An Updated Review of Mineral Trioxide Aggregate Part-2: Biological Properties, Clinical Applications and Alternate Materials

Shahbaz Khan1                                        BDS, MPhil (Scholar)

Muhammad Amber Fareed2              BDS, MSc, PhD

Muhammad Kaleem3                            BDS, MSc, PhD

Shahab Ud Din3                                       BDS, MSc, PhD

Kefi Iqbal4                                                 BDS, MSc, PhD

INTRODUCTION

The use of a material for restoration of endodontic and its associated periodontal defects require excellent integrity and compatibility with the surrounding biological environment¹. In addition to excellent sealing ability and marginal adaptation², an ideal endodontic material is required to generate a conductive healing environment for pulpal  tissues¹. The introduction of Mineral Trioxide Aggregate (MTA) led to considerable interests in its wide spread endodontic applications because of superior physical and biological properties over other materials. MTA is reported as material of choice for various clinical applications such as, pulp capping³, pulpotomy⁴, apexification⁵, repair of perforations⁶ and root end filling⁷ due to its favorable properties like excellent biocompatibility⁸, sealing ability⁹, marginal adaption¹⁰, minimal solubility¹¹, and ability to regenerate dentin¹² and cementum⁶.

An updated review of current knowledge regarding compositional analysis, material characteristics, setting behavior, mechanism of action and physical properties of MTA was provided in part-1 of the review. Whereas, aims of the part-2 updated review are to emphasize biological properties of MTA, its clinical applications and to provide a comprehensive comparison of MTA  with other alternative materials. Therefore, a systematic research of previously published work in PubMed/MEDLINE (National Library of Medicine, Bethesda, MD), Scopus and Google Scholar databases were conducted from 1995 to November 2014 using different combinations of the following key words: “mineral trioxide aggregate”, “biological properties”, “clinical applications” and “calcium silicate cements”. The literature was screened by authors for relevancy and key findings of the current concepts of MTA are reported here.

2. Biological properties

2.1 Biocompatibility

Endodontic materials are often placed in direct contact with periodontal tissues therefore they are required to be biocompatible¹³. MTA is a non-mutagenic¹⁴ and nonneurotoxic material¹⁵ which does not exert adverse effects on microcirculation¹⁶ therefore, it is considered as the least cytotoxic dental materia^8,17-20. Torabinejad et al., showed that MTA either freshly mixed or set, is less cytotoxic then Super EBA (alumina-fortified cement) and IRM (reinforced zinc oxide-eugenol cement)⁸. Moreover, cytotoxicity and cellular attachment of cell cultures have reported better results for MTA compared to Ketac Silver¹⁷, glass ionomers²¹, gutta percha²², Diaket²¹, Dycal²³ and calcium hydroxide²⁴ and have comparable degree of cytotoxicity as that of chemically inert titanium alloy¹⁸. MTA have good interaction with mineral tissue forming cells and released collagen²⁵. According to Koh et al., MTA acts as a biologically active substrate for bone forming cells and up regulates interleukin production²⁶ and shows minimal or no inflammatory response when placed in contact with soft tissues²⁷. Moreover, intraosseous implantation studies also revealed mild reaction to MTA with only minor inflammation^22,28.

2.2 Mineralization

MTA induced mineralization of dentine and cementum^12,29-31 and the induction of mineral tissue formation by MTA is attributed to its excellent sealing ability, biocompatibility, alkalinity and other material characteristics^2,10,32. According to Holland et al., calcium released from MTA reacts with carbon dioxide present in pulp tissue to form calcite crystals followed by observation of fibronectin rich extracellular network around the crystals to initiate mineral tissue formation³³.

The ability of MTA to induce mineral tissue formation is considered similar to calcium hydroxide³⁴ however, in the case of MTA hard tissue bridge formation is more fast, thick and with uniform structural integrity in comparison to calcium hydroxide^35,36. Ford et al., compared calcium hydroxide and MTA for direct pulp capping and reported that all teeth capped with MTA were free from inflammation and at five months showed formation of calcified bridges, whereas, calcium hydroxide treated teeth showed inflammation and significantly less calcification³⁷.

2.3 Bioactivity of HA surface layer

The precipitation of HA on MTA surface is of great significance since HA is a biocompatible, bioactive, osteoconductive and osteogenic material^38,39. It should be emphasized that cellular adhesion and spreading is dependent on specific interactions between integrins and extracellular matrix⁴⁰. These interactions control intracellular signals and significantly influence a number of cellular functions such as, proliferation, differentiation and apoptosis^41,42. HA have strong adsorptive affinity for proteins and its bioactive nature may be explained by its ability of binding to serum proteins and growth factors which promotes adhesion and proliferation of mineral tissue forming cells^43,44.

