of reactive oxygen species on hyaluronan. Biomacromolecules 7:659–668

    Article  CAS  PubMed  Google Scholar 

  • Spandorfer PR, Mace SE, Okada PJ et al (2012) A randomized clinical trial of recombinant human hyaluronidase-facilitated subcutaneous versus intravenous rehydration in mild to moderately dehydrated children in the emergency department. Clin Ther 34:2232–2245

    Article  CAS  PubMed  Google Scholar 

  • Speth F, Haas JP, Hinze CH (2016) Treatment with high-dose recombinant human hyaluronidase-facilitated subcutaneous immune globulins in patients with juvenile dermatomyositis who are intolerant to intravenous immune globulins: a report of 5 cases. Pediatr Rheumatol Online J 14:52

    Article  PubMed  PubMed Central  Google Scholar 

  • Stanford BL, Hardwicke F (2003) A review of clinical experience with paclitaxel extravasations. Support Care Cancer 11:270–277

    Article  PubMed  Google Scholar 

  • Stebliuk PN (1972) Combined effect of hyaluronidase, ribonuclease and antibiotics on pathogenous Staphylococci. Vrach Delo 4:151

    CAS  PubMed  Google Scholar 

  • Stern R (2008) Hyaluronidases in cancer biology. Semin Cancer Biol 18:275–280

    Article  CAS  PubMed  Google Scholar 

  • Stern R, Asari AA, Sugahara KN (2006) Hyaluronan fragments: an information-rich system. Eur J Cell Biol 85:699–715

    Article  CAS  PubMed  Google Scholar 

  • Stocks D, Sundaram H, Michaels J et al (2011) Rheological evaluation of the physical properties of hyaluronic acid dermal fillers. J Drugs Dermatol 10:974–980

    CAS  PubMed  Google Scholar 

  • Sundaram H, Voigts B, Beer K et al (2010) Comparison of the rheological properties of viscosity and elasticity in two categories of soft tissue fillers: calcium hydroxylapatite and hyaluronic acid. Dermatol Surg 36(Suppl 3):1859–1865

    Article  CAS  PubMed  Google Scholar 

  • Tammi R, Ripellino JA, Margolis RU et al (1988) Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe. J Invest Dermatol 90:412–414

    Article  CAS  PubMed  Google Scholar 

  • Tezel A, Fredrickson GH (2008) The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 10:35–42

    Article  PubMed  Google Scholar 

  • Thomas JR, Wallace MS, Yocum RC et al (2009) The INFUSE-Morphine study: use of recombinant human hyaluronidase (rHuPH20) to enhance the absorption of subcutaneously administered morphine in patients with advanced illness. J Pain Symptom Manag 38:663–672

    Article  CAS  Google Scholar 

  • Thorpe JN (1951) Procaine with hyaluronidase as local anesthetic. Lancet 1:210–211

    Article  CAS  PubMed  Google Scholar 

  • Tran C, Carraux P, Micheels P et al (2014) In vivo bio-integration of three hyaluronic acid fillers in human skin: a histological study. Dermatology 228:47–54

    Article  CAS  PubMed  Google Scholar 

  • Valko M, Leibfritz D, Moncol J et al (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84

    Article  CAS  PubMed  Google Scholar 

  • Vaughn DE, Yocum RC, Muchmore DB et al (2009) Accelerated pharmacokinetics and glucodynamics of prandial insulins injected with recombinant human hyaluronidase. Diabetes Technol Ther 11:345–352

    Article  CAS  PubMed  Google Scholar 

  • Volpi N, Schiller J, Stern R et al (2009) Role, metabolism, chemical modifications and applications of hyaluronan. Curr Med Chem 16:1718–1745

    Article  CAS  PubMed  Google Scholar 

  • Wang CL, Cohan RH, Ellis JH et al (2007) Frequency, management, and outcome of extravasation of nonionic iodinated contrast medium in 69,657 intravenous injections. Radiology 243:80–87

    Article  PubMed  Google Scholar 

  • Wang M, Li W, Zhang Y et al (2017) Comparison of intra-arterial and subcutaneous testicular hyaluronidase injection treatments and the vascular complications of hyaluronic acid filler. Dermatol Surg 43:246–254

