Biocompatibility Evaluation of Resin-Based Restorative Materials: A Review

Abstract

Biocompatibility is described as an appropriate biological response of a biomaterial in a living organism. It is known that biomaterials are not inert and the materials should be tested before they are allowed to be used in clinical practice. Various test methods have been developed and protocols have been determined for this purpose. Resin-based restorative materials are extensively used in dentistry due to the increased aesthetic demands of patients and the ease of use in clinical practice. As the restorative materials function in the mouth for long years, concerns regarding the biocompatibility of resin-based restorative materials become more important. Regarding the importance of this issue, the purpose of this review is to evaluate the local and systemic potential toxicity of resin-based restorative materials, toxicity test methods, and the mechanism of the cytotoxicity in living tissues.

Keywords

• biocompatibility
• cytotoxicity
• dental restorative material
• photopolymerization
• resin monomer

References

1. Perrotti V, Piattelli A, Quaranta A, Gómez-Moreno G, Iezzi G. Biocompatibility of Dental Biomaterials. In: Shelton R, editor. Biocompatibility of Dental Biomaterials. 1st ed. Elsevier; 2017. p:1-7.
2. Wataha JC. Principles of biocompatibility for dental practitioners. J Prosthet Dent. 2001;86(2):203-9.
3. Schmalz G, Arenholt-Bindslev D. Biocompatibility of dental materials. Vol. 1. Berlin: Springer; 2009.
4. Freshney RI. Culture of animal cells: a manual of basic technique and specialized applications: John Wiley & Sons; 2015.
5. Sakaguchi RL, Ferracane J, Powers J. Craig's restorative dental materials 13rd ed. Philadelphia, PA: Elsevier/Mosby; 2012.
6. Urcan E, Haertel U, Styllou M, Hickel R, Scherthan H, Reichl FX. Real-time xCELLigence impedance analysis of the cytotoxicity of dental composite components on human gingival fibroblasts. Dent Mater. 2010;26(1):51-8.
7. Teng Z, Kuang X, Wang J, Zhang X. Real-time cell analysis–a new method for dynamic, quantitative measurement of infectious viruses and antiserum neutralizing activity. J Virol Methods. 2013;193(2):364-70.
8. Balkan A, Balkan M. Hayvan Çalismalarinda Etik, Laboratuar Standardizasyonu ve Hayvan Bakimi ile Ilgili Yasal Zorunluluklar Turk Toraks Dergisi. 2013;14:6.

9. Murray PE, García Godoy C, García Godoy F. How is the biocompatibilty of dental biomaterials evaluated? Med Oral Patol Oral Cir Bucal. 2007;12(3):258-66.
10. Goldberg M. In vitro and in vivo studies on the toxicity of dental resin components: a review. Clin Oral Investig. 2008;12(1):1-8.
11. Zorzin J, Maier E, Harre S, Fey T, Belli R, Lohbauer U, et al. Bulk-fill resin composites: polymerization properties and extended light curing. Dent Mater. 2015;31(3):293-301.
12. Pratap B, Gupta RK, Bhardwaj B, Nag M. Resin based restorative dental materials: characteristics and future perspectives. Jpn Dent Sci Rev. 2019;55(1):126-38.
13. Leprince JG, Palin WM, Hadis MA, Devaux J, Leloup G. Progress in dimethacrylate-based dental composite technology and curing efficiency. Dent Mater. 2013;29(2):139-56.
14. Komurcuoglu E, Olmez S, Vural N. Evaluation of residual monomer elimination methods in three different fissure sealants in vitro. J Oral Rehabil. 2005;32(2):116-21.
15. Putzeys E, De Nys S, Cokic SM, Duca RC, Vanoirbeek J, Godderis L, et al. Long-term elution of monomers from resin-based dental composites. Dent Mater. 2019;35(3):477-85.
16. Ferracane JL. Elution of leachable components from composites. J Oral Rehabil. 1994;21(4):441-52.
17. Hensten-Pettersen A. Skin and mucosal reactions associated with dental materials. Eur J Oral Sci. 1998;106(2 Pt 2):707.
18. Lacerda-Santos R, de Meneses IHC, de Morais Sampaio GA, Pithon MM, Alves PM. Effect of degree of conversion on in vivo biocompatibility of flowable resin used for bioprotection of mini-implants. Angle Orthod. 2016;86(1):157-63.