2.4 Antibacterial and antifungal properties

The antibacterial effects of MTA can be attributed to its high pH² and its ability to prevent bacterial ingress into root canals by virtue of its excellent marginal adaptation and sealing ability⁴⁵. However, its direct antibacterial effect is limited and dependant on powder/water ratio used for mixing². Torabinejad et al., investigated antibacterial effect of MTA, amalgam, zinc oxide eugenol and super EBA on nine facultative and seven anaerobic bacteria and

showed that MTA have antibacterial effect on some of facultative bacteria, but no effect on anaerobes. Whereas, zinc oxide eugenol and super EBA showed some antibacterial effect on both types of bacteria⁴⁶. Whereas, Estrela et al. reported superior antibacterial activity for calcium hydroxide paste compared to MTA against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Bacillus subtilis and Candida albican⁴⁷.

3.Clinical applications and performance of MTA

MTA is a material of choice for a number of endodontic applications such as pulp capping³, pulpotomy⁴, perforation repair⁶, apexification⁵ and root end filling⁷. This section will discuss the following clinical application bellow.

3.1 Pulp capping

Aeinehchi et al. compared MTA and calcium hydroxide as pulp capping agents after mechanical pulp exposure and reported the formation of dentinal bridge and mild chronic inflammation at 2 months after capping with MTA. While teeth capped with calcium hydroxide showed irregular and thin dentinal bridge formation with associated pulpal inflammation, hyperemia and necrosis after 3 months³⁵. Nair et al., compared the histological outcomes of MTA and calcium hydroxide after capping intact third molars and showed that most MTA specimens were free from inflammation after 7 days, whereas at 1 month majority of specimens showed the presence of hard tissue formation which advanced and thicken with time. In contrast, specimens treated with calcium hydroxide showed inconsistent hard tissue formation³. Tuna and Olmez investigated the performance of calcium hydroxide and MTA in capped primary molar teeth and reported clinical as well as radiographic success for both materials after 24 months⁴⁸. Moreover, successful treatment of either mechanically or cariously exposed pulps of permanent teeth by MTA is also reported^49,50. Bogen et al., reported clinical and radiographic success rate of 97.96% in permanent teeth capped with GMTA or WMTA after carious exposure⁵¹.

3.2 Pulpotomy

MTA is advocated as a suitable material for pulpotomy and an alternative to calcium hydroxide⁵². Holan et al., reported 14% higher success rate for GMTA compared to Formocresol as pulpotomy material in primary molars⁵³. Chako and Kurikose investigated outcomes of MTA and calcium hydroxide as pulpotomy materials in premolars and reported relatively less inflammation and better dentinal bridge formation in specimens treated with MTA³⁰. Similarly, histological study of cariously exposed pulps showed complete bridge formation at 2 months after treatment with MTA⁵⁴.

3.3 Root end filling

MTA is considered as the most biocompatible material for root end filling⁵⁵. Favieri et al. reported successful treatment of a maxillary lateral incisor having perforationof buccal cortical bone with MTA as a root end filling in combination with lyophilized bone and calcium sulphate for osteoinductivity and osteoconductivity⁵⁶. A prospective case series study on 276 teeth with root end fillings of WMTA reported clinical and radiographic (88.8%) success after 4-72 months⁵⁷. A clinical trial that compared WMTA root end filling with orthograde guttapercha showed significantly better healing in teeth with WMTA root end filling⁵⁸.

3.4 Apexification

Calcium hydroxide is considered as the material of choice for apexification and its use has been advocated for many years⁵⁹. However, calcium hydroxide apexification procedures require multiple visits and are also susceptible to root fractures^59,60. Several studies have reported successful effects of MTA for the treatment of teeth with necrotic pulps and open apexes^61-63. Pradhan et al., assessed the outcomes of calcium hydroxide and GMTA for forming apical barrier and reported that calcium hydroxide required significantly longer time to induce hard tissue barrier compared to GMTA⁶². Similarly, evaluation of WMTA and calcium hydroxide for the  treatment of immature roots showed no failure for WMTA treated teeth, whereas clinical and radiographic signs of failure were shown by 13.33% calcium hydroxide treated teeth⁶³. Holden et al., studied the outcomes of WMTA or GMTA for inducing apical barrier in cases with necrotic pulps and open apexes for a period of 12-43 months and reported 85% success rates⁶⁴.

3.5 Repair of root perforation and resorption

The use of MTA is also promoted for root perforations repair and has demonstrated successful outcomes^65,66. Main et al., reported no clinical and radiographic pathological changes in teeth with various types of perforations treated with MTA after 12-45 months⁶. Likewise, 90% teeth healed after treatment of perforations in furcation or cervical third of root with MTA⁶⁶. Additionally, a number of studies reported successful treatment of external as well as internal resorption with MTA67-69.

4. Other available materials

Although MTA embraces ideal characteristics of an endodontic filling material but its usage in dentistry remained limited due to certain potential drawbacks such as difficult handling characteristics, extended setting time, discoloration and higher cost². Due to the shortcomings of MTA, a need for modifications in its properties was felt and led to extensible research to develop improved versions of MTA. The white variant of MTA is considered as first modified version of MTA