Baixe Revisão sistemática MTA e outras Notas de estudo em PDF para Odontologia, somente na Docsity! R M t H a b M c d a A R R 2 A K H P B P A R P E G W M M m D 0 d d e n t a l m a t e r i a l s 2 4 ( 2 0 0 8 ) 149–164 avai lab le at www.sc iencedi rec t .com journa l homepage: www. int l .e lsev ierhea l th .com/ journa ls /dema eview ineral trioxide aggregate material use in endodontic reatment: A review of the literature oward W. Robertsa,∗, Jeffrey M. Tothb, David W. Berzinsc, David G. Charltond USAF Dental Evaluation and Consultation Service, Dental Biomaterials Evaluation, Great Lakes, IL, United States Medical College of Wisconsin, Department of Orthopedics; Marquette University School of Dentistry, Graduate Dental Biomaterials; ilwaukee WI, USA Marquette University School of Dentistry, Graduate Dental Biomaterials; Milwaukee WI, USA US Navy Institute for Dental and Biomedical Research, Great Lakes IL, USA r t i c l e i n f o rticle history: eceived 26 July 2005 eceived in revised form 3 April 2007 ccepted 30 April 2007 eywords: ydroxyapatite ortland cement iocompatibility ulp-capping pexification oot-end filling ulpotomy ndodontics MTA MTA TA a b s t r a c t Objective. The purpose of this paper was to review the composition, properties, biocompati- bility, and the clinical results involving the use of mineral trioxide aggregate (MTA) materials in endodontic treatment. Methods. Electronic search of scientific papers from January 1990 to August 2006 was accom- plished using PubMed and Scopus search engines (search terms: MTA, GMTA, WMTA, mineral AND trioxide AND aggregate). Results. Selected exclusion criteria resulted in 156 citations from the scientific, peer-reviewed dental literature. MTA materials are derived from a Portland cement parent compound and have been demonstrated to be biocompatible endodontic repair materials, with its biocom- patible nature strongly suggested by its ability to form hydroxyappatite when exposed to physiologic solutions. With some exceptions, MTA materials provide better microleakage protection than traditional endodontic repair materials using dye, fluid filtration, and bac- terial penetration leakage models. In both animal and human studies, MTA materials have been shown to have excellent potential as pulp-capping and pulpotomy medicaments but studies with long-term follow-up are limited. Preliminary studies suggested a favorable MTA material use as apical and furcation restorative materials as well as medicaments for apex- ogenesis and apexification treatments; however, long-term clinical studies are needed in these areas. Conclusion. MTA materials have been shown to have a biocompatible nature and have excel-ineral trioxide aggregate lent potential in endodontic use. MTA materials are a refined Portland cement material and the substitution of Portland cement for MTA products is presently discouraged. Existing human studies involving MTA materials are very promising, however, insufficient random- ized, double-blind clinica clinical indications. Furth © 2007 Academy None of the authors have any financial interests in any of the prod anuscript are solely those of the authors and do not represent the o epartment of Defense, or the United States Government. ∗ Corresponding author. Present address: 310C B Street, Building 1H, Gre E-mail address: Howard.roberts@med.navy.mil (H.W. Roberts). 109-5641/$ – see front matter © 2007 Academy of Dental Materials. Pu oi:10.1016/j.dental.2007.04.007l studies of sufficient duration exist involving MTA for all of its er clinical studies are needed in these areas. of Dental Materials. Published by Elsevier Ltd. All rights reserved. ucts mentioned in this manuscript. The opinions stated in this pinion of the United States Air Force, the United States Navy, the at Lakes, IL 60088, USA. Tel.: +1 847 688 7670; fax: +1 847 688 7667. blished by Elsevier Ltd. All rights reserved. 150 d e n t a l m a t e r i a l s 2 4 ( 2 0 0 8 ) 149–164 Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 2. Chemical, physical, and mechanical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 3. Microleakage studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 3.1. In vitro dye/fluid filtration method leakage studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 3.2. In vitro bacterial leakage studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 3.3. Biocompatibility studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 3.3.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 3.3.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 3.4. Characterization of MTA biocompatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 4. Clinical applications of mineral trioxide aggregate materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 4.1. Pulp-capping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 4.1.1. Animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 4.2. