Triethylene glycol dimethacrylate (TEGDMA) is a dentin-bonding agent and a major component of various dental restorative biomaterials. TEGDMA monomers are released from dental resins and induce dental pulp inflammation and necrosis. In this study, we have investigated the mechanism of TEGDMA-induced cytotoxicity of fibroblasts. Treatment of cultured human gingival and pulpal fibroblasts with 0.1-3 mM of TEGDMA for 24 h induced a concentration-dependent and variable cytotoxic effect. Fifty percent of toxicity (TC(50)) was obtained with 1.2 +/- 0.9 and 2.6 +/- 1.1 mM of TEGDMA for gingival and pulpal fibroblasts, respectively. Moreover, TEGDMA-induced cytotoxicity was associated with an early and drastic depletion of cellular glutathione (GSH), which started at 15-30 min and was almost complete at 4-6 h. Antioxidants, such as Trolox (0.01 mM), ascorbate (0.2 mM), and N-acetylcysteine (NAC) (5 mM) prevented the TEGDMA-induced cytotoxicity while GSH depletion was partially inhibited. Finally, a late production of reactive oxygen species (ROS) occurred in fibroblasts treated with TEGDMA for 3-4 h, as determined by 2',7'-dichlorofluorescein fluorescence, and was completely inhibited by Trolox (5 microM). The data show that TEGDMA induced a drastic GSH depletion followed by production of ROS, which may contribute to the toxicity of gingival and pulpal fibroblasts. Antioxidants, such as NAC, ascorbate, and particularly Trolox, appear useful in preventing cell damage mediated by resin-containing dental restorative materials.
To evaluate the effects of bioactive molecules in pulpal wound healing, we carried out experiments using the rat upper molars as an in vivo model. Cavities were prepared on the mesial aspect, and pulp perforation was accomplished by the application of pressure with the tip of a steel probe. After the pulp-capping procedure, the cavities were filled with a glass-ionomer cement. Comparison was made between and among: (1) sham-operated controls with dentin and predentin fragments implanted in the pulp during perforation after 8, 14, and 28 days; (2) carrier without bioactive substance; (3) calcium hydroxide; (4) Bone Sialoprotein (BSP); (5) different concentrations of Bone Morphogenetic Protein-7 (BMP-7), also termed Osteogenic Protein-1 (OP-1); and (6) N-Acetyl Cysteine (NAC), an anti-oxidant agent preventing glutathione depletion. Histologic and morphometric comparison, carried out among the first 4 groups on demineralized tissue sections, indicated that, at 28 days after implantation, BSP was the most efficient bioactive molecule, inducing homogeneous and well-mineralized reparative dentin. BMP-7 gave reparative dentin of the osteodentin type in the coronal part of the pulp, and generated the formation of a homogeneous mineralized structure in the root canal. These findings indicate that the crown and radicular parts of the pulp bear their own specificity. Both BSP and BMP-7 were superior to calcium hydroxide in their mineralization-inducing properties, and displayed larger areas of mineralization containing fewer pulp tissue inclusions. The overall mineralization process to these molecules appeared to proceed by mechanisms that involved the recruitment of cells which differentiate into osteoblast-like cells, producing a mineralizing extracellular matrix. We also provide preliminary evidence that NAC induces reparative dentin formation in the rat molar model. Pulp-capping with bioactive molecules provides new prospects for dental therapy.
Resin-modified glass ionomer cements (RM-GICs) are the last generation of GICs commonly used in restorative dentistry. They contain various resins that improve their mechanical properties. These modifications, however, may also affect their biocompatibility. We compared the cytotoxicity of seven biomaterials (five RM-GICs, one metal-reinforced GIC (M-GIC), and a zinc-oxyphosphate cement) using an assay of pulp cell viability in vitro (MTT assay). The most toxic materials appeared to be the M-GIC Hi-Dense and the RM-GIC Vitremer. The less toxic ones appeared to be the RM-GICs Compoglass and Photac-Fil. Attempts made to identify the factors responsible for their cytotoxicity indicated that in vitro cytotoxicity did not seem to be caused by any change in pH of the biomaterial eluates. Adsorption of biomaterial eluates on dentin powder significantly reduced the cytotoxicity of all biomaterials. The concentration of F-, Sr2+, and Al3+ (major ionic elements present in GICs) in the eluate of six glass ionomer containing biomaterials was too low to be cytotoxic. However, Cu2+ and Ag+ (present in alloys of M-GIC) were present in toxic concentrations in Hi-Dense eluates. Unpolymerized monomers leached from resins were identified by Fourier transform IR spectroscopy in biomaterial eluates. The monomers hydroxyethyl methacrylate (HEMA), triethylene glycol dimethacrylate (TEGDMA), and poly(acrylic) acid were identified in eluates of Vitremer, Compoglass, and Hi-Dense, respectively. After ethanol elution of HEMA and TEGDMA from Vitremer and Compoglass, respectively, the cytotoxicity of these two RM-GICs was drastically reduced. Our results suggest that the principal compounds responsible for cytotoxicity are unpolymerized resin monomers in the two RM-GICs and Cu2+ and Ag+ in the M-GIC.
Eight biomaterials eluted from four different types of dental restorative biomaterials, that is, from glass-ionomer cement (GIC: Ketac-fil and Fuji II), resin-modified glass ionomer cement (RM-GIC: Fuji II LC and Photac-fil), composite (Z100 MP and Tetric-flow), and compomer (Compoglass F and F-2000), were studied for their cytotoxic properties in relation to glutathione (GSH) content in cultured human gingival fibroblasts. Z100 MP, Tetric-flow, and Compoglass F were less cytotoxic than the others, with a toxic concentration of 50% (TC 50) > 24% (of eluate), as determined by the MTT test. F-2000, Tetric-flow, and the other biomaterials were relatively more cytotoxic (TC 50 = 9-16%). With the exception of Z100 MP, all the biomaterials induced a depletion of cellular glutathione (GSH) that was variable depending upon the biomaterial eluates. The strongest GSH depletion was with F-2000, Fuji II, and Photac-fil. GSH depletion, with Compoglass and F-2000, was rapid-detectable after one h of cell treatment and complete within 3 h-whereas a longer period of incubation was required for the other biomaterials. Interestingly, the drug cytotoxic effects induced by all the biomaterials were prevented by cell treatment with the antioxidant N-acetylcysteine (NAC). This study provides evidence that the cytotoxic property of dental restorative biomaterials is associated with depletion of the glutathione level in gingival fibroblasts. While the molecular mechanisms of this phenomenon require further investigations, our data suggest that NAC may be useful in preventing the cellular damage induced by dental restorative biomaterials.
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