The Diverse Roles of Hyaluronidase: Revealing Its Biochemical, Preclinical, and Clinical Applications
Hyaluronidase; from biology to therapy
-
Mahdiyeh Safary
,
Seyyed Mohammad Hassan Modarressi
,
Mobina Tajdari
,
Amirreza Peyrovinasab
,
amir rezazadeh
,
Sakineh Alijanpour
,
Mohammad Hossein Modarressi
Abstract
Hyaluronidase, a group of enzymes that catalyze the hydrolysis of hyaluronic acid, plays a pivotal role in modulating the extracellular matrix and enhancing tissue permeability. Hyaluronidase has gained widespread attention for its diverse biochemical properties and expanding therapeutic potential. This review provides a comprehensive overview of hyaluronidase, focusing on its biochemical characteristics, mechanisms of action, and regulatory pathways. We examine its utility in preclinical models, highlighting its role in drug delivery, tissue remodeling, and cancer research. Clinically, hyaluronidase has been employed in various domains including ophthalmology, dermatology, oncology, and as an adjuvant in subcutaneous and intramuscular drug administration. Additionally, its role in reversing complications of dermal filler injections has led to increased use in aesthetic medicine. Despite its broad application, challenges such as immunogenicity, variability in enzyme sources, and potential adverse effects warrant continued investigation. Through an integrated analysis of current evidence, this review aims to elucidate the multifaceted roles of hyaluronidase and explore its emerging applications in modern medicine.
1. Jung H. Hyaluronidase: An overview of its properties, applications, and side effects. Arch Plast Surg. 2020;47(04):297-300. https://doi.org/10.5999/aps.2020.00752
2. Mohankumar A, Rajan M. Role of hyaluronidase as an adjuvant in local anesthesia for cataract surgery. Indian J Ophthalmol. 2023;71(7):2649-55. https://doi.org/10.4103/ijo.ijo_2515_22
3. Weber GC, Buhren BA, Schrumpf H, Wohlrab J, Gerber PA. Clinical applications of hyaluronidase. Therapeutic enzymes: function and clinical implications. 2019:255-77.
4. Kroumpouzos G, Treacy P. Hyaluronidase for dermal filler complications: review of applications and dosage recommendations. JMIR Dermatol. 2024;7(1):e50403. https://doi.org/10.2196/50403
5. Ahmadian E, Dizaj SM, Eftekhari A, Dalir E, Vahedi P, Hasanzadeh A, et al. The potential applications of hyaluronic acid hydrogels in biomedicine. Drug Res. 2020;70(01):6-11. https://doi.org/10.1055/a-0991-7585
6. Marković-Housley Z, Miglierini G, Soldatova L, Rizkallah PJ, Müller U, Schirmer T. Crystal structure of hyaluronidase, a major allergen of bee venom. Structure. 2000;8(10):1025-35. https://doi.org/10.1016/s0969-2126(00)00511-6
7. Kaul A, Short WD, Wang X, Keswani SG. Hyaluronidases in human diseases. Int J Mol Sci. 2021;22(6):3204. https://doi.org/10.3390/ijms22063204
8. Stern R, Jedrzejas MJ. Hyaluronidases: their genomics, structures, and mechanisms of action. Chem Rev. 2006;106(3):818-39. https://doi.org/10.1021/cr050247k
9. Csoka AB, Frost GI, Stern R. The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol. 2001;20(8):499-508. https://doi.org/10.1016/s0945-053x(01)00172-x
10. Chowdhury B, Hemming R, Hombach-Klonisch S, Flamion B, Triggs-Raine B. Murine hyaluronidase 2 deficiency results in extracellular hyaluronan accumulation and severe cardiopulmonary dysfunction. J Biolo Chem. 2013;288(1):520-8. https://doi.org/10.1074/jbc.m112.393629
11. Triggs-Raine B, Natowicz MR. Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism. World J Biol Chem. 2015;6(3):110. https://doi.org/10.4331/wjbc.v6.i3.110
12. West DC, Shaw DM, Lorenz P, Adzick NS, Longaker MT. Fibrotic healing of adult and late gestation fetal wounds correlates with increased hyaluronidase activity and removal of hyaluronan. Int J Biochem Cell Biol. 1997;29(1):201-10. https://doi.org/10.1016/s1357-2725(96)00133-1