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 4.2.1. Pulp-capping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 4.2.2. Pulpotomy dressing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 4.2.3. Other MTA material use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 5. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 1. Introduction It is estimated that over 24 million endodontic procedures are performed on an annual basis, with up to 5.5% of those procedures involving endodontic apical surgery, perforation repair, and apexification treatment [1]. Endodontic surgery is performed to resolve inflammatory processes that cannot be successfully treated by conventional techniques, which may be due to complex canal and/or apical anatomy and external inflammatory processes [2]. Surgical procedures may also be indicated for the resolution of procedural misadven- tures, to include root perforation that may occur either during canal instrumentation or post-space preparation [2,3]. Surgi- cal treatment usually involves the placement of a material designed to seal the root canal contents from the peri- radicular tissues and repair root defects [2]. Understandably, this material should demonstrate the ability to form a seal with dental tissues while also exhibiting biocompatible behav- ior with the periodontal tissues [3]. An ideal endodontic repair material ideally would adhere to tooth structure, maintain a sufficient seal, be insoluble in tis- sue fluids, dimensionally stable, non-resorbable, radiopaque, and exhibit biocompatibility if not bioactivity [2,4,5]. A number of materials have historically been used for retrograde fillings and perforation repair, such as amalgam, zinc-oxide-eugenol cements, composite resin, and glass-ionomer cements [4,6]. Unfortunately, none of these materials have been able to sat- isfy the total requirements of an ideal material [4,5]. Mineral trioxide aggregate (MTA) is a biomaterial that has been investigated for endodontic applications since the early 1990s. MTA was first described in the dental scientific liter- ature in 1993 [7] and was given approval for endodontic use of this article is to present a systematic review of the physi- cal properties, biocompatibility testing, and pertinent clinical studies involving MTA materials. A structured literature review was performed for articles published between January 1990 and August 2006. The Inter- net database PubMed (www.ncbi.nlm.nih.gov/entrez) and Scopus (www.scopus.com) was used to search for the key- words MTA, GMTA, WMTA, and mineral AND trioxide AND aggregate. For further refinement, the following exclusion criteria were defined: Publications were limited to those of English language and from the scientific, peer-reviewed literature. Furthermore, publications possessing a question- able peer-review process (e.g., manufacturer-supported) were excluded for consideration. Although clinical case reports were included, only clinical studies involving appropriate number, sufficient controls and analysis were given serious consideration [9]. Using the search keywords limited to dental publications produced a total of 245 results, of which applica- tion of inclusion criteria produced the 156 citations that forms the basis for this review (Fig. 1). 2. Chemical, physical, and mechanical properties MTA materials are a mixture of a refined Portland cement and bismuth oxide, and are reported to contain trace amounts of SiO2, CaO, MgO, K2SO4, and Na2SO4 [10–12]. The major component, Portland cement, is a mixture of dicalcium sil- icate, tricalcium silicate, tricalcium aluminate, gypsum, and tetracalcium aluminoferrite [10–12]. Gypsum is an important determinant of setting time, as is tetracalcium aluminoferrate,by the U.S. Food and Drug Administration in 1998 [8]. As it will soon follow, MTA materials are derived from a Portland cement parent compound: it is interesting that no information has been published regarding to any investigations that led to the precise delineation of the present MTA materials. The aimalthough to a lesser extent [12]. MTA products may contain approximately half the gypsum content of Portland cement, as well as smaller amounts of aluminum species, which provides a longer working time than Portland cement. Although it may be inferred that Portland cement could serve as a MTA substi- 2 4 a T m d r t f m o 5 u e p c e c c t n h h a p t a r a t a e s i 3 T o e u t 3 T t m G a r [ c i p r e s w f d e n t a l m a t e r i a l s lbicans than WMTA prepared with sterile water alone [38]. his finding should be tempered with knowledge that MTA aterials may not set when mixed with some chlorhexi- ine preparations [20]. Both freshly mixed and set GMTA was eported to be inhibitory to C. albicans using an antifungal ube-dilution method [39] while another study reported dif- erences in that GMTA and WMTA at different powder/liquid ixtures were not equally effective