19. Lee M-J, Kim M-J, Kwon J-S, Lee S-B, Kim K-M. Cytotoxicity of Light-Cured Dental Materials according to Different Sample Preparation Methods. Materials (Basel). 2017;10(3):288.
20. Zabrovsky A, Beyth N, Pietrokovski Y, Ben-Gal G, Houri-Haddad Y. Biocompatibility and functionality of dental restorative materials. In: Shelton R, editor. Biocompatibility of Dental Biomaterials: Elsevier; 2017. p. 63-72.
21. Moharamzadeh K, Van Noort R, Brook IM, Scutt AM. HPLC analysis of components released from dental composites with different resin compositions using different extraction media. J Mater Sci Mater Med. 2007;18(1):133-7.
22. Spencer P, Ye Q, Misra A, Goncalves SdP, Laurence J. Proteins, pathogens, and failure at the composite-tooth interface. J Dent Res. 2014;93(12):1243-9.
23. Mazzoni A, Tjäderhane L, Checchi V, Di Lenarda R, Salo T, Tay FR, et al. Role of Dentin MMPs in Caries Progression and Bond Stability. J Dent Res. 2015;94(2):241-51.
24. Alshali RZ, Salim NA, Sung R, Satterthwaite JD, Silikas N. Analysis of long-term monomer elution from bulk-fill and conventional resin-composites using high performance liquid chromatography. Dent Mater. 2015;31(12):1587-98.
25. Polydorou O, König A, Hellwig E, Kümmerer K. Long-term release of monomers from modern dental-composite materials. Eur J Oral Sci. 2009;117(1):68-75.
26. Emmler J, Seiss M, Kreppel H, Reichl FX, Hickel R, Kehe K. Cytotoxicity of the dental composite component TEGDMA and selected metabolic by-products in human pulmonary cells. Dent Mater. 2008;24(12):1670-5.
27. Oysaed H, Ruyter IE, Sjøvik Kleven IJ. Release of formaldehyde from dental composites. J Dent Res. 1988;67(10):1289-94.
28. Reichl F-X, Durner J, Hickel R, Spahl W, Kehe K, Walther U, et al. Uptake, clearance and metabolism of TEGDMA in guinea pigs. Dent Mater. 2002;18(8):581-9.
29. Hong SB, Hong YC, Kim JW, Park EJ, Shin MS, Kim BN, et al. Bisphenol A in relation to behavior and learning of school-age children. J Child Psychol Psychiatry. 2013;54(8):890-9.
30. Miodovnik A, Engel SM, Zhu C, Ye X, Soorya LV, Silva MJ, et al. Endocrine disruptors and childhood social impairment. Neurotoxicology. 2011;32(2):261-7.
31. Evans SF, Kobrosly RW, Barrett ES, Thurston SW, Calafat AM, Weiss B, et al. Prenatal bisphenol A exposure and maternally reported behavior in boys and girls. Neurotoxicology. 2014 Dec;45:91-9.
32. Authority EFS, Gundert‐Remy U, Bodin J, Bosetti C, FitzGerald R, Hanberg A, et al. Bisphenol A (BPA) hazard assessment protocol. EFSA Supporting Publications. 2017;14(12):1354E.
33. USEPA. [Internet]. Bisphenol A Action Plan Summary. [Cited: 2021 Feb 21]. Available from: http://www.epa.gov/oppt/existingchemicals/pubs/actionplans/bpa.html
34. Kang Y-G, Kim J-Y, Kim J, Won P-J, Nam J-H. Release of bisphenol A from resin composite used to bond orthodontic lingual retainers. Am J Orthod Dentofacial Orthop. 2011;140(6):779-89.
35. Fleisch AF, Sheffield PE, Chinn C, Edelstein BL, Landrigan PJ. Bisphenol A and related compounds in dental materials. Pediatrics. 2010;126(4):760-8.
36. Tarumi H, Imazato S, Narimatsu M, Matsuo M, Ebisu S. Estrogenicity of fissure sealants and adhesive resins determined by reporter gene assay. J Dent Res. 2000;79(11):1838-43.
