The Use of Mineral Trioxide Aggregate in Endodontics Status Report. Zastosowanie Mineral Trioxide Aggregate w endodoncji obecny stan wiedzy

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1 EDITORIAL Dent. Med. Probl. 2008, 45, 1, 5 11 ISSN X Copyright by Silesian Piasts University of Medicine in Wrocław and Polish Stomatological Association BEATA CZARNECKA 1, 2, NICHOLA J. COLEMAN 2, HONORATA SHAW 1, JOHN W. NICHOLSON 2 The Use of Mineral Trioxide Aggregate in Endodontics Status Report Zastosowanie Mineral Trioxide Aggregate w endodoncji obecny stan wiedzy 1 Department of Biomaterials and Experimental Dentistry, University of Medical Sciences, Poznań, Poland 2 Department of Environmental, Chemical and Pharmaceutical Sciences, University of Greenwich, UK Abstract Mineral trioxide aggregate (MTA) is a clinical product comprising a mixture of Portland cement and bismuth oxide which is currently used as a root filling material in dentistry. It has good biological compatibility, is capable of pro moting both osteogenesis and cementogensis, and is finding increasing use in endodontic therapy. It is dimension ally stable, and provides an acceptable and durable seal for endodontically treated teeth. This article reviews the chemistry and applications of MTA, and highlights the fact that very little is currently known about the hydration chemistry, phase evolution and stability of this cement in physiological environments. However, biological effects of MTA have been well documented and are considered in detail. The article concludes that this material is a use ful addition to the range of materials available for clinical application in endodontics (Dent. Med. Probl. 2008, 45, 1, 5 11). Key words: mineral trioxide aggregate, endodontics, root canal sealer. Streszczenie MTA (mineral trioxide aggregate) składa się z mieszaniny cementu portlandzkiego i tlenku bizmutu, jest mate riałem obecnie stosowanym w stomatologii jako uszczelniacz kanałowy. Charakteryzuje się biokompatybilnością, pobudza osteogenezę oraz cementogenezę, zachowuje stabilne wymiary podczas wiązania i szczelnie wypełnia kanały korzeniowe. Praca jest przeglądem piśmiennictwa na temat składu, reakcji wiązania i zastosowania MTA. Niewiele obecnie wiadomo na temat uwodnienia, przemian fazowych i stabilności tego cementu, w warunkach fizjologicznych działanie biologiczne MTA jest jednak dobrze udokumentowane i zostało szczegółowo omówione. Można zatem wyciągnąć wniosek, że MTA jest ważnym uzupełnieniem uszczelniaczy kanałowych znajdujących się na rynku (Dent. Med. Probl. 2008, 45, 1, 5 11). Słowa kluczowe: mineral trioxide aggregate, endodoncja, uszczelniacz kanałowy. Mineral trioxide aggregate (MTA) has been used in endondontics since the mid 1990s, having been patented by Torabinejad and White in 1995 [1]. This material is based on hydraulic calcium (alumino)silicate cement, and since 1995, there have been approximately 200 published reports on this material and its potential for clinical use in dental and bone contact applications [2 17]. Published work includes in vitro, in vivo and clin ical studies, though these tend to have been short term studies. To date, there have been no pub lished accounts of the performance or durability of MTA over the longer term. MTA, as presented for clinical use, is a pow der composed of small (below 50 µm) particles consisting mainly of tricalcium silicate, tricalcium aluminate and tricalcium oxide. It also includes bismuth oxide which makes the material radio paque. It is mixed with sterile water for clinical use, forming a paste which gradually sets to give a brittle inorganic solid. It was originally proposed as a retrograde filling material for use in endodon

2 6 B. CZARNECKA et al. tics, and in cases of intraradicular and furcal per forations [18]. Since then its use has been extend ed to such functions as communicating internal and external resorptions, capping mechanically exposed pulps, and as an apical plug to lock the master gutta percha cone in place [19]. The sealing ability of MTA apical plugs has been investigated [20 25], and it is generally concluded that 4 mm plug thickness is the optimum in terms of sealing ability and resistance to displacement. The general finding from both clinical and biological studies is that MTA has exhibited supe rior biocompatibility in endodontic applications compared with other commercially available restoratives, such as glass ionomer cements, gutta percha and amalgam. This success in endodontics has prompted speculation that hydraulic calcium (alumino)silicate cements of this type may also be appropriate for use in orthopaedic repair [5]. In this review, we discuss the present applications of MTA in endodontics and relate these to its under lying chemical and biological properties. MTA, as specified in the original patent of Torabinejad and White [1] has been approved by the US Federal Drug Administration (FDA) for use in surgical endodontic procedures. It is pro duced commercially in two forms, grey and white. The specific products are respectively ProRoot MTA (Tulsa Dental Products, USA) and MTA Angelus (Angelus Soluções Odontológicas, Brazil). In both cases, the principal