at preventing the growth f C. albicans [40]. Both WMTA and GMTA in concentrations of 0 and 25 mg/ml were equally inhibitive against C. albicans for p to 7 days; however, at lower concentrations only GMTA was ffective [40]. This is evidence of not only the importance of roper powder/liquid ratios but also raises possible questions oncerning that the two MTA preparations may not be equally ffective in some clinical applications. In conclusion, MTA materials are derived from Portland ement, and although it could be inferred that Portland ement could serve as a suitable substitute, it is important o emphasize that MTA products and Portland cement are ot identical materials. MTA materials have been reported to ave a smaller mean particle size, contain less heavy metals, ave a longer working time, and appears to have undergone dditional processing/purification than the Portland cement arent compound. WMTA has been marketed since 2002 due o esthetic considerations and contains less iron, aluminum, nd magnesium oxides than its GMTA counterpart. Both mate- ials undergo a hydration setting reaction that is said to reach n initial set in 3–4 h but whose maturation and resistance o dislodgement increases with time. The physical properties nd setting time of MTA materials can be affected by differ- nt preparation liquids and both WMTA and GMTA have been hown to possess antibacterial and antifungal activity, which s presumably due to its pH. . Microleakage studies he success of an endodontic material may largely depend n its sealing ability, as most post-treatment endodontic dis- ase is thought to occur due to tissue and other materials in ncleaned and/or unobturated areas of the root canal system hat egress into the surrounding tissues [41]. .1. In vitro dye/fluid filtration method leakage studies he microleakage of MTA materials compared to other tradi- ional endodontic materials via in vitro dye and fluid filtration ethods have been the subject of many studies [42–64]. MTA has been reported to have less microleakage than malgam [42–45,47,48,51,52], zinc-oxide-eugenol (ZOE) prepa- ations [42–44], and a conventional glass-ionomer material 59] when used as a root-end restoration following api- al resection. However, other studies reported no difference n leakage between MTA materials and zinc-oxide-eugenol reparations [45,51,52,59], and conventional glass-ionomer estorative materials [48]. The minimal thickness for MTA to ffectively seal the apical area has been investigated with one tudy reporting a placement thickness of at least 3 mm [49] ith another report stating a minimal of 4 mm is required or significant microleakage prevention [50]. The addition of( 2 0 0 8 ) 149–164 153 calcium chloride has been reported to enhance the sealing ability of both GMTA and WMTA, probably by the effect of cal- cium chloride’s enhancement of MTA material setting time [57]. WMTA and GMTA have been compared for the sealing of simulated canals with open apices using thicknesses of 2 and 5 mm followed by gutta percha obturation either immedi- ately after MTA material placement or 24 h later [53]. Results found that GMTA had less microleakage than WMTA in sam- ples obturated 24 h after MTA placement; in all groups 5 mm of MTA material allowed less leakage. Based on the results, the authors recommended a 5-mm GMTA apical barrier placed for treatment of open apices with gutta percha obturation fol- lowed 24 h later [53]. Visual topography evaluations of root-end restorations restored with GMTA, ZOE materials, and amalgam have reported that root-end restoration finishing method had no effect on marginal adaptation of GMTA and ZOE material [63] while another report stated that GMTA appeared to have better root-end marginal adaptation than amalgam [64]. For repair of furcation perforations, a ZOE preparation was reported to provide a better seal than GMTA at 24 h, after which no difference in leakage was observed [60]. However, in another report, GMTA was found to allow more microleak- age in furcation repairs when compared to a ZOE preparation and a self-etch, one step bonding agent [58]. The furcation perforation repair microleakage of GMTA and WMTA was com- pared from both an orthograde and retrograde direction [56]. The results found no difference in leakage between the two MTA materials; but the more interesting findings were that significantly more leakage was found from a microleakage challenge from an orthograde direction [56]. This suggests an impelling need for an adequate coronal barrier material over MTA furcation repairs to adequately protect against coronal microleakage. The microleakage of MTA materials used for root canal obturation has been reported by two studies [54,61]. The first study suggested that GMTA displayed more microleakage than laterally-condensed as well as thermoplasticized gutta percha [54] but this was contrasted by the other study which reported that both WMTA and GMTA allowed less apical microleak- age than warm, vertically condensed gutta percha [61]. The second study also reported no significant difference in leak- age between GMTA and WMTA, but importantly noted that root canal obturation with MTA materials would severely limit retreatment options and should be considered in only select cases [61]. Another report reported that root resection of canals obturated with GMTA did not affect its sealing ability [62]. 