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In Vivo Models for the Study of Hyaluronic Acid Fillers: A Review

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  • Non-Surgical Aesthetic
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Abstract

Background

Hyaluronic acid (HA) filler application is one of the most frequent minimally invasive aesthetic procedures used worldwide. Its properties and characterization, performance, effects in other tissues, and response to complication treatments have been studied in several animal models. This review aims to categorize animal models considering the advantages and disadvantages regarding the purpose of the study.

Methods

Literature research was made using MEDLINE via PubMed by two reviewers using keywords “hyaluronic acid” “filler” and “animal model”. Full-text articles published in English and with an in vivo animal model were included for data extraction.

Results

The rat model was the most common animal used to evaluate properties or characteristics and degradation of HA fillers. Rabbits were preferred for evaluating HA embolism treatments; however, anatomical names of the arteries differ in some studies. Mice and rats used as vascular occlusion model are challenging due to the size of the vessels and viscosity of the filler.

Conclusion

There is a wide variability of options of in vivo animal models to evaluate HA fillers. The animal characteristics, laboratory resources, and HA properties should be considered in accordance with the objective of the study, when choosing the ideal model.

Level of Evidence III

This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

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References

  1. Kablik J, Monheit GD, Yu LP, Chang G, Gershkovich J (2009) Comparative physical properties of hyaluronic acid dermal fillers. Dermatol Surg 35(Suppl 1):302–312

    Article  CAS  PubMed  Google Scholar 

  2. Gutowski KA (2016) Hyaluronic acid fillers: science and clinical uses. Clin Plast Surg 43(3):489–496

    Article  PubMed  Google Scholar 

  3. De Maio M (2021) MD codes ™: a methodological approach to facial aesthetic treatment with injectable hyaluronic acid fillers. Aesthetic Plast Surg 45(2):690–709

    Article  PubMed  Google Scholar 

  4. Farolch-Prats L, Nome-Chamorro C (2019) Facial contouring by using dermal fillers and botulinum toxin a: a practical approach. Aesthetic Plast Surg 43(3):793–802

    Article  PubMed  PubMed Central  Google Scholar 

  5. De Maio M, DeBoulle K, Braz A, Rohrich RJ (2017) Facial assessment and injection guide for botulinum toxin and injectable hyaluronic acid filler: focus on midface. Plast Reconstr Surg 140(4):540e–550e

    Article  PubMed  Google Scholar 

  6. Merola F, Scrima M, Melito C, Iorio A, Pisano C, Giori A, Ferravante A (2018) A novel animal model for residence time evaluation of injectable hyaluronic acid-based fillers using high-frequency ultrasound-based approach. Clin Cosmet Investig Dermatol 11:339–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Paliwal S, Fagien S, Sun X, Holt T, Kim T, Hee CK, Epps DV, Messina DJ (2014) Skin extracellular matrix stimulation following injection of a hyaluronic acid-based dermal filler in a rat model. Plast Reconstr Surg 134(6):1224–1233

    Article  CAS  PubMed  Google Scholar 

  8. Nowacki M, Pietkun K, Pokrywczyńska M, Rasmus M, Warda K, Kloskowski T, Jundziłł A, Gagat M, Grzanka A, Bodnar M, Marszałek A, Drewa T, Czajkowski R (2014) Filling effects, persistence, and safety of dermal fillers formulated with stem cells in an animal model. Aesthetic Surg J 34(8):1261–1269

    Article  Google Scholar 

  9. Moure SP, de Vargas KF, Borghetti RL, Salum FG, Cherubini K, da Silva VD, de Figueiredo MA (2012) Clinical and pathological characteristics of polymethylmethacrylate and hyaluronic acid in the rat tongue. Int J Oral Maxillofac Surg 41(10):1296–1303

    Article  CAS  PubMed  Google Scholar 

  10. Hee CK, Shumate GT, Narurkar V, Bernardin A, Messina DJ (2015) Rheological properties and in vivo performance characteristics of soft tissue fillers. Dermatol Surg 41(Suppl 1):S373-381

    Article  PubMed  Google Scholar 

  11. Park KY, Kim HK, Kim BJ (2013) Comparative study of hyaluronic acid fillers by in vitro and in vivo testing. J Eur Acad Dermatology Venereol 28(5):565–568

    Article  Google Scholar 

  12. Cho SY, Park JW, An H, Ko HJ, Kim H, Choi JK, Choi SY, Kim SM, Ko EJ, Kim BJ (2018) Physical properties of a novel small-particle hyaluronic acid filler: in vitro, in vivo, and clinical studies. J Cosmet Dermatol 17(3):347–354

    Article  PubMed  Google Scholar 

  13. Cena RB, Park JG, Kim HJ, Son KY, Kim DS, Kang MI, Park SI, du Moon G, Yang DY, Yu DS, Lee JI, Cho KO (2014) Effects of crosslinked dextran in hydroxylpropyl methylcellulose on soft tissue augmentation in rats. J Biomed Mater Res B Appl Biomater 102(1):131–140

