Etiology of Delayed Inflammatory Reaction Induced by Hyaluronic Acid Filler

Abstract

The etiology and pathophysiology of delayed inflammatory reactions caused by hyaluronic acid fillers have not yet been elucidated. Previous studies have suggested that the etiology can be attributed to the hyaluronic acid filler itself, patient's immunological status, infection, and injection technique. Hyaluronic acid fillers are composed of high-molecular weight hyaluronic acids that are chemically cross-linked using substances such as 1,4-butanediol diglycidyl ether (BDDE). The mechanism by which BDDE cross-links the two hyaluronic acid disaccharides is still unclear and it may exist as a fully reacted cross-linker, pendant cross-linker, deactivated cross-linker, and residual cross-linker. The hyaluronic acid filler also contains impurities such as silicone oil and aluminum during the manufacturing process. Impurities can induce a foreign body reaction when the hyaluronic acid filler is injected into the body. Aseptic hyaluronic acid filler injections should be performed while considering the possibility of biofilm formation or delayed inflammatory reaction. Delayed inflammatory reactions tend to occur when patients experience flu-like illnesses; thus, the patient's immunological status plays an important role in delayed inflammatory reactions. Large-bolus hyaluronic acid filler injections can induce foreign body reactions and carry a relatively high risk of granuloma formation.

Keywords

hyaluronic acid filler - delayed inflammatory reaction - filler complication - delayed hypersensitivity

Authors' Contributions

Conceptualization and writing: W.L.; Review, editing, and supervision: S.S-D., N-K.R., and J.C. All authors have read and agreed to the published version of the manuscript.