3.2. In vitro bacterial leakage studies The microleakage of MTA materials has also been evalu- ated, to a lesser extent, using bacterial penetration methods [31,41,65–75]. GMTA has been evaluated for resistance against apical bacterial leakage when utilized as a root-end filling compared with amalgam and ZOE materials within endodon- tically prepared but unobturated root canals inoculated with Staphylococcus epidermis [41] and Serratia marcescens [65]. GMTA was found to have significantly more resistance to S. epider- mis penetration than amalgam and ZOE preparations with no leakage evident after 90 days, with the other materials exhibit- l s 2154 d e n t a l m a t e r i a ing bacterial penetration ranging from 6 to 57 days [41]. The second study found that GMTA resisted S. macescens penetra- tion for up to 49 days after inoculation while the amalgam and ZOE materials displayed trends for more bacterial penetration [65]. WMTA and a bonded polymer-based material were found to exhibit similar root-end bacterial leakage resistance using a Streptococcus salivarius model with both materials having sig- nificantly less bacterial leakage than a ZOE preparation [71]. GMTA was also reported to allow significantly less E. coli endo- toxin penetration using a modified Limulus Amebocyte Lysate test than amalgam and two ZOE preparations over a 12-week evaluation [69]. In contrast, GMTA was found to have the same bacte- rial penetration resistance as a ZOE preparation, amalgam, a bonded resin composite, as well as a bonded amalgam dur- ing a 12-week evaluation using Streptococcus salivarius [68]. Similar results were reported during a 47-day study with GMTA compared against a polyacid-modified resin composite and a ZOE preparation using Prevotella nigrescens [70]. Fur- thermore, WMTA root-end fillings contaminated with either blood, saline, or saliva during placement were found to dis- play varying resistance to Staphylococcus epidermidis with saliva contamination causing significantly more leakage [72]. When used as perforation repair materials, GMTA did not demonstrate any bacterial leakage during a 45-day evaluation while approximately half of the amalgam-repaired furcations allowed penetration and transmission of F. nucleatum [68]. Fur- thermore, no significant difference was found between GMTA and WMTA in the resistance to F. nucleatum penetration when used for furcation repair [67]. When used in the treatment of immature apices, GMTA has been reported to provide resis- tance to bacterial penetration by E. faecalis and S. epidermis but not Enterobacter aerogenes [31]. A similar report reinforced GMTA resistance to E. faecalis penetration with no leakage identified by E. faecalis 16S rDNA polymerase chain reaction assay after 10 days [73]. GMTA was also evaluated against Acti- nomyces viscosus microleakage for up to 70 days in simulated immature apices that had received either a 2- or 5-mm apical GMTA restoration, or a series of 2-mm GMTA apical retrograde fillings. Results reported that only the 5-mm thick restoration resisted microleakage for the entire evaluation, and exhib- ited significantly less leakage compared to the positive control and other GMTA groups [74]. When evaluated as a coronal barrier, no difference against human saliva bacterial penetra- tion was found between GMTA, WMTA, or a resin-modified glass-ionomer restorative material [75]. One study attempted to evaluate the in vivo coronal sealing ability of WMTA in canine endodontically prepared and obturated root canals, but no conclusive results were found [76]. In conclusion, MTA materials have been investigated using dye, fluid filtration and bacterial infiltration leakage methods. The majority of the dye and fluid filtration studies suggest that MTA materials overall allow less microleakage than tra- ditional materials when used as an apical restoration while providing equivalent protection as a ZOE preparation when used to repair furcation perforations. GMTA and WMTA were shown to provide equivocal results compared against gutta percha when used as a root canal obturation material in the limited number of microleakage studies. MTA materials have been suggested to afford less microleakage than traditional4 ( 2 0 0 8 ) 149–164 materials in a majority of bacteria-based microleakage stud- ies when used as an apical restoration, furcation repair, and in the treatment of immature apices. In both fluid filtration and bacterial leakage models, 3 mm of MTA material is suggested as the minimal amount for protection against microleakage while 5 mm is suggested in the treatment of immature apices. 