37. Lee J-H, Yi S-K, Kim S-Y, Kim J-S, Son S-A, Jeong S-H, et al. Salivary bisphenol A levels and their association with composite resin restoration. Chemosphere. 2017;172:46-51.
38. Berge TLL, Lygre GB, Lie SA, Lindh CH, Björkman L. Bisphenol A in human saliva and urine before and after treatment with dental polymer-based restorative materials. Eur J Oral Sci. 2019 Oct;127(5):435-44.
39. Manoj MK, Ramakrishnan R, Babjee S, Nasim R. High-performance liquid chromatography analysis of salivary bisphenol A levels from light-cured and chemically cured orthodontic adhesives. Am J Orthod Dentofacial Orthop. 2018;154(6):803-8.
40. Kingman A, Hyman J, Masten SA, Jayaram B, Smith C, Eichmiller F, et al. Bisphenol A and other compounds in human saliva and urine associated with the placement of composite restorations. J Am Dent Assoc. 2012;143(12):1292-302.
41. Martin M, Bajet D, Woods J, Dills R, Poulten E. Detection of dental composite and sealant resin components in urine. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2005;4(99):429.
42. Marzouk T, Sathyanarayana S, Kim AS, Seminario AL, McKinney CM. A Systematic Review of Exposure to Bisphenol A from Dental Treatment. JDR Clin Trans Res. 2019;4(2):106-15.
43. Maserejian NN, Trachtenberg FL, Wheaton OB, Calafat AM, Ranganathan G, Kim HY, et al. Changes in urinary bisphenol A concentrations associated with placement of dental composite restorations in children and adolescents. J Am Dent Assoc. 2016 Aug;147(8):620-30.
44. Moreira MR, Matos LG, de Souza ID, Brigante TAV, Queiroz MEC, Romano FL, et al. Bisphenol A release from orthodontic adhesives measured in vitro and in vivo with gas chromatography. Am J Orthod Dentofacial Orthop. 2017;151(3):477-83.
45. Maserejian NN, Shrader P, Trachtenberg FL, Hauser R, Bellinger DC, Tavares M. Dental sealants and flowable composite restorations and psychosocial, neuropsychological, and physical development in children. Pediatr Dent. 2014;36(1):68-75.
46. Sasaki N, Okuda K, Kato T, Kakishima H, Okuma H, Abe K, et al. Salivary bisphenol-A levels detected by ELISA after restoration with composite resin. J Mater Sci Mater Med. 2005;16(4):297-300.
47. Paula AB, Toste D, Marinho A, Amaro I, Marto C-M, Coelho A, et al. Once resin composites and dental sealants release Bisphenol-A, How might this affect our clinical management?—A systematic review. Int. J. Environ. Res. Public Health. 2019;16(9):1627.
48. Eramo S, Urbani G, Sfasciotti GL, Brugnoletti O, Bossù M, Polimeni A. Estrogenicity of bisphenol A released from sealants and composites: a review of the literature. Ann Stomatol (Roma). 2010;1(3-4):14-21.
49. Wada H, Tarumi H, Imazato S, Narimatsu M, Ebisu S. In vitro Estrogenicity of Resin Composites. J Dent Res. 2004;83(3):222-6.
50. Manabe A, Kaneko S, Numazawa S, Itoh K, Inoue M, Hisamitsu H, et al. Detection of bisphenol-A in dental materials by gas chromatography-mass spectrometry. Dent Mater J. 2000 Mar;19(1):75-86.
51. Schmalz G, Preiss A, Arenholt-Bindslev D. Bisphenol-A content of resin monomers and related degradation products. Clin Oral Investig. 1999 Sep;3(3):114-9.
52. Al-Hiyasat AS, Darmani H, Milhem MM. Cytotoxicity evaluation of dental resin composites and their flowable derivatives. Clin Oral Investig. 2005 Mar;9(1):21-5.
53. Marquardt W, Seiss M, Hickel R, Reichl FX. Volatile methacrylates in dental practices. J Adhes Dent. 2009 Apr;11(2):101-7.
54. Van Landuyt KL, Nawrot T, Geebelen B, De Munck J, Snauwaert J, Yoshihara K, et al. How much do resin-based dental materials release? A meta-analytical approach. Dent Mater. 2011 Aug;27(8):723-47.