Publication History

Received: 03 June 2023

Accepted: 26 August 2023

Accepted Manuscript online:
29 September 2023

Article published online:
07 February 2024

• References

• 1 The aesthetic society's cosmetic surgery national data bank: Statistics 2019. Aesthet Surg J 2020; 40 (Suppl. 01) 1-26
• 2 DeLorenzi C. Complications of injectable fillers, part I. Aesthet Surg J 2013; 33 (04) 561-575
• 3 Koh IS, Lee W. Filler-induced hypersensitivity inflammation and granuloma. In: Filler complications. 1st ed.. Singapore: Springer; 2019: 41-51
• 4 Chung KL, Convery C, Ejikeme I, Ghanem AM. A systematic review of the literature of delayed inflammatory reactions after hyaluronic acid filler injection to estimate the incidence of delayed type hypersensitivity reaction. Aesthet Surg J 2020; 40 (05) NP286-NP300
• 5 Kokoska RE, Lima AM, Kingsley MM. Review of delayed reactions to 15 hyaluronic acid fillers. Dermatol Surg 2022; 48 (07) 752-757
• 6 Artzi O, Cohen JL, Dover JS. et al. Delayed inflammatory reactions to hyaluronic acid fillers: a literature review and proposed treatment algorithm. Clin Cosmet Investig Dermatol 2020; 13: 371-378
• 7 Goodman GJ, McDonald CB, Lim A. et al. Making sense of late tissue nodules associated with hyaluronic acid injections. Aesthet Surg J 2023; 43 (06) NP438-NP448
• 8 Urdiales-Gálvez F, Delgado NE, Figueiredo V. et al. Treatment of soft tissue filler complications: expert consensus recommendations. Aesth Plast Surg 2018; 42 (02) 498-510
• 9 Ibrahim O, Overman J, Arndt KA, Dover JS. Filler nodules: inflammatory or infectious? A review of biofilms and their implications on clinical practice. Dermatol Surg 2018; 44 (01) 53-60
• 10 Funt DK. Treatment of delayed-onset inflammatory reactions to hyaluronic acid filler: an algorithmic approach. Plast Reconstr Surg Glob Open 2022; 10 (06) e4362
• 11 De Boulle K, Glogau R, Kono T. et al. A review of the metabolism of 1,4-butanediol diglycidyl ether-crosslinked hyaluronic acid dermal fillers. Dermatol Surg 2013; 39 (12) 1758-1766
• 12 Micheels P, Sarazin D, Tran C, Salomon D. Effect of different crosslinking technologies on hyaluronic acid behavior: a visual and microscopic study of seven hyaluronic acid gels. J Drugs Dermatol 2016; 15 (05) 600-606
• 13 Choi SC, Yoo MA, Lee SY. et al. Modulation of biomechanical properties of hyaluronic acid hydrogels by crosslinking agents. J Biomed Mater Res A 2015; 103 (09) 3072-3080
• 14 Tezel A, Fredrickson GH. The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 2008; 10 (01) 35-42
• 15 Guarise C, Barbera C, Pavan M, Panfilo S, Beninatto R, Galesso D. HA-based dermal filler: downstream process comparison, impurity quantitation by validated HPLC-MS analysis, and in vivo residence time study. J Appl Biomater Funct Mater 2019; 17 (03) 2280800019867075
• 16 Yang B, Guo X, Zang H, Liu J. Determination of modification degree in BDDE-modified hyaluronic acid hydrogel by SEC/MS. Carbohydr Polym 2015; 131: 233-239
• 17 Wende FJ, Gohil S, Nord LI, Helander Kenne A, Sandström C. 1D NMR methods for determination of degree of cross-linking and BDDE substitution positions in HA hydrogels. Carbohydr Polym 2017; 157: 1525-1530
• 18 Kenne L, Gohil S, Nilsson EM. et al. Modification and cross-linking parameters in hyaluronic acid hydrogels–definitions and analytical methods. Carbohydr Polym 2013; 91 (01) 410-418
• 19 Lee W, Rho NK, Yang EJ. Determination of hyaluronic acid dermal filler impurities using SEM/EDS analysis. Polymers (Basel) 2023; 15 (07) 1649
• 20 Langille SE. Particulate matter in injectable drug products. PDA J Pharm Sci Technol 2013; 67 (03) 186-200
• 21 Bohrer D, do Nascimento PC, Binotto R, Becker E. Influence of the glass packing on the contamination of pharmaceutical products by aluminium. Part III: Interaction container-chemicals during the heating for sterilisation. J Trace Elem Med Biol 2003; 17 (02) 107-115
• 22 Moon SH, Shin EC, Noh YW, Lim YT. Evaluation of hyaluronic acid-based combination adjuvant containing monophosphoryl lipid A and aluminum salt for hepatitis B vaccine. Vaccine 2015; 33 (38) 4762-4769