3.3. Biocompatibility studies 3.3.1. In vitro studies In vitro biocompatibility evaluations of MTA materials have been richly reported in the literature [77–103]. The mutagenic- ity of GMTA, ZOE-based, root-end filling materials, as well as positive and negative controls were evaluated using an Ames mutagenicity assay in which the materials were incubated with Salmonella Typhimurium LT-2 strains with reverting bac- teria colony counts measured [77]. None of the root-end filling materials, including GMTA, produced statistically significant higher Ames test reversion rates, which indicates that none of the root-end filling materials would be considered mutagens [77]. Other evaluations have reported no genotoxic effects of WMTA or Portland cements by single cell gel (comet) assay on peripheral human lymphocytes [78], mouse lymphoma cells [79], as well as Chinese hamster ovary cells [80]. Taken as a whole, none of the studies have shown genotoxic effects of MTA. Although specific carcinogenicity testing for MTA mate- rials was not found in the literature, it is thought that all carcinogens are mutagens. Therefore, based on the existing literature, it is unlikely that MTA is a carcinogenic substance since it is not a mutagenic substance. The cytotoxicity of GMTA, amalgam, ZOE, as well as positive and negative controls was measured using a cell viability assay for mitochondrial dehydrogenase activity in human periodontal ligament fibroblasts after 24-h exposure to extracts of varying concentrations of the test materi- als, in both freshly mixed and 24-h set states [82]. In the freshly mixed state, the sequence of toxicity was amal- gam > Super-EBA > MTA. In the 24-h set state, the sequence of toxicity at a low extract concentration was Super-EBA > MTA, amalgam; while at higher extract concentrations was Super- EBA > amalgam > MTA [82]. Similarly, another report reinforced that GMTA did not negatively affect human periodontal lig- ament fibroblast mitochondrial dehydrogenase activity [86]. SEM analysis of periodontal ligament fibroblasts was found to have a normal morphology and exhibit growth and attach- ment to 24-h set MTA surfaces [83]. However, in the freshly mixed GMTA samples, the cells were round, less in density, exhibited surface defects, and lacked attachment to MTA [83]. If the quality and quantity of cell attachment to the root- end filling materials can be used as a criterion to evaluate material’s toxicity, then set GMTA appears to be less cyto- toxic than fresh GMTA [83]. In a comparable study involving resected root surfaces, PDL cell attachment was observed on GMTA but was absent on gutta percha [87]. Similarly, PDL fibroblasts have been reported to display enhanced prolifer- ation on WMTA in a study that analyzed cellular metabolic activity [88]. These analyses indicated that WMTA induced a general osteogenic phenotype in PDL fibroblasts, with induc- tion of alkaline phosphatase activity, as well as production of osteonidogen, osteonectin, and osteopontin [88]. 2 4 w l o c n t i t w G r a c s n p r f P m i c s o o a i a a i c w w a d t m t a t c c b f b S v a i ( i r f o O a d e n t a l m a t e r i a l s The cytotoxicity of amalgam, ZOE preparations, and GMTA as reported via an ATC L-929 mouse fibroblast agar over- ay and radiochromium method [81]. Results of the agar verlay found that set amalgam was significantly less toxic ompared to the other materials, while the set GMTA was sig- ificantly less toxic than the ZOE preparations. Contrasting, he radiochromium method suggested that GMTA was signif- cantly less toxic than amalgam. Although it was suggested hat the increased agar cytotoxicity of the ZOE preparations as due to the leaching of eugenol, the report concluded that MTA was no more cytotoxic than other root-end filling mate- ials currently in use [81]. These findings were reinforced by nother study using human gingival fibroblasts and a L-929 ell line [85]. GMTA and a CP titanium alloy was found to have imilar affect on gingival fibroblast cellular activity, causing o negative affect on cell viability, Prostaglandin E2 assays, rotein and lactate synthesis, and cell proliferation. Overall esults indicated that gingival fibroblast growth was similar or both GMTA and titanium, as either material did not initiate GE2 release or cause alteration of gingival fibroblast cellular etabolism [84]. The high pH value of freshly mixed GMTA was found to nduce cell lysis in L-929 mouse fibroblasts and macrophage ell lines in direct contact with the material; however, et GMTA demonstrated favorable biocompatibility with no bserved effect on cell morphology as well as limited impact n cell growth at 72 h [89]. WMTA, as well as calcium hydroxide nd a ZOE sealer, was shown not to affect the