    Article  PubMed  Google Scholar 

  14. Chung E, Sim C, Kim HJ (2019) Delayed adverse reactions caused by consecutive injections of different fillers in the same region: Murine skin study. J Cosmet Laser Ther 21(1):33–38

    Article  PubMed  Google Scholar 

  15. Fernández-Cossío S, Castaño-Oreja MT (2006) Biocompatibility of two novel dermal fillers: histological evaluation of implants of a hyaluronic acid filler and a polyacrylamide filler. Plast Reconstr Surg 117(6):1789–1796

    Article  PubMed  Google Scholar 

  16. Huh JB, Kim JH, Kim S, Lee SH, Shim KM, Kim SE, Kang SS, Jeong CM (2015) Effects of PMMA and cross-linked dextran filler for soft tissue augmentation in rats. Int J Mol Sci 16(12):28523–28533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hillel AT, Nahas Z, Unterman S, Reid B, Axelman J, Sutton D, Matheson C, Petsche J, Elisseeff JH (2012) Validation of a small animal model for soft tissue filler characterization. Dermatol Surg 38(3):471–478

    Article  CAS  PubMed  Google Scholar 

  18. England LJ, Tan MH, Shumaker PR, Egbert BM, Pittelko K, Orentreich D, Pope K (2005) Effects of monopolar radiofrequency treatment over soft-tissue fillers in an animal model. Lasers Surg Med 37(5):356–365

    Article  PubMed  Google Scholar 

  19. Shumate GT, Chopra R, Jones D, Messina DJ, Hee CK (2018) In vivo degradation of crosslinked hyaluronic acid fillers by exogenous hyaluronidases. Dermatol Surg 44(8):1075–1083

    Article  CAS  PubMed  Google Scholar 

  20. Chen Y, Zhang YL, Luo SK (2019) Experimentally induced arterial embolism by hyaluronic acid injection: clinicopathologic observations and treatment. Plast Reconstr Surg 143(4):1088–1097

    Article  CAS  PubMed  Google Scholar 

  21. Hahn HM, Lee WB, Lee IJ (2021) The effects of subcutaneously injected novel biphasic cross-linked hyaluronic acid filler. In vivo Study. Aesthetic Plast Surg 45(1):322–331

    Article  PubMed  Google Scholar 

  22. Urdiales-Gálvez F, Delgado NE, Figueiredo V, Lajo-Plaza JV, Mira M, Moreno A, Ortíz-Martí F, Del Rio-Reyes R, Romero-Álvarez N, Del Cueto SR, Segurado MA, Rebenaque CV (2018) Treatment of soft tissue filler complications: expert consensus recommendations. Aesthetic Plast Surg 42(2):498–510

    Article  PubMed  PubMed Central  Google Scholar 

  23. Cohen JL, Biesman BS, Dayan SH, DeLorenzi C, Lambros VS, Nestor MS, Sadick N, Sykes J (2015) Treatment of hyaluronic acid filler-induced impending necrosis with hyaluronidase: consensus recommendations. Aesthet Surg J 35(7):844–849

    Article  PubMed  Google Scholar 

  24. Philipp-Dormston WG, Bergfeld D, Sommer BM, Sattler G, Cotofana S, Snozzi P, Wollina U, Hoffmann KPJ, Salavastru C, Fritz K (2017) Consensus statement on prevention and management of adverse effects following rejuvenation procedures with hyaluronic acid-based fillers. J Eur Acad Dermatol Venereol 31(7):1088–1095

    Article  CAS  PubMed  Google Scholar 

  25. Signorini M, Liew S, Sundaram H, De Boulle KL, Goodman GJ, Monheit G, Wu Y, Trindade de Almeida AR, Swift A, Vieira Braz A, Global Aesthetics Consensus Group (2016) Global aesthetics consensus: avoidance and management of complications from hyaluronic acid fillers-evidence- and opinion-based review and consensus recommendations. Plast Reconstr Surg 137(6):961e–971e

    Article  CAS  PubMed  Google Scholar 

  26. Chiang C, Zhou S, Liu K (2016) Intravenous hyaluronidase with urokinase as treatment for arterial hyaluronic acid embolism. Plast Reconstr Surg 137(1):114–121

    Article  CAS  PubMed  Google Scholar 

  27. Wang M, Li W, Zhang Y, Tian W, Wang H (2017) Comparison of intra-arterial and subcutaneous testicular hyaluronidase injection treatments and the vascular complications of hyaluronic acid filler. Dermatol Surg 43(2):246–254

    Article  CAS  PubMed  Google Scholar 

  28. Zhang L, Feng X, Shi H, Wu WTL, Wu S (2020) Blindness after facial filler injections: the role of extravascular hyaluronidase on intravascular hyaluronic acid embolism in the rabbit experimental model. Aesthetic Surg J 40(3):319–326

    Google Scholar 

  29. Baley-Spindel I, Villaseñor-Villalpando E, Márquez-Espirella C, Rivera-Salgado MI, Dávila-Díaz R (2020) Perivascular hyaluronidase with alteplase as treatment for hyaluronic acid thrombosis. Aesthet Surg J 40(5):551–559