13. Schwartz DM, Jumper MD, Lui G-M, Dang S, Schuster S, Stern R. Corneal endothelial hyaluronidase: a role in anterior chamber hyaluronic acid catabolism. Cornea. 1997;16(2):188-91. https://doi.org/10.1097/00003226-199703000-00011
14. Reitinger S, Lepperdinger G. Hyaluronan, a ready choice to fuel regeneration: a mini-review. Gerontology. 2012;59(1):71-6. https://doi.org/10.1159/000342200
15. Fronza M, Caetano GF, Leite MN, Bitencourt CS, Paula-Silva FW, Andrade TA, et al. Hyaluronidase modulates inflammatory response and accelerates the cutaneous wound healing. PLoS One. 2014;9(11):e112297. https://doi.org/10.1371/journal.pone.0112297
16. Seol D-W, Joo SH, Kim Y-H, Song B-S, Sim B-W, Kim S-U, et al. Sperm hyaluronidase is critical to mammals’ fertilization for its ability to disperse cumulus–oocyte complex layer. Asian J Androl. 2022;24(4):411-5. https://doi.org/10.4103/aja202176
17. Lokeshwar VB, Selzer MG. Hyaluronidase: both a tumor promoter and suppressor. Hyaluronan Cancer Biol. 2009:189-206. https://doi.org/10.1016/b978-012374178-3.10011-0
18. Chowdhury B, Xiang B, Liu M, Hemming R, Dolinsky VW, Triggs-Raine B. Hyaluronidase 2 deficiency causes increased mesenchymal cells, congenital heart defects, and heart failure. Circ Cardiovasc Genet. 2017;10(1):e001598. https://doi.org/10.1161/circgenetics.116.001598
19. Jung M, Ma Y, Iyer RP, DeLeon-Pennell KY, Yabluchanskiy A, Garrett MR, et al. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol. 2017;112:1-14. https://doi.org/10.1007/s00395-017-0622-5
20. Yoshino Y, Goto M, Hara H, Inoue S. The role and regulation of TMEM2 (transmembrane protein 2) in HYBID (hyaluronan (HA)-binding protein involved in HA depolymerization/KIAA1199/CEMIP)-mediated HA depolymerization in human skin fibroblasts. Biochem Biophys Res Commun. 2018;505(1):74-80. https://doi.org/10.1016/j.bbrc.2018.09.097
21. Chopra D, Brehm JE, Morrison B. Hyaluronidase as a successful treatment modality for scleroderma-induced microstomia. Dermatol Surg. 2022;48(9):1014-5. https://doi.org/10.1097/dss.0000000000003543
22. Averbeck M, Gebhardt CA, Voigt S, Beilharz S, Anderegg U, Termeer CC, et al. Differential regulation of hyaluronan metabolism in the epidermal and dermal compartments of human skin by UVB irradiation. J Invest Dermatol. 2007;127(3):687-97. https://doi.org/10.1038/sj.jid.5700614
23. Colombaro V, Jadot I, Declèves A-E, Voisin V, Giordano L, Habsch I, et al. Hyaluronidase 1 and hyaluronidase 2 are required for renal hyaluronan turnover. Acta Histochemica. 2015;117(1):83-91. https://doi.org/10.1016/j.acthis.2014.11.007
24. Harada H, Takahashi M. CD44-dependent intracellular and extracellular catabolism of hyaluronic acid by hyaluronidase-1 and-2. J Biol Chem. 2007;282(8):5597-607. https://doi.org/10.1074/jbc.m608358200
25. Kim J, Seki E. Hyaluronan in liver fibrosis: basic mechanisms, clinical implications, and therapeutic targets. Hepatol Commun. 2023;7(4):e0083. https://doi.org/10.1097/hc9.0000000000000083
26. Orăşan OH, Sava M, Iancu M, Cozma A, Saplonţai-Pop A, Sarlea Ţărmure S, et al. Serum hyaluronic acid in chronic viral hepatitis B and C: a biomarker for assessing liver fibrosis in chronic hemodialysis patients. Int Urol Nephrol. 2015;47:1209-17. https://doi.org/10.1007/s11255-015-1017-x
27. Rezaei‐Agdam H, Moshari S, Nahari E, Minas A, Daliri Z, Hallaj M, et al. Zeta and hyaluronic acid assessments, novel sperm selection procedures, in animal model for male infertility. Andrologia. 2019;51(11):e13447. https://doi.org/10.1111/and.13447
28. Nasr-Esfahani M, Razavi S, Vahdati A, Fathi F, Tavalaee M. Evaluation of sperm selection procedure based on hyaluronic acid binding ability on ICSI outcome. J Assist Reprod Genet. 2008;25:197-203. https://doi.org/10.1007/s10815-008-9223-4