cell viabil- ty or the Prostaglandin E2 synthesis of murine macrophages nd fibroblasts [91]. In a different study, murine fibroblast nd macrophage cells displayed significantly greater cytotox- city using flow cytometry with WMTA prepared with 0.12% hlorhexidine gluconate than to WMTA prepared with sterile ater [90]. MG-63 cultured human osteoblasts were exposed to GMTA ith cellular response evaluated via alkaline phosphatase ctivity as well as inflammatory cytokine and osteocalcin pro- uction [92]. The MG-63 cells were found to adhere closely o the GMTA surface while cytokines for osteoclast recruit- ent (M-CSF) and activation (IL-1, IL-1, IL-6) were found o be produced, along with observed osteocalcin production nd alkaline phosphatase activity [92]. This led to specula- ion that GMTA causes osteoblast adhesion with release of ytokines from the attached osteoblasts resulting in osteo- last activation via coupled resorption. Therefore, MTA might e considered a suitable substitute for PMMA when used or an orthopedic bone cement [92]. This was corroborated y another study that found that MG-63 osteoblast-like and aos-2 human osteosarcoma cells exposed to GMTA exhibited iability, attachment, proliferation, and collagen production fter 24 h [96]. ELISA assays have been used to assess the osteocompat- bility of GMTA by monitoring the expression of Interleukin IL)-1, IL-6, IL-8, IL-11 and macrophage colony stimulat- ng factor (M-CSF) [93]. Although osteoblast cell growth was eported, production of IL-1 and IL-11 were not detected rom the cells exposed to the GMTA materials. However, steoblastic IL-6 and IL-8 were detected as well as M-CSF [93]. steoblasts in another study were found to demonstrate good dhesion and spreading on GMTA surface, but did not demon-( 2 0 0 8 ) 149–164 155 strate the same ultrastructural characteristics when exposed to a ZOE preparation and amalgam [94]. GMTA osteocom- patibility was reported after U2OS human osteosarcoma cell lines were incubated with GMTA and evaluated using West- ern blot assay [95]. In this study, GMTA had a positive effect on the mitogen-activated protein kinase (MAPK) pathways. The authors also reported that a dose-dependent influence was present on the extracellular signal-regulated kinase MAPK pathway, which is a known pathway leading to osteoblastic activation and overgrowth [95]. This was reinforced by another study that reported both 1- and 28-day cured GMTA and WMTA displayed biocompatibility when exposed to a Saos-2 human osteosarcoma cell line [97], while an additional another study reported both cell attachment and IL-4 and IL-10 cytokine pro- duction [98]. Freshly mixed or set GMTA has been reported to display little to no neurotoxicity. Neurotoxicity effects were quan- titatively assessed by exposing fetal mice cortical neuronal and glial cells and measuring lactate dehydrogenase activity, an assay for cell death [99]. In this study, an amalgam, ZOE preparation, and a resin endodontic sealer exhibited neuro- toxicity that affected approximately 50–100% of the neuronal and glial cells, while GMTA exhibited little to no neurotoxicity [99]. GMTA has also been reported to be biocompatible with a murine cementoblast model, with the cementoblasts display- ing ultrastructural attachment to GMTA surface with normal reverse transcriptase polymerase chain reaction analysis (RT- PCR) indicating osteocalcin production [100]. Another study suggested that WMTA was more biocompatible than GMTA in supporting human cementoblast and keratinocyte growth [103]. WMTA effect on dental pulp cell viability and proliferation has been evaluated using mouse MDPC-23 odontoblast-like cells and OD-21 undifferentiated pulp cells. After 24-h expo- sure to WMTA, apoptosis was not induced in either cell line, and WMTA was reported to cause DNA synthesis increase, suggesting a positive effect on cellular proliferation [101]. This was reinforced by another report that suggested that WMTA had more of a stimulating effect on human dental pulp cells than a commercial calcium hydroxide preparation [102]. 3.3.2. In vivo studies GMTA was reported to induce little or no inflammation com- pared to a ZOE preparation when implanted into guinea pig mandibles, with one GMTA sample demonstrating bone for- mation on its surface [104]. Similar tissue reactions with both GMTA and Portland cement that demonstrate direct bone deposition on the materials’ surfaces have been reported [105]. Another study found no inflammation difference in rat connective tissue exposed to both WMTA and a Port- land cement mixture [106]. An additional study reported a more favorable tissue reaction to GMTA compared to amal- gam and two ZOE preparations that were implanted in guinea pig tibias and mandibles with direct bone apposition observed on some GMTA samples [107]. However, a differ- ent study found no difference in rat bone tissue reaction between WMTA, GMTA, amalgam, and