constituent is an ASTM Type I ordinary Portland cement blended with bismuth oxide, Bi 2 O 3. The ordinary Portland cement component has a defined particle size, given by a specific surface area (Blaine number) in the range 4000 to 5500 cm 2 g 1. The patent endorses a particular commercial brand of ordinary Portland cement, namely Colton Fast-Set, marketed by the California Portland Cement Company, USA, as the preferred ingredient for MTA, although it also allows other brands to be used instead. As already mentioned, the patent also claims the use of bismuth oxide to impart radiopacity. This is necessary because Portland cement is not intrinsically radiopaque and adding bismuth oxide allows implanted MTA to be monitored radiologi cally. Torabinejad and White s patent also allows for the incorporation of other additives listed under the general headings preservatives, stabi lizers and desensitizers and these could confer additional therapeutic benefits on MTA. Compositions of current MTA materials are shown in Table 1. These materials are expensive, even by the standards of dental materials and, for example, the current (2008) price of ProRoot MTA is $ 249 USD for 5 doses. For this amount of money, it is possible to purchase 6 tonnes of the ordinary Portland cement component. Although MTA has been approved for clinical endodontic procedures, its principal constituent, industrially manufactured ordinary Portland cement (OPC), is not currently recommended for use in the human body. Given the similar compo sition of MTA and OPC, and the much lower cost of the latter, an increasing number of researchers and clinicians are studying the biological respons es of various tissue types to OPC to determine its suitability for use as a biomedical material [6, 8 10, 12, 13, 26 28]. MTA in the Physiological Environment A number of brief and cursory studies have been carried out to compare the composition and setting characteristics of MTA and OPC [29, 30]. In spite of this, surprisingly little is currently known about the hydration chemistry, phase evo lution and microstructures of MTA when it is cured in physiological environments [31]. Human body fluid contains many inorganic ions (see Table 2), as well as metabolites and pro teins, which are likely to alter the usual hydration processes with the cement. The body is a dynamic environment and, since the physiological fluid is perpetually replenished, the exposure of any mate rial to its constituents will be significantly greater than is implied by the static composition listed in Table 1. Composition of current MTA materials Tabela 1. Skład współczesnych materiałów MTA Material Portland cement Bismuth oxide Gypsum ProRoot MTA 75% ordinary PC 20% 5% (grey) ProRoot MTA 75% white PC 20% 5% (tooth coloured) MTA Angelus 80% ordinary PC 20%

3 MTA in Endodontics 7 Table 2. Ion composition of simulated body fluid (SBF) and human blood plasma [34] Tabela 2. Skład jonów doświadczalnego płynu ciała (SBF) i osocza krwi ludzkiej [34] Ion Human blood Original SBF/mmol (Jon) plasma/mmol (Doświadczalny płyn (Osocze krwi/mmol) ciała mmol) Na K Mg Ca Cl HCO HPO SO Table 2. The persistent presence of chloride, sul phate, and carbonate anions, for example, will cer tainly alter the setting of Portland cement. To date, however, there have been no reports of the impact of these ions on the chemical and mechanical properties of clinically implanted OPC. In addition, the dissolution characteristics of MTA and OPC will be affected by placement in a physiological environment. This may raise minor local health issues when these materials are used in dental applications because, for example, aluminium is known to cause structural defects in bone [32]. On the other hand, soluble silicate species are known to stimulate genes which pro mote bone tissue regeneration [33, 34] and this may be beneficial. Physiological fluid is supersaturated with respect to hydroxyapatite, (Ca) 10 (PO 4 ) 6 (OH) 2, which constitutes the inorganic phases of dentin, enamel and bone [35]. A number of recent studies have indicated that, on exposure to tissue culture containing phosphate, freshly prepared and partial ly cured MTA and OPC cause precipitation of hydroxyapatite crystals onto their surfaces in vitro [36 38]. It is significant that OPC behaves in this way, since this finding suggests that it may also have the potential for use in endodontics, and other related applications [38]. This deposited hydroxya patite provides a focus for the attachment and pro liferation of living cells and underpins the ability of both MTA and OPC to stimulate the regeneration of autogenous living tissue in vivo. The capacity of an implant material to develop a stable bond with living tissue via the deposition of hydroxyapatite is referred to as bioactivity [39, 40]. The Setting and Handling Properties of MTA From a clinical point of view, the handing properties of MTA are not ideal. Clinicians report that, when combined with water at the recom mended water: powder ratio of 1:3, the MTA paste is grainy, of poor consistency, difficult to deliv er to the required site and not easy to compact [36]. Furthermore, the reported working time of 4 min