29. Nixon B, Schjenken JE, Burke ND, Skerrett-Byrne DA, Hart HM, De Iuliis GN, et al. New horizons in human sperm selection for assisted reproduction. Front Endocrinol 2023;14:1145533. https://doi.org/10.3389/fendo.2023.1145533
30. Sawan D, Hersant B. Therapeutic use of hyaluronidase in obstetrics. Open J Obstet Gynecol. 2021;11(11):1581-8. https://doi.org/10.4236/ojog.2021.1111147
31. Kwon H, Park HS, Shim J-Y, Lee KW, Choi S-J, Choi GY. Randomized, double-blind, placebo-controlled trial on the efficacy of hyaluronidase in preventing perineal trauma in nulliparous women. Yonsei Med J. 2020;61(1):79-84. https://doi.org/10.3349/ymj.2020.61.1.79
32. Gomes T-P, Palma L-F, Tornelli M-J, Tornelli H-R, Fukuoka C-Y, Borsatti M-A. Hyaluronidase following buccal infiltrations of articaine with epinephrine for anesthesia of mandibular first molars: a split-mouth, double-blind, placebo-controlled randomized clinical trial. J Clin Exp Dent. 2022;14(11):e938. https://doi.org/10.4317/jced.59809
33. Silverstein SM, Greenbaum S, Stern R. Hyaluronidase in ophthalmology. J Appl Res. 2012;12(1).
34. Benozzi J, Nahum LP, Campanelli JL, Rosenstein RE. Effect of hyaluronic acid on intraocular pressure in rats. Invest Ophthalmol Vis Sci. 2002;43(7):2196-200.
35. Signorini M, Liew S, Sundaram H, De Boulle KL, Goodman GJ, Monheit G, et al. Global aesthetics consensus: avoidance and management of complications from hyaluronic acid fillers—evidence-and opinion-based review and consensus recommendations. Plast Reconstr Surg. 2016;137(6):961e-71e. https://doi.org/10.1097/prs.0000000000002184
36. Borzabadi-Farahani A, Mosahebi A, Zargaran D. A scoping review of hyaluronidase use in managing the complications of aesthetic interventions. Aesthet Plast Surg. 2024;48(6):1193-209. https://doi.org/10.1007/s00266-022-03207-9
37. Wohlrab J, Finke R, Franke WG, Wohlrab A. Clinical trial for safety evaluation of hyaluronidase as diffusion enhancing adjuvant for infiltration analgesia of skin with lidocaine. Dermatol Surg. 2012;38(1):91-6. https://doi.org/10.1111/j.1524-4725.2011.02146.x
38. Feighery C, McCoy E, Johnston P, Armstrong D. Delayed hypersensitivity to hyaluronidase (Hyalase™) used during cataract surgery. Contact Dermatitis. 2007;57(5). https://doi.org/10.1111/j.1600-0536.2007.01038.x
39. Pardue EL, Ibrahim S, Ramamurthi A. Role of hyaluronan in angiogenesis and its utility to angiogenic tissue engineering. Organogenesis. 2008;4(4):203-14. https://doi.org/10.4161/org.4.4.6926
40. Spinelli FM, Vitale DL, Demarchi G, Cristina C, Alaniz L. The immunological effect of hyaluronan in tumor angiogenesis. Clin Transl Immunol. 2015;4(12):e52. https://doi.org/10.1038/cti.2015.35
41. Shibata Y, Taogoshi T, Matsuo H. Extravasation of noncytotoxic agents: skin injury and risk classification. Biol Pharm Bull. 2023;46(6):746-55. https://doi.org/10.1248/bpb.b22-00850
42. Ong J, Van Gerpen R. Recommendations for management of noncytotoxic vesicant extravasations. J Infus Nurs. 2020;43(6):319-43. https://doi.org/10.1097/nan.0000000000000392
43. Stefanos SS, Kiser TH, MacLaren R, Mueller SW, Reynolds PM. Management of noncytotoxic extravasation injuries: A focused update on medications, treatment strategies, and peripheral administration of vasopressors and hypertonic saline. Pharmacotherapy. 2023;43(4):321-37. https://doi.org/10.1002/phar.2794
44. Muggenthaler MM, Chowdhury B, Hasan SN, Cross HE, Mark B, Harlalka GV, et al. Mutations in HYAL2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice. PLoS Genet. 2017;13(1):e1006470. https://doi.org/10.1371/journal.pgen.1006470