55. Gupta SK, Saxena P, Pant VA, Pant AB. Release and toxicity of dental resin composite. Toxicol Int. 2012;19(3):225.
56. Al-Hiyasat AS, Darmani H. In vivo effects of BISGMA—a component of dental composite—on male mouse reproduction and fertility. J Biomed Mater Res A. 2006;78A(1):66-72.
57. Seiss M, Marquardt W, Hickel R, Reichl F-X. Excretion of dental resin monomers and metabolic intermediates via urine in guinea pigs. Dent Mater. 2009 2009/04/01/;25(4):481-5.
58. echa.europa.eu [Internet]. Guidance on the Application of the CLP Criteria. [Cited 2021 Feb 21]. Available from: https://echa.europa.eu/documents/10162/23047722/clp_criteria_hh_revised_draft_guidance_rev_7_rac_forum_201305_en.pdf/fddb2d48-4007-47b3-9816-50d2b8ea33d0
59. Nascimento AS, Lima DB, Fook MVL, Albuquerque MSd, Sabino MA, Borges SMP, et al. Physicomechanical characterization and biological evaluation of bulk-fill composite resin. Braz Oral Res. 2018;32:e107.
60. Gonçalves F, Campos LMdP, Rodrigues-Júnior EC, Costa FV, Marques PA, Francci CE, et al. A comparative study of bulk-fill composites: degree of conversion, post-gel shrinkage and cytotoxicity. Braz Oral Res. 2018;32:e107
61. Susila AV, Balasubramanian V. Correlation of elution and sensitivity of cell lines to dental composites. Dent Mater. 2016;32(3):e63-e72.
62. Geurtsen W, Lehmann F, Spahl W, Leyhausen G. Cytotoxicity of 35 dental resin composite monomers/additives in permanent 3T3 and three human primary fibroblast cultures. J Biomed Mater Res A. 1998;41(3):474-80. 474-80.
63. Brzović Rajić V, Želježić D, Malčić Ivanišević A, Verzak Ž, Baraba A, Miletić I. Cytotoxicity and Genotoxicity of Resin Based Dental Materials in Human Lymphocytes In Vitro. Acta Clin Croat. 2018 Jun;57(2):278-85.
64. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organ J. 2012 Jan;5(1):9-19.
65. Kurutas EB. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutr J. 2016 Jul 25;15(1):71.
66. Engelmann J, Janke V, Volk J, Leyhausen G, Von Neuhoff N, Schlegelberger B, et al. Effects of BisGMA on glutathione metabolism and apoptosis in human gingival fibroblasts in vitro. Biomaterials. 2004;25(19):4573-80.
67. Volk J, Engelmann J, Leyhausen G, Geurtsen W. Effects of three resin monomers on the cellular glutathione concentration of cultured human gingival fibroblasts. Dent Mater. 2006;22(6):499-505.
68. Chang HH, Guo MK, Kasten FH, Chang MC, Huang GF, Wang YL, et al. Stimulation of glutathione depletion, ROS production and cell cycle arrest of dental pulp cells and gingival epithelial cells by HEMA. Biomaterials. 2005 Mar;26(7):745-53.
69. Chang MC, Chen LI, Chan CP, Lee JJ, Wang TM, Yang TT, et al. The role of reactive oxygen species and hemeoxygenase-1 expression in the cytotoxicity, cell cycle alteration and apoptosis of dental pulp cells induced by BisGMA. Biomaterials. 2010 Nov;31(32):8164-71.
70. Stanislawski L, Lefeuvre M, Bourd K, Soheili-Majd E, Goldberg M, Périanin A. TEGDMA-induced toxicity in human fibroblasts is associated with early and drastic glutathione depletion with subsequent production of oxygen reactive species. J Biomed Mater Res A. 2003 Sep 1;66(3):476-82.
71. Nocca G, De Palma F, Minucci A, De Sole P, Martorana GE, Callà C, et al. Alterations of energy metabolism and glutathione levels of HL-60 cells induced by methacrylates present in composite resins. J Dent. 2007;35(3):187-94.
72. Chang HH, Chang MC, Wang HH, Huang GF, Lee YL, Wang YL, et al. Urethane dimethacrylate induces cytotoxicity and regulates cyclooxygenase-2, hemeoxygenase and carboxylesterase expression in human dental pulp cells. Acta Biomater. 2014;10(2):722-31.