• 23 Cua M, Martin D, Meza P. et al. Method to determine syringe silicone oil layer heterogeneity and investigation of its impact on product particle counts. J Pharm Sci 2020; 109 (11) 3292-3299
• 24 Melo GB, Shoenfeld Y, Rodrigues EB. The risks behind the widespread use of siliconized syringes in the healthcare practice. Int J Retina Vitreous 2021; 7 (01) 66
• 25 United States Pharmacopeia and National Formulary. United States Pharmacopeial Convention, Inc.: 2021; Rockville, MD.
• 26 Pharmaeuropa. European Pharmacopoeia. Strasbourg, France: Council of Europe; 2019
• 27 Nikitovic D, Kouvidi K, Karamanos NK, Tzanakakis GN. The roles of hyaluronan/RHAMM/CD44 and their respective interactions along the insidious pathways of fibrosarcoma progression. BioMed Res Int 2013; 2013: 929531
• 28 Hamilton SR, Fard SF, Paiwand FF. et al. The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells. J Biol Chem 2007; 282 (22) 16667-16680
• 29 Fundarò SP, Salti G, Malgapo DMH, Innocenti S. The rheology and physicochemical characteristics of hyaluronic acid fillers: their clinical implications. Int J Mol Sci 2022; 23 (18) 10518
• 30 Rayahin JE, Buhrman JS, Zhang Y, Koh TJ, Gemeinhart RA. High and low molecular weight hyaluronic acid differentially influence macrophage activation. ACS Biomater Sci Eng 2015; 1 (07) 481-493
• 31 Corduff N, Juniarti L, Lim TS. et al. Current practices in hyaluronic acid dermal filler treatment in Asia Pacific and practical approaches to achieving safe and natural-looking results. Clin Cosmet Investig Dermatol 2022; 15: 1213-1223
• 32 Hee CK, Messina DJ. In vitro inflammatory and immune response to uncrosslinked hyaluronic acid (HA) and HA fillers. J Immunol Regen Med 2022; 17: 100065
• 33 Lee W. Hyaluronic acid filler property and hyaluronidase. In: Safe filler injection techniques. 1st ed.. Singapore: Springer; 2022: 11-17
• 34 Sze JH, Brownlie JC, Love CA. Biotechnological production of hyaluronic acid: a mini review. 3 Biotech 2016; 6 (01) 67
• 35 US Food and Drug Administration. Summary of safety and effectiveness data 2006. Accessed March 3, 2023 at: https:// www.accessdata.fda.gov/cdrh_docs/pdf5/P050047b.pdf
• 36 Yang E-J. Physical properties and rheological approach for hyaluronic acid fillers. In: Won L. ed. Minimally Invasive Aesthetic Surgery Techniques. 1st ed.. Singapore: Springer; 2022
• 37 Edsman K, Nord LI, Ohrlund A, Lärkner H, Kenne AH. Gel properties of hyaluronic acid dermal fillers. Dermatol Surg 2012; 38 (7 Pt 2): 1170-1179
• 38 Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol 2008; 20 (02) 86-100
• 39 Lemperle G, Gauthier-Hazan N, Wolters M, Eisemann-Klein M, Zimmermann U, Duffy DM. Foreign body granulomas after all injectable dermal fillers: part 1. Possible causes. Plast Reconstr Surg 2009; 123 (06) 1842-1863
• 40 Lee JM, Kim YJ. Foreign body granulomas after the use of dermal fillers: pathophysiology, clinical appearance, histologic features, and treatment. Arch Plast Surg 2015; 42 (02) 232-239
• 41 Turkmani MG, De Boulle K, Philipp-Dormston WG. Delayed hypersensitivity reaction to hyaluronic acid dermal filler following influenza-like illness. Clin Cosmet Investig Dermatol 2019; 12: 277-283
• 42 Decates TS, Velthuis PJ, Jhingoerie R, Gibbs S, Bachour Y, Niessen FB. No association found between late-onset inflammatory adverse events after soft tissue filler injections and the adaptive immune system. J Cosmet Dermatol 2023; 22 (02) 458-463
• 43 Philipp-Dormston WG, Goodman GJ, De Boulle K. et al. Global approaches to the prevention and management of delayed-onset adverse reactions with hyaluronic acid-based fillers. Plast Reconstr Surg Glob Open 2020; 8 (04) e2730
• 44 Decates TS, Velthuis PJ, Schelke LW. et al. Increased risk of late-onset, immune-mediated, adverse reactions related to dermal fillers in patients bearing HLA-B*08 and DRB1*03 haplotypes. Dermatol Ther 2021; 34 (01) e14644
• 45 Al Ghafri TS, Al Balushi L, Al Balushi Z. et al. Reporting at least one adverse effect post-COVID-19 vaccination from primary health care in Muscat. Cureus 2021; 13 (08) e17055