45. Zaaba MIS, Mokhtar KI, Rajion ZA. Revisiting Genetics of Cleft Lip with or without Cleft Palate and Cleft Palate Only: A Narrative Review. Arch Orofac Sci. 2023;18(2). https://doi.org/10.21315/aos2023.1802.rv01
46. Watson D, Reuther MS, Wong VW, Sah RL, Masuda K, Briggs KK. Effect of hyaluronidase on tissue‐engineered human septal cartilage. Laryngoscope. 2016;126(9):1984-9. https://doi.org/10.1002/lary.25720
47. Collins MN, Birkinshaw C. Hyaluronic acid based scaffolds for tissue engineering—A review. Carbohydr Polym. 2013;92(2):1262-79. https://doi.org/10.1016/j.carbpol.2012.10.028
48. Ran X, Du Y, Wang Z, Wang H, Pu F, Ren J, et al. Hyaluronic acid-templated Ag nanoparticles/graphene oxide composites for synergistic therapy of bacteria infection. CS Appl Mater Interfaces. 2017;9(23):19717-24. https://doi.org/10.1021/acsami.7b05584
49. Velesiotis C, Vasileiou S, Vynios DH. A guide to hyaluronan and related enzymes in breast cancer: biological significance and diagnostic value. FEBS J. 2019;286(15):3057-74. https://doi.org/10.1111/febs.14860
50. Whatcott CJ, Han H, Posner RG, Hostetter G, Von Hoff DD. Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look. Cancer Discov. 2011;1(4):291-6. https://doi.org/10.1158/2159-8290.cd-11-0136
51. Shakouri A, Parvan R, Adljouy N, Abdolalizadeh J. Purification of h yaluronidase as an anticancer agent inhibiting CD44. Biomed Chromatogr. 2020;34(1):e4709. https://doi.org/10.1002/bmc.4709
52. Roh K, Cho S, Park J-h, Yoo BC, Kim W-K, Kim S-k, et al. Therapeutic effects of hyaluronidase on acquired lymphedema using a newly developed mouse limb model. Exp Biol Med. 2017;242(6):584-92. https://doi.org/10.1177/1535370216688570
53. Cho S, Roh K, Park J, Park YS, Lee M, Cho S, et al. Hydrolysis of hyaluronic acid in lymphedematous tissue alleviates fibrogenesis via TH1 cell-mediated cytokine expression. Sci Rep. 2017;7(1):35. https://doi.org/10.1038/s41598-017-00085-z
54. Dalaei F, Bucan A, Wiinholt A, Jørgensen MG, Hansen CR, Baun C, et al. Short term treatment of secondary lymphedema with hyaluronidase injections reduces mouse hindlimb lymphedema. J Plast Surg Hand Surg. 2023;58:40-7. https://doi.org/10.2340/jphs.v58.7791
55. Kramer MW, Golshani R, Merseburger AS, Knapp J, Garcia A, Hennenlotter J, et al. HYAL-1 hyaluronidase: a potential prognostic indicator for progression to muscle invasion and recurrence in bladder cancer. Eur Urol. 2010;57(1):86-94. https://doi.org/10.1016/j.eururo.2009.03.058
56. Chib R, Raut S, Fudala R, Chang A, Mummert M, Rich R, et al. FRET based ratio-metric sensing of hyaluronidase in synthetic urine as a biomarker for bladder and prostate cancer. Curr Pharm Biotechnol. 2013;14(4):470-4. https://doi.org/10.2174/13892010113149990222
57. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418-29. https://doi.org/10.1016/j.ccr.2012.01.007
58. Tan AR, Im S-A, Mattar A, Colomer R, Stroyakovskii D, Nowecki Z, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85-97. https://doi.org/10.1016/s1470-2045(20)30536-2
59. Krupkova O, Greutert H, Boos N, Lemcke J, Liebscher T, Wuertz-Kozak K. Expression and activity of hyaluronidases HYAL-1, HYAL-2 and HYAL-3 in the human intervertebral disc. Eur Spine J. 2020;29:605-15. https://doi.org/10.1007/s00586-019-06227-3
60. Muto J, Sayama K, Gallo RL, Kimata K. Emerging evidence for the essential role of hyaluronan in cutaneous biology. J Dermatol Sci. 2019;94(1):190-5. https://doi.org/10.1016/j.jdermsci.2019.01.009
2. Mohankumar A, Rajan M. Role of hyaluronidase as an adjuvant in local anesthesia for cataract surgery. Indian J Ophthalmol. 2023;71(7):2649-55. https://doi.org/10.4103/ijo.ijo_2515_22
3. Weber GC, Buhren BA, Schrumpf H, Wohlrab J, Gerber PA. Clinical applications of hyaluronidase. Therapeutic enzymes: function and clinical implications. 2019:255-77.