73. Schweikl H, Hartmann A, Hiller KA, Spagnuolo G, Bolay C, Brockhoff G, et al. Inhibition of TEGDMA and HEMA-induced genotoxicity and cell cycle arrest by N-acetylcysteine. Dent Mater. 2007;23(6):688-95.
74. Schweikl H, Spagnuolo G, Schmalz G. Genetic and cellular toxicology of dental resin monomers. J Dent Res. 2006;85(10):870-7.
75. Reichl F-X, Esters M, Simon S, Seiss M, Kehe K, Kleinsasser N, et al. Cell death effects of resin-based dental material compounds and mercurials in human gingival fibroblasts. Arch Toxicol. 2006;80(6):370-7.
76. Ahmed RH, Aref MI, Hassan RM, Mohammed NR. Cytotoxic effect of composite resin and amalgam filling materials on human labial and buccal epithelium. Nature and science. 2010;8(10):48-53.
77. Issa Y, Watts D, Brunton P, Waters C, Duxbury A. Resin composite monomers alter MTT and LDH activity of human gingival fibroblasts in vitro. Dent Mater. 2004;20(1):12-20.
78. Johnson MD, Schilz J, Djordjevic MV, Rice JR, Shields PG. Evaluation of in vitro assays for assessing the toxicity of cigarette smoke and smokeless tobacco. Cancer Epidemiol Biomarkers Prev. 2009;18(12):3263-304.
79. Huang FM, Kuan YH, Lee SS, Chang YC. Cytotoxicity and genotoxicity of triethyleneglycol-dimethacrylate in macrophages involved in DNA damage and caspases activation. Environ Toxicol. 2015;30(5):581-8.
80. Shehata M, Durner J, Eldenez A, Van Landuyt K, Styllou P, Rothmund L, et al. Cytotoxicity and induction of DNA double-strand breaks by components leached from dental composites in primary human gingival fibroblasts. Dent Mater. 2013;29(9):971-9.
81. Wisniewska-Jarosinska M, Poplawski T, Chojnacki CJ, Pawlowska E, Krupa R, Szczepanska J, et al. Independent and combined cytotoxicity and genotoxicity of triethylene glycol dimethacrylate and urethane dimethacrylate. Mol. Biol. Rep. 2011;38(7):4603-11.
82. Li YC, Kuan YH, Huang FM, Chang YC. The role of DNA damage and caspase activation in cytotoxicity and genotoxicity of macrophages induced by bisphenol‐A‐glycidyldimethacrylate. Int Endod J. 2012;45(6):499-507.
83. Di Pietro A, Visalli G, La Maestra S, Micale R, Baluce B, Matarese G, et al. Biomonitoring of DNA damage in peripheral blood lymphocytes of subjects with dental restorative fillings. Mutat Res Genet Toxicol Environ Mutagen 2008;650(2):115-22.
84. Pettini F, Savino M, Corsalini M, Cantore S, Ballini A. Cytogenetic genotoxic investigation in peripheral blood lymphocytes of subjects with dental composite restorative filling materials. J Biol Regul Homeost. 2015;29(1):229-33.
85. Priya EL, Ranganathan K, Rao UDK, Joshua E, Mathew DG, Wilson K. A study of sister chromatid exchange in patients with dental amalgam restorations. Indian J Dent Res. 2014;25(6):772.
86. Hansel C, Leyhausen G, Mai UE, Geurtsen W. Effects of various resin composite (co)monomers and extracts on two caries-associated micro-organisms in vitro. J Dent Res. 1998 Jan;77(1):60-7.
87. Khalichi P, Cvitkovitch DG, Santerre JP. Effect of composite resin biodegradation products on oral streptococcal growth. Biomaterials. 2004;25(24):5467-72.
88. Bergenholtz G. Evidence for bacterial causation of adverse pulpal responses in resin-based dental restorations. Crit Rev Oral Biol Med. 2000;11(4):467-80.
89. Di Giulio M, D'Ercole S, Zara S, Cellini L. Streptococcus mitis/human gingival fibroblasts co-culture: The best natural association in answer to the 2-hydroxyethyl methacrylate release. APMIS 2012;120:139-46.