is short and the setting times, which vary between 50 min and 2 h 45 min, are relatively long. In an attempt to improve handling characteris tics, experiments have been done in which MTA has been mixed with a variety of substances. These include: antiseptic, oxidising and lubricating gels such as chlorhexidine gluconate gel, sodium chlo rate gel and K Y Jelly [41]. The latter is a lubri cating jelly based on a viscous solution of sodium carboxymethylcellulose in water. Sodium chlorate gel and K Y Jelly were found to reduce the setting time from 50 to 20 min, but also caused decreases in 7 day compressive strength from 28.4 MPa, which was reported for the control MTA samples, to 18.3 and 17.1 MPa, respectively. Sodium chlo rate gel improved the workability, whereas K Y Jelly produced an inhomogeneous, unwork able mixture and the paste prepared with chlorhex idine gluconate gel failed to set within the 4 hr observation period [41]. Other substances have been added to MTA in experiments designed to improve the setting behaviour. For example, calcium chloride has been reported to reduce the setting time to 25 min. It does not improve the workability, however, and has no effect on the biocompatibility, as deter mined by cell culture studies [40]. Another study used a mixture of lidocaine and epinephrine in water to prepare MTA, and found that it retarded the setting to 120 min, but enhanced the 7 day compressive strength slightly (ie from 28.4 to 32.6 MPa) [41]. These studies show that the chemistry is altered by these additives and that setting times and final strength vary unpredictably. The liquid that is properly used for preparing MTA is sterile water and this is clearly the best option for clinical application of MTA. The influence of fresh blood, which is likely to be present during retrograde endodontic procedures, on the properties of MTA is not well documented. A recent report demonstrates that, as expected, blood contaminated MTA fillings have less resis tance to mechanical displacement than their uncont aminated counterparts [42]. However, this was the only account of the effect of fresh blood on the prop erties of MTA that we have found in the literature.

4 8 Biological Properties Recent research has shown that both MTA and OPC can support the sustained attachment and pro liferation of human bone forming cells (osteoblasts) in vitro [5]. The biocompatibility of freshly mixed and cured MTA and OPC has also been confirmed in vitro using mouse fibroblasts and lymphomas (tumour cells) [7, 9], Chinese hamster ovary cells [8] and human lymphocytes [12] which indicated that the materials are neither cyto, nor genotoxic. In vivo guinea pig [7], rat [10] and dog [11] models have also indicated that MTA causes cell attachment and stimulate the production of new hard and soft tissues with minimal inflammatory response. The biological response to MTA has been found to be good in the weeks immediately after placement in animal studies using dogs [43]. In these studies, experiments were conducted on the healthy teeth of dogs. Pulps were removed and root canals prepared and filled with gutta percha and MTA sealer. Periradicular tissue reactions were examined histologically at time periods of up to 5 weeks. The authors observed the growth of tissue which they described simply as hard tis sue on the MTA surface. This material developed progressively from the peripheral root walls along the interface between the MTA and the soft tissue [43]. Connective tissue was apparent by the first week after treatment, and there were occasional occurrences of inflammation. The overall conclu sion from this study is that MTA is biocompatible in this application, and stimulates periradicular tis sue repair at the apex of the root [43]. Clinical Applications and Properties of MTA Mineral trioxide aggregate is currently used in dentistry as an orthograde filling to seal off the root canal system, following the removal of the pulp [1]. During this procedure, the diseased pulp is accessed and extirpated from the root canal via the coronal region of the tooth which is then re filled with a suitable material. MTA is also used as a retrograde filling to repair the root tip during apectomy. In this proce dure, the patient is anaesthetised and the apex of the root is resected and the root canal filled via an incision in the gum [1]. For the cement, this place ment is in a hostile environment in which body fluids, blood, saline, anaesthetics, oxidising and bleaching agents, and pathogenic bacteria will be encountered to varying extents. In both root canal therapy and apoectomy, the complete sealing of communications between the B. CZARNECKA et al. root canal and surrounding tissues is essential if re infection from bacterial invasion and subse quent revision surgery are to be avoided. Hence, the biological, chemical and mechanical demands placed on root filling materials are considerable. For instance an ideal root end filling material is required to provide good adhesion to the dentinal walls on application, and to set in a humid envi ronment, to create an impervious barrier, and to have sufficient strength and dimensional stability to support