4. Kroumpouzos G, Treacy P. Hyaluronidase for dermal filler complications: review of applications and dosage recommendations. JMIR Dermatol. 2024;7(1):e50403. https://doi.org/10.2196/50403
5. Ahmadian E, Dizaj SM, Eftekhari A, Dalir E, Vahedi P, Hasanzadeh A, et al. The potential applications of hyaluronic acid hydrogels in biomedicine. Drug Res. 2020;70(01):6-11. https://doi.org/10.1055/a-0991-7585
6. Marković-Housley Z, Miglierini G, Soldatova L, Rizkallah PJ, Müller U, Schirmer T. Crystal structure of hyaluronidase, a major allergen of bee venom. Structure. 2000;8(10):1025-35. https://doi.org/10.1016/s0969-2126(00)00511-6
7. Kaul A, Short WD, Wang X, Keswani SG. Hyaluronidases in human diseases. Int J Mol Sci. 2021;22(6):3204. https://doi.org/10.3390/ijms22063204
8. Stern R, Jedrzejas MJ. Hyaluronidases: their genomics, structures, and mechanisms of action. Chem Rev. 2006;106(3):818-39. https://doi.org/10.1021/cr050247k
9. Csoka AB, Frost GI, Stern R. The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol. 2001;20(8):499-508. https://doi.org/10.1016/s0945-053x(01)00172-x
10. Chowdhury B, Hemming R, Hombach-Klonisch S, Flamion B, Triggs-Raine B. Murine hyaluronidase 2 deficiency results in extracellular hyaluronan accumulation and severe cardiopulmonary dysfunction. J Biolo Chem. 2013;288(1):520-8. https://doi.org/10.1074/jbc.m112.393629
11. Triggs-Raine B, Natowicz MR. Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism. World J Biol Chem. 2015;6(3):110. https://doi.org/10.4331/wjbc.v6.i3.110
12. West DC, Shaw DM, Lorenz P, Adzick NS, Longaker MT. Fibrotic healing of adult and late gestation fetal wounds correlates with increased hyaluronidase activity and removal of hyaluronan. Int J Biochem Cell Biol. 1997;29(1):201-10. https://doi.org/10.1016/s1357-2725(96)00133-1
13. Schwartz DM, Jumper MD, Lui G-M, Dang S, Schuster S, Stern R. Corneal endothelial hyaluronidase: a role in anterior chamber hyaluronic acid catabolism. Cornea. 1997;16(2):188-91. https://doi.org/10.1097/00003226-199703000-00011
14. Reitinger S, Lepperdinger G. Hyaluronan, a ready choice to fuel regeneration: a mini-review. Gerontology. 2012;59(1):71-6. https://doi.org/10.1159/000342200
15. Fronza M, Caetano GF, Leite MN, Bitencourt CS, Paula-Silva FW, Andrade TA, et al. Hyaluronidase modulates inflammatory response and accelerates the cutaneous wound healing. PLoS One. 2014;9(11):e112297. https://doi.org/10.1371/journal.pone.0112297
16. Seol D-W, Joo SH, Kim Y-H, Song B-S, Sim B-W, Kim S-U, et al. Sperm hyaluronidase is critical to mammals’ fertilization for its ability to disperse cumulus–oocyte complex layer. Asian J Androl. 2022;24(4):411-5. https://doi.org/10.4103/aja202176
17. Lokeshwar VB, Selzer MG. Hyaluronidase: both a tumor promoter and suppressor. Hyaluronan Cancer Biol. 2009:189-206. https://doi.org/10.1016/b978-012374178-3.10011-0
18. Chowdhury B, Xiang B, Liu M, Hemming R, Dolinsky VW, Triggs-Raine B. Hyaluronidase 2 deficiency causes increased mesenchymal cells, congenital heart defects, and heart failure. Circ Cardiovasc Genet. 2017;10(1):e001598. https://doi.org/10.1161/circgenetics.116.001598
19. Jung M, Ma Y, Iyer RP, DeLeon-Pennell KY, Yabluchanskiy A, Garrett MR, et al. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol. 2017;112:1-14. https://doi.org/10.1007/s00395-017-0622-5