an epoxy-based, cal- cium hydroxide root canal sealer [108]. In a rat connective tissue model, GMTA was observed to induce calcification which served as a nidus for ossification [109], whereas in a l s 2158 d e n t a l m a t e r i a GMTA and formocresol were compared as pulpotomy dressings in primary molars with carious pulp exposures, with only one reported failure (internal resorption in a formocresol- treated specimen) in the 32 teeth available for evaluation ranging 6–30 months [135]. Pulp canal obliteration was noted at a higher frequency in GMTA-treated specimens (7/17) than that seen with formocresol (2/15) [135]. Another study com- pared GMTA, WMTA, and formocresol as pulpotomy dressings in primary teeth demonstrating radiographic caries pulpal involvement with recalls at 1, 3, 6, and 12 months [136]. All teeth were judged as clinical and radiographic successes at 1 month, while at 3 months one WMTA-treated tooth failed due to abscess formation; all remaining teeth were rated Fig. 2 – (A) Preoperative radiograph of maxillary central incisor. ( WMTA apical restoration placed. (C) Post-operative radiograph. Im4 ( 2 0 0 8 ) 149–164 successful at 6 months. At 12 months all GMTA specimens were judged to be successful, but three WMTA-treated teeth were found to be clinical and radiographic failures, along with two formocresol-treated teeth. GMTA as found to provide a significantly better outcome than WMTA, with no differ- ence found between WMTA and formocresol [136]. These results were contrasted by a different randomized, prospective study that compared formocresol and WMTA as pulpotomy medicaments in primary molars. At 24 months none of the WMTA-treated teeth exhibited clinical or radiographic pathology while the formocresol-treated teeth demonstrated approximately 13% radiographic and 2% clinical failure [139]. Another longer (range 4–74, mean 38 months) prospective, B) Reveals apical surgical procedure accomplished with ages courtesy of Dr. Brian Min. 2 4 r r s p r c i t W a t w o i [ t g [ b l p c s d w a m t p a t p r t g t r t c a c t i m I r c p i d h f p 2 p 6 d 4.2.3. Other MTA material use Compared to other clinical usage of MTA materials, very few clinical studies exist that report the outcome of clinical use ofd e n t a l m a t e r i a l s andomized study found both formocresol and a MTA mate- ial (authors did not delineate MTA material type) equally uccessful statistically when used as pulpotomy dressings in rimary molars with carious pulp exposures [140]. Similar esults were reported in a 12-month study in which WMTA was ompared with calcium hydroxide for pulpotomy treatment n 90 cariously exposed primary molars [141]. In this study, reatment was curiously provided in two sessions, in which MTA and/or the calcium hydroxide paste was applied after n interim dressing of a corticosteroid/antibiotic solution. At he end of the evaluation period six failures had occurred ith the calcium hydroxide treatments and two failures had ccurred with the WMTA treatments [141]. GMTA and WMTA were evaluated as pulpotomy dress- ngs for primary molars in two different short-term studies 137,138] by the same group of researchers. The first reported hat GMTA exhibited clinical success at 6 months with radio- raphic dentin bridges observed in 50% of the specimens 137]. The second study found similar results with WMTA ut radiographic analysis was limited only to the mandibu- ar teeth. Within this limitation, results were that 69% of the ulp canals demonstrated signs of stenosis, 11.5% of the pulp anals exhibited dentin bridges, and one canal exhibited pos- ible early signs of internal resorption adjacent to the WMTA ressing [138]. In these two studies no statistical difference as found in the rate of pulp canal stenosis between GMTA nd WMTA whereas GMTA was found to produce significantly ore dentin bridges [137,138]. One prospective clinical study reported GMTA as a pulpo- omy medicament in 31 vital, cariously exposed, first molar ermanent teeth [142]. At 24 months, 79% of the 28 teeth avail- ble for evaluation maintained a positive response to vitality esting with the remainder free of clinical or radiographic athology. Sixty-four percent of the specimens had pulpal adiographic hard tissue bridge formation, while seven teeth hat initially presented with immature apices displayed radio- raphic signs of continued root development [142]. Although his study is favorable, it should be noted that the teeth were estored immediately with the manufacturer recommenda- ion of interim placement of the MTA dressing with a moist otton pellet not observed. However, this did not appear to ffect the results and could identify the importance of an early oronal seal provided by a definitive restoration, especially in he pediatric population. Furthermore, it would have been of nterest if this study had been able to compare other treat- ent groups using traditional