    Article  CAS  PubMed  Google Scholar 

  • Warnery, Dumon G, Brin et al (1954) Antibiotics and hyaluronidase combined in aerosols in the treatment of lesions of pulmonary tuberculosis; 20 months’ trial. Rev Tuberc 18:37–45

    CAS  PubMed  Google Scholar 

  • Wasserman RL (2017) Recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin infusion in primary immunodeficiency diseases. Immunotherapy 9:1035–1050

    Article  CAS  PubMed  Google Scholar 

  • Wasserman RL, Melamed I, Stein MR et al (2012) Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency. J Allergy Clin Immunol 130:951–7 e11

    Article  CAS  PubMed  Google Scholar 

  • Wasserman RL, Melamed I, Kobrynski L et al (2016) Recombinant human hyaluronidase facilitated subcutaneous immunoglobulin treatment in pediatric patients with primary immunodeficiencies: long-term efficacy, safety and tolerability. Immunotherapy 8:1175–1186

    Article  CAS  PubMed  Google Scholar 

  • Weigel PH (2015) Hyaluronan synthase: the mechanism of initiation at the reducing end and a pendulum model for polysaccharide translocation to the cell exterior. Int J Cell Biol 2015:367579

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weller K, Maurer M, Fridman M et al (2017) Health-related quality of life with hereditary angioedema following prophylaxis with subcutaneous C1-inhibitor with recombinant hyaluronidase. Allergy Asthma Proc 38:143–151

    Article  CAS  PubMed  Google Scholar 

  • Wiegand R, Brown J (2010) Hyaluronidase for the management of dextrose extravasation. Am J Emerg Med 28:257 e1–257 e2

    Article  Google Scholar 

  • Wohlrab J, Finke R, Franke WG et al (2012a) Clinical trial for safety evaluation of hyaluronidase as diffusion enhancing adjuvant for infiltration analgesia of skin with lidocaine. Dermatol Surg 38:91–96

    Article  CAS  PubMed  Google Scholar 

  • Wohlrab J, Finke R, Franke WG et al (2012b) Efficacy study of hyaluronidase as a diffusion promoter for lidocaine in infiltration analgesia of skin. Plast Reconstr Surg 129:771e–772e

    Article  CAS  PubMed  Google Scholar 

  • Wohlrab J, Wohlrab D, Wohlrab L et al (2014) Use of hyaluronidase for pharmacokinetic increase in bioavailability of intracutaneously applied substances. Skin Pharmacol Physiol 27:276–282

    Article  CAS  PubMed  Google Scholar 

  • Yocum RC, Kennard D, Heiner LS (2007) Assessment and implication of the allergic sensitivity to a single dose of recombinant human hyaluronidase injection: a double-blind, placebo-controlled clinical trial. J Infus Nurs 30:293–299

    Article  PubMed  Google Scholar 

  • Yui N, Nihira J, Okano T et al (1993) Regulated release of drug microspheres from inflammation responsive degradable matrices of crosslinked hyaluronic acid. J Control Release 25:133–143

    Article  CAS  Google Scholar 

  • Zahl K, Jordan A, Mcgroarty J et al (1991) Peribulbar anesthesia. Effect of bicarbonate on mixtures of lidocaine, bupivacaine, and hyaluronidase with or without epinephrine. Ophthalmology 98:239–242

    Article  CAS  PubMed  Google Scholar 

  • Zaneveld LJ, Polakoski KL, Schumacher GF (1973) Properties of acrosomal hyaluronidase from bull spermatozoa. Evidence for its similarity to testicular hyaluronidase. J Biol Chem 248:564–570

    Article  CAS  PubMed  Google Scholar 

  • Zaoli G (1958) Hyaluronidase-antibiotic association in the treatment of acute otitis media of the infant & child. Minerva Otorinolaringol 8:354–358

    CAS  PubMed  Google Scholar 

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Weber, G.C., Buhren, B.A., Schrumpf, H., Wohlrab, J., Gerber, P.A. (2019). Clinical Applications of Hyaluronidase. In: Labrou, N. (eds) Therapeutic Enzymes: Function and Clinical Implications. Advances in Experimental Medicine and Biology, vol 1148. Springer, Singapore. https://doi.org/10.1007/978-981-13-7709-9_12

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