20. Yoshino Y, Goto M, Hara H, Inoue S. The role and regulation of TMEM2 (transmembrane protein 2) in HYBID (hyaluronan (HA)-binding protein involved in HA depolymerization/KIAA1199/CEMIP)-mediated HA depolymerization in human skin fibroblasts. Biochem Biophys Res Commun. 2018;505(1):74-80. https://doi.org/10.1016/j.bbrc.2018.09.097
21. Chopra D, Brehm JE, Morrison B. Hyaluronidase as a successful treatment modality for scleroderma-induced microstomia. Dermatol Surg. 2022;48(9):1014-5. https://doi.org/10.1097/dss.0000000000003543
22. Averbeck M, Gebhardt CA, Voigt S, Beilharz S, Anderegg U, Termeer CC, et al. Differential regulation of hyaluronan metabolism in the epidermal and dermal compartments of human skin by UVB irradiation. J Invest Dermatol. 2007;127(3):687-97. https://doi.org/10.1038/sj.jid.5700614
23. Colombaro V, Jadot I, Declèves A-E, Voisin V, Giordano L, Habsch I, et al. Hyaluronidase 1 and hyaluronidase 2 are required for renal hyaluronan turnover. Acta Histochemica. 2015;117(1):83-91. https://doi.org/10.1016/j.acthis.2014.11.007
24. Harada H, Takahashi M. CD44-dependent intracellular and extracellular catabolism of hyaluronic acid by hyaluronidase-1 and-2. J Biol Chem. 2007;282(8):5597-607. https://doi.org/10.1074/jbc.m608358200
25. Kim J, Seki E. Hyaluronan in liver fibrosis: basic mechanisms, clinical implications, and therapeutic targets. Hepatol Commun. 2023;7(4):e0083. https://doi.org/10.1097/hc9.0000000000000083
26. Orăşan OH, Sava M, Iancu M, Cozma A, Saplonţai-Pop A, Sarlea Ţărmure S, et al. Serum hyaluronic acid in chronic viral hepatitis B and C: a biomarker for assessing liver fibrosis in chronic hemodialysis patients. Int Urol Nephrol. 2015;47:1209-17. https://doi.org/10.1007/s11255-015-1017-x
27. Rezaei‐Agdam H, Moshari S, Nahari E, Minas A, Daliri Z, Hallaj M, et al. Zeta and hyaluronic acid assessments, novel sperm selection procedures, in animal model for male infertility. Andrologia. 2019;51(11):e13447. https://doi.org/10.1111/and.13447
28. Nasr-Esfahani M, Razavi S, Vahdati A, Fathi F, Tavalaee M. Evaluation of sperm selection procedure based on hyaluronic acid binding ability on ICSI outcome. J Assist Reprod Genet. 2008;25:197-203. https://doi.org/10.1007/s10815-008-9223-4
29. Nixon B, Schjenken JE, Burke ND, Skerrett-Byrne DA, Hart HM, De Iuliis GN, et al. New horizons in human sperm selection for assisted reproduction. Front Endocrinol 2023;14:1145533. https://doi.org/10.3389/fendo.2023.1145533
30. Sawan D, Hersant B. Therapeutic use of hyaluronidase in obstetrics. Open J Obstet Gynecol. 2021;11(11):1581-8. https://doi.org/10.4236/ojog.2021.1111147
31. Kwon H, Park HS, Shim J-Y, Lee KW, Choi S-J, Choi GY. Randomized, double-blind, placebo-controlled trial on the efficacy of hyaluronidase in preventing perineal trauma in nulliparous women. Yonsei Med J. 2020;61(1):79-84. https://doi.org/10.3349/ymj.2020.61.1.79
32. Gomes T-P, Palma L-F, Tornelli M-J, Tornelli H-R, Fukuoka C-Y, Borsatti M-A. Hyaluronidase following buccal infiltrations of articaine with epinephrine for anesthesia of mandibular first molars: a split-mouth, double-blind, placebo-controlled randomized clinical trial. J Clin Exp Dent. 2022;14(11):e938. https://doi.org/10.4317/jced.59809