pulpotomy dressing materials. t is hoped that the authors will report the continued follow-up esults of this work. The histologic pulpal response comparing WMTA to cal- ium hydroxide as pulpotomy dressings was investigated in remolar teeth extracted for orthodontic purposes, report- ng that WMTA induced a more homogenous and continuous entin bridge with less pulpal inflammation than calcium ydroxide at both 4 and 8 weeks after treatment [126]. A avorable outcome was also reported in a private endodontic ractice assessment using WMTA as a pulpotomy dressing in 3 permanent teeth that exhibited clinical signs of irreversible ulpal disease [143]. Of the 19 teeth available for recall (range –53 months) one tooth presented signs of persistent pulpal isease; this case did not receive a permanent restoration and( 2 0 0 8 ) 149–164 159 presented with recurrent caries upon recall. Based on these limited results, the authors reported a Kaplan–Meier survival probability of 0.95 [143].Fig. 3 – (A) Preoperative radiograph of mandibular second molar with furcal perforation. (B) Shows WMTA placement. (C) Post-operative radiograph. Images courtesy of Dr. Brian Min. l s 2 r 160 d e n t a l m a t e r i a MTA materials as root-end filling materials and root repair, as in the clinical cases noted in Figs. 2 and 3. A prospective 24- month clinical study compared GMTA to a ZOE preparation as root-end filling materials in 122 adult patients referred for endodontic surgery [144]. At both 12- and 24-month recalls, acceptable results were noted with both materials; while the authors implied a higher success rate with GMTA treatment, no statistical difference was noted between the two materials [144]. It is hoped that this 24-month report will continue to be followed. A retrospective study concerning GMTA use for root perforation repair in 16 cases within an endodontic resi- dency caseload has been reported [145]. This report involved five lateral root perforations, five strip perforations, three fur- cation perforations, and three apical perforations that were treated with a follow-up range of 12–45 months. Results were that all treatments demonstrated clinical and radiographic signs of healing with return of normal radiographic architec- ture to the repair sites [145]. Although these initial results are promising, this study represents a limited number of clinical cases and no comparison group was included. Clinical case reports in which GMTA has been used to repair horizontal root fractures, root resorption, internal resorption, and furcation perforations with both clinical and radiographic success have also been reported [146–152]. At the time of this review, no prospective studies using MTA materials for apexification and/or apexogenesis pro- cedures have been reported. However, successful individual case reports of using GMTA and/or WMTA for apexifica- tion/apexogenesis treatments do exist [147,148,153–156]. 5. Conclusion The physical properties, sealing ability, biocompatibility, and clinical performance of MTA materials have been discussed. MTA materials appear not only to demonstrate acceptable biocompatible behavior but also exhibits acceptable in vivo biologic performance when used for root-end fillings, perfora- tion repairs, pulp-capping and pulpotomy, and apexification treatment. However, it should be noted that the supporting data have been overwhelmingly from either in vitro or animal studies. Reports have strongly suggested that the favorable biologic performance exhibited by MTA materials is due to hydroxyapatite formation when these materials are exposed to physiologic solutions. Although some studies suggest that the less-expensive Portland cement parent compound could possibly be used in the place of MTA, characterization studies have shown that MTA materials are compositionally differ- ent than Portland cement and it is not recommended at this time that Portland cement can serve as a suitable MTA substitute. GMTA has been investigated more than the more- esthetic WMTA, and while some reports suggest that GMTA may invoke a more desirable biologic response than WMTA, existing reports as a whole are equivocal and more stud- ies are encouraged. Although the overall results in human studies involving MTA materials are very positive, further lon- gitudinal studies are encouraged, as at present insufficient well-designed and controlled clinical studies exists that allow systematic and meta-analysis review of MTA materials in all of its suggested clinical indications.4 ( 2 0 0 8 ) 149–164 Acknowledgements The authors wish to express appreciation to Col. Richard Rut- ledge, Majors Dennis Holt, James Watts, Kim Wilkinson; and Captain Brian Min at the Endodontic Residency, 59 Dental Group, Lackland Air Force Base, Texas, for corroboration with the clinical photographs. e f e r e n c e s [1] Nash KD, Brown J, Hicks ML. 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