    Article  PubMed  Google Scholar 

  30. Hwang CJ, Morgan PV, Pimentel A, Sayre JW, Goldberg RA, Duckwiler G (2016) Rethinking the role of nitroglycerin ointment in ischemic vascular filler complications: an animal model with ICG imaging. Ophthalmic Plast Reconstr Surg 32(2):118–122

    Article  PubMed  Google Scholar 

  31. Hwang CJ, Mustak H, Gupta AA, Ramos RM, Goldberg RA, Duckwiler GR (2019) Role of retrobulbar hyaluronidase in filler-associated blindness: evaluation of fundus perfusion and electroretinogram readings in an animal model. Ophthalmic Plast Reconstr Surg 35(1):33–37

    Article  PubMed  Google Scholar 

  32. Nie F, Xie H, Wang G, An Y (2019) Risk comparison of filler embolism between polymethyl methacrylate (PMMA) and hyaluronic acid (HA). Aesthetic Plast Surg 43(3):853–860

    Article  PubMed  PubMed Central  Google Scholar 

  33. Li J, Xu Y, Wang Y, Hsu Y, Wang P, Li J (2019) The role of hyaluronidase for the skin necrosis caused by hyaluronic acid injection-induced embolism: a rabbit auricular model study. Aesthetic Plast Surg 43(5):1362–1370

    Article  PubMed  Google Scholar 

  34. Salinas-Alvarez Y, Welsh EC, Soto-Dominguez A, Quiroga-Garza A, Hernandez-Garate YAK, De-La-Garza-Castro O, Elizondo-Omaña RE, Guzman-Lopez S (2021) Hyaluronic acid embolism treated with subcutaneous high and low hyaluronidase doses: efficacy and surrounding tissue effect. Plast Reconstr Surg 148(6):1281–1288

    Article  CAS  PubMed  Google Scholar 

  35. Chang SH, Yousefi S, Qin J, Tarbet K, Dziennis S, Wang R, Chappell MC (2016) External compression versus intravascular injection: a mechanistic animal model of filler-induced tissue ischemia. Ophthalmic Plast Reconstr Surg 32(4):261–266

    Article  PubMed  Google Scholar 

  36. Kim DW, Yoon ES, Ji YH, Park SH, Lee BI, Dhong ES (2011) Vascular complications of hyaluronic acid fillers and the role of hyaluronidase in management. J Plast Reconstr Aesthet Surg 64(12):1590–1595

    Article  PubMed  Google Scholar 

  37. Zhuang Y, Yang M, Liu C (2016) An Islanded rabbit auricular skin flap model of hyaluronic acid injection-induced embolism. Aesthetic Plast Surg 40(3):421–427

    Article  PubMed  Google Scholar 

  38. Lee W, Oh W, Oh SM, Yang EJ (2020) Comparative Effectiveness of Different Interventions of Perivascular Hyaluronidase. Plast Reconstr Surg 145(4):957–964

    Article  CAS  PubMed  Google Scholar 

  39. Chiang C, Zhou S, Chen C, Ho DS, Zhang H, Liu K (2016) Intravenous hyaluronidase with urokinase as treatment for rabbit retinal artery hyaluronic acid embolism. Plast Reconstr Surg 138(6):1121–1129

    Article  Google Scholar 

  40. Lee SH, Ha TJ, Koh KS, Song WC (2019) External and internal diameters of the facial artery relevant to intravascular filler injection. Plast Reconstr Surg 143(4):1031–1037

    Article  CAS  PubMed  Google Scholar 

  41. Sheptulin V, Fedorov A, Prause J, Fay A, Grusha Y (2019) Hyaluronic acid gel biodegradation after intrapalpebral and intraorbital injection in experimental study. Ophthalmic Plastic Reconstr Surg 35(6):558–561

    Article  Google Scholar 

  42. Summerfield A, Meurens F, Ricklin ME (2015) The immunology of the porcine skin and its value as a model for human skin. Mol Immunol 66(1):14–21

    Article  CAS  PubMed  Google Scholar 

  43. Gudjonsson JE, Johnston A, Dyson M, Valdimarsson H, Elder JT (2007) Mouse models of psoriasis. J Invest Dermatol 127(6):1292–1308

    Article  CAS  PubMed  Google Scholar 

  44. DeLorenzi C (2020) Commentary on: blindness after facial filler injections: the role of extravascular hyaluronidase on intravascular hyaluronic acid embolism in the rabbit experimental model. Aesthet Surg J 40(3):327–329

    Article  PubMed  Google Scholar 

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Correspondence to Rodrigo Enrique Elizondo-Omaña.

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Salinas-Alvarez, Y., Quiroga-Garza, A., Soto-Dominguez, A. et al. In Vivo Models for the Study of Hyaluronic Acid Fillers: A Review. Aesth Plast Surg 47, 1185–1191 (2023). https://doi.org/10.1007/s00266-022-03212-y

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