33. Silverstein SM, Greenbaum S, Stern R. Hyaluronidase in ophthalmology. J Appl Res. 2012;12(1).
34. Benozzi J, Nahum LP, Campanelli JL, Rosenstein RE. Effect of hyaluronic acid on intraocular pressure in rats. Invest Ophthalmol Vis Sci. 2002;43(7):2196-200.
35. Signorini M, Liew S, Sundaram H, De Boulle KL, Goodman GJ, Monheit G, et al. Global aesthetics consensus: avoidance and management of complications from hyaluronic acid fillers—evidence-and opinion-based review and consensus recommendations. Plast Reconstr Surg. 2016;137(6):961e-71e. https://doi.org/10.1097/prs.0000000000002184
36. Borzabadi-Farahani A, Mosahebi A, Zargaran D. A scoping review of hyaluronidase use in managing the complications of aesthetic interventions. Aesthet Plast Surg. 2024;48(6):1193-209. https://doi.org/10.1007/s00266-022-03207-9
37. Wohlrab J, Finke R, Franke WG, Wohlrab A. Clinical trial for safety evaluation of hyaluronidase as diffusion enhancing adjuvant for infiltration analgesia of skin with lidocaine. Dermatol Surg. 2012;38(1):91-6. https://doi.org/10.1111/j.1524-4725.2011.02146.x
38. Feighery C, McCoy E, Johnston P, Armstrong D. Delayed hypersensitivity to hyaluronidase (Hyalase™) used during cataract surgery. Contact Dermatitis. 2007;57(5). https://doi.org/10.1111/j.1600-0536.2007.01038.x
39. Pardue EL, Ibrahim S, Ramamurthi A. Role of hyaluronan in angiogenesis and its utility to angiogenic tissue engineering. Organogenesis. 2008;4(4):203-14. https://doi.org/10.4161/org.4.4.6926
40. Spinelli FM, Vitale DL, Demarchi G, Cristina C, Alaniz L. The immunological effect of hyaluronan in tumor angiogenesis. Clin Transl Immunol. 2015;4(12):e52. https://doi.org/10.1038/cti.2015.35
41. Shibata Y, Taogoshi T, Matsuo H. Extravasation of noncytotoxic agents: skin injury and risk classification. Biol Pharm Bull. 2023;46(6):746-55. https://doi.org/10.1248/bpb.b22-00850
42. Ong J, Van Gerpen R. Recommendations for management of noncytotoxic vesicant extravasations. J Infus Nurs. 2020;43(6):319-43. https://doi.org/10.1097/nan.0000000000000392
43. Stefanos SS, Kiser TH, MacLaren R, Mueller SW, Reynolds PM. Management of noncytotoxic extravasation injuries: A focused update on medications, treatment strategies, and peripheral administration of vasopressors and hypertonic saline. Pharmacotherapy. 2023;43(4):321-37. https://doi.org/10.1002/phar.2794
44. Muggenthaler MM, Chowdhury B, Hasan SN, Cross HE, Mark B, Harlalka GV, et al. Mutations in HYAL2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice. PLoS Genet. 2017;13(1):e1006470. https://doi.org/10.1371/journal.pgen.1006470
45. Zaaba MIS, Mokhtar KI, Rajion ZA. Revisiting Genetics of Cleft Lip with or without Cleft Palate and Cleft Palate Only: A Narrative Review. Arch Orofac Sci. 2023;18(2). https://doi.org/10.21315/aos2023.1802.rv01
46. Watson D, Reuther MS, Wong VW, Sah RL, Masuda K, Briggs KK. Effect of hyaluronidase on tissue‐engineered human septal cartilage. Laryngoscope. 2016;126(9):1984-9. https://doi.org/10.1002/lary.25720
47. Collins MN, Birkinshaw C. Hyaluronic acid based scaffolds for tissue engineering—A review. Carbohydr Polym. 2013;92(2):1262-79. https://doi.org/10.1016/j.carbpol.2012.10.028