• 46 Kalantari Y, Aryanian Z, Mirahmadi SM, Alilou S, Hatami P, Goodarzi A. A systematic review on COVID-19 vaccination and cosmetic filler reactions: a focus on case studies and original articles. J Cosmet Dermatol 2022; 21 (07) 2713-2724
• 47 Rowland-Warmann MJ. Hypersensitivity reaction to Hyaluronic Acid Dermal filler following novel Coronavirus infection - a case report. J Cosmet Dermatol 2021; 20 (05) 1557-1562
• 48 Shome D, Doshi K, Vadera S, Kapoor R. Delayed hypersensitivity reaction to hyaluronic acid dermal filler post-COVID-19 viral infection. J Cosmet Dermatol 2021; 20 (05) 1549-1550
• 49 Munavalli GG, Guthridge R, Knutsen-Larson S, Brodsky A, Matthew E, Landau M. “COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment”. Arch Dermatol Res 2022; 314 (01) 1-15
• 50 Savva D, Battineni G, Amenta F, Nittari G. Hypersensitivity reaction to hyaluronic acid dermal filler after the Pfizer vaccination against SARS-CoV-2. Int J Infect Dis 2021; 113: 233-235
• 51 Sloan B. July 2021: Lisinopril for delayed inflammatory responses to hyaluronic acid fillers after COVID-19 vaccinations. J Am Acad Dermatol 2021; 85 (01) 34
• 52 Munavalli GG, Knutsen-Larson S, Lupo MP, Geronemus RG. Oral angiotensin-converting enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid fillers following COVID-19 vaccination-a model for inhibition of angiotensin II-induced cutaneous inflammation. JAAD Case Rep 2021; 10: 63-68
• 53 Funt D, Pavicic T. Dermal fillers in aesthetics: an overview of adverse events and treatment approaches. Plast Surg Nurs 2015; 35 (01) 13-32
• 54 Bhojani-Lynch T. Late-onset inflammatory response to hyaluronic acid dermal fillers. Plast Reconstr Surg Glob Open 2017; 5 (12) e1532
• 55 Saththianathan M, Johani K, Taylor A. et al. The role of bacterial biofilm in adverse soft-tissue filler reactions: a combined laboratory and clinical study. Plast Reconstr Surg 2017; 139 (03) 613-621
• 56 Alam M, Cohen JL, Petersen B. et al. Association of different surgical sterile prep solutions with infection risk after cutaneous surgery of the head and neck. JAMA Dermatol 2017; 153 (08) 830-831
• 57 Winslow CP. The management of dermal filler complications. Facial Plast Surg 2009; 25 (02) 124-128
• 58 Born TM, Airan L, Motakis D. Soft-tissue fillers. Plast Surg (Oakv) 2013; 2: 39-54
• 59 Bentkover SH. The biology of facial fillers. Facial Plast Surg 2009; 25 (02) 73-85
• 60 Doshi N, Mitragotri S. Macrophages recognize size and shape of their targets. PLoS ONE 2010; 5 (04) e10051
• 61 Artzi O, Loizides C, Verner I, Landau M. Resistant and recurrent late reaction to hyaluronic acid-based gel. Dermatol Surg 2016; 42 (01) 31-37
• 62 Williams GT, Williams WJ. Granulomatous inflammation–a review. J Clin Pathol 1983; 36 (07) 723-733
• 63 Lemperle G, Gauthier-Hazan N. Foreign body granulomas after all injectable dermal fillers: part 2. Treatment options. Plast Reconstr Surg 2009; 123 (06) 1864-1873
• 64 Signorini M, Liew S, Sundaram H. et al; Global Aesthetics Consensus Group. 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 (06) 961e-971e
• 65 Dugaret AS, Bertino B, Gauthier B. et al. An innovative method to quantitate tissue integration of hyaluronic acid-based dermal fillers. Skin Res Technol 2018; 24 (03) 423-431
• 66 Choi MS, Kwak S, Kim J. et al. Comparative analyses of inflammatory response and tissue integration of 14 hyaluronic acid-based fillers in mini pigs. Clin Cosmet Investig Dermatol 2021; 14: 765-778
• 67 Flynn TC, Sarazin D, Bezzola A, Terrani C, Micheels P. Comparative histology of intradermal implantation of mono and biphasic hyaluronic acid fillers. Dermatol Surg 2011; 37 (05) 637-643
• 68 Micheels P, Besse S, Flynn TC, Sarazin D, Elbaz Y. Superficial dermal injection of hyaluronic acid soft tissue fillers: comparative ultrasound study. Dermatol Surg 2012; 38 (7 Pt 2): 1162-1169
• 69 Sheptulin V, Fedorov A, Prause J, Fay A, Grusha Y. Hyaluronic acid gel biodegradation after intrapalpebral and intraorbital injection in experimental study. Ophthal Plast Reconstr Surg 2019; 35 (06) 558-561