the functions of the tooth. The material must also be non toxic and compatible with the host tissues, easy to handle, readily sterilised by autoclaving, radiation or chemical means, and radiopaque to short wavelength X rays [1, 17]. In addition to these essential characteristics, intrinsic anti microbial properties and the ability to stimu late the repair of proximal tissue are also highly advantageous. MTA has promising properties as a material for use in endodontics [5]. For example, studies have indicated that MTA shows good adhesion and acceptable (though not perfect) sealing properties [43 46]. It also has adequate mechanical strength [42, 44]. Reports suggest that its biocompatibility at the tooth apex is very good, despite the fact that the freshly mixed MTA paste has a highly alkaline ph of 12 or slightly less [3, 4 16]. It has been found to promote the regeneration of original tis sues [11, 47, 48] and is reported to possess anti microbial action against a range of bacterial and fungal pathogens [49 51], both of which arise from its high ph. Also MTA is easily sterilised and capable of setting in the presence of body fluids. There have been a variety of reports of the clinical performance of MTA. For example, one study involved an assessment of 64 patients in which the root end was resected perpendicularly and a root end cavity prepared ultrasonically and filled with MTA. Patients were studied radi ographically immediately after surgery, then at 12 and 24 months [52]. After 12 months, complete healing was observed in 84% of patients, a figure which had risen to 92% after 24 months. The remaining patients showed either incomplete heal ing or uncertain and unsatisfactory healing, but these represented only five patients in the cohort, showing that MTA has a high success rate in clin ical endodontics. MTA is not just mechanically suitable for endodontic sealing, it also has antimicrobial activi ty. In a recent study, Tanomaru Filho et al. [53] evaluated the antimicrobial activity of a variety of root canal filling materials, including white and grey MTA Angelus and grey Pro Root MTA. They used the agar diffusion method, and a variety of micro organisms, such as Staphylococcus aureus,

5 MTA in Endodontics 9 Pseudomonas aeruginosa and Enterococcus fae calis. All materials, including the various types of MTA, developed inhibition zones around them selves, thus demonstrating their microbiological activity. Such antimicrobial activity, while obvious ly beneficial, was not unique to MTA and MTA was found to have comparable performance to other endodontic materials, such as Sealapex and zinc oxide eugenol. Perforations may occur during endodontic treatment, causing difficulties in the completion of surgical procedures [54]. MTA has been used to seal such perforations, since it can induce both osteogenesis and cementogenesis [55]. One study compared the properties of MTA and Sealapex in repairing perforations, using histological analysis after 30 and 180 days [56]. It found that there was no inflammation with MTA, and that there was clear deposition of cementum. By contrast, Sealapex showed chronic inflammation and only slight deposition of cementum [56]. Such deposi tion of cementum has been confirmed, even where lateral perforations were allowed to become cont aminated by being left open for 7 days [57]. Despite these findings, some authors advocate the fabrication of a calcium hydroxide plug to pre vent overflow from the root apex [58, 59]. It is also recommended that MTA be placed carefully, using the minimum pressure [60]. The appropriate clini cal procedure is to ensure that MTA does not fill the periodontal space [54], though MTA appears to show no cytotoxicity if inadvertently allowed to come into contact with the human periodiontal lig ament [61]. However MTA has some disadvantages, as recorded in the literature. For example, it sets rel atively slowly, and in general its handling proper ties are not ideal [5, 62, 63]. It is also not known whether MTA has adequate long term chemical stability and mechanical integrity in a physiologi cal environment, since no long term clinical obser vations have been published. There is also some experimental evidence that teeth repaired with MTA leak slightly [64]. Bernardineli et al. carried out a leakage study using several candidate root end filling materials based on zinc oxide eugenol cement as well as MTA [64] in which newly filled extracted teeth were placed in 2% methylene blue to test for leak age. All groups showed some leakage, though it was not considered unacceptable in any case, and there were no significant differences between any of the materials examined [64]. The authors described mineral trioxide aggre gate (MTA) as a material for use in clinical endodontics. MTA is composed of a variety of cal cium salts, and has a high ph on mixing and as it sets. It is biocompatible in root canal applications, as well able to promote both osteogenesis and cementogenesis. Although not able to give a per fect seal to the repaired root, it does provide an adequate one, and also has inherently antimicro bial properties. 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