48. Ran X, Du Y, Wang Z, Wang H, Pu F, Ren J, et al. Hyaluronic acid-templated Ag nanoparticles/graphene oxide composites for synergistic therapy of bacteria infection. CS Appl Mater Interfaces. 2017;9(23):19717-24. https://doi.org/10.1021/acsami.7b05584
49. Velesiotis C, Vasileiou S, Vynios DH. A guide to hyaluronan and related enzymes in breast cancer: biological significance and diagnostic value. FEBS J. 2019;286(15):3057-74. https://doi.org/10.1111/febs.14860
50. Whatcott CJ, Han H, Posner RG, Hostetter G, Von Hoff DD. Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look. Cancer Discov. 2011;1(4):291-6. https://doi.org/10.1158/2159-8290.cd-11-0136
51. Shakouri A, Parvan R, Adljouy N, Abdolalizadeh J. Purification of h yaluronidase as an anticancer agent inhibiting CD44. Biomed Chromatogr. 2020;34(1):e4709. https://doi.org/10.1002/bmc.4709
52. Roh K, Cho S, Park J-h, Yoo BC, Kim W-K, Kim S-k, et al. Therapeutic effects of hyaluronidase on acquired lymphedema using a newly developed mouse limb model. Exp Biol Med. 2017;242(6):584-92. https://doi.org/10.1177/1535370216688570
53. Cho S, Roh K, Park J, Park YS, Lee M, Cho S, et al. Hydrolysis of hyaluronic acid in lymphedematous tissue alleviates fibrogenesis via TH1 cell-mediated cytokine expression. Sci Rep. 2017;7(1):35. https://doi.org/10.1038/s41598-017-00085-z
54. Dalaei F, Bucan A, Wiinholt A, Jørgensen MG, Hansen CR, Baun C, et al. Short term treatment of secondary lymphedema with hyaluronidase injections reduces mouse hindlimb lymphedema. J Plast Surg Hand Surg. 2023;58:40-7. https://doi.org/10.2340/jphs.v58.7791
55. Kramer MW, Golshani R, Merseburger AS, Knapp J, Garcia A, Hennenlotter J, et al. HYAL-1 hyaluronidase: a potential prognostic indicator for progression to muscle invasion and recurrence in bladder cancer. Eur Urol. 2010;57(1):86-94. https://doi.org/10.1016/j.eururo.2009.03.058
56. Chib R, Raut S, Fudala R, Chang A, Mummert M, Rich R, et al. FRET based ratio-metric sensing of hyaluronidase in synthetic urine as a biomarker for bladder and prostate cancer. Curr Pharm Biotechnol. 2013;14(4):470-4. https://doi.org/10.2174/13892010113149990222
57. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418-29. https://doi.org/10.1016/j.ccr.2012.01.007
58. Tan AR, Im S-A, Mattar A, Colomer R, Stroyakovskii D, Nowecki Z, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85-97. https://doi.org/10.1016/s1470-2045(20)30536-2
59. Krupkova O, Greutert H, Boos N, Lemcke J, Liebscher T, Wuertz-Kozak K. Expression and activity of hyaluronidases HYAL-1, HYAL-2 and HYAL-3 in the human intervertebral disc. Eur Spine J. 2020;29:605-15. https://doi.org/10.1007/s00586-019-06227-3
60. Muto J, Sayama K, Gallo RL, Kimata K. Emerging evidence for the essential role of hyaluronan in cutaneous biology. J Dermatol Sci. 2019;94(1):190-5. https://doi.org/10.1016/j.jdermsci.2019.01.009
| Files | ||
| Issue | Vol 3 No 2 (2025) | |
| Section | Review Article(s) | |
| Keywords | ||
| Biomedical application Biostructure Hyaluronic acid Hyaluronidase Novel treatment | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Safary M, Modarressi SMH, Tajdari M, Peyrovinasab A, rezazadeh amir, Alijanpour S, Modarressi MH. The Diverse Roles of Hyaluronidase: Revealing Its Biochemical, Preclinical, and Clinical Applications. ABI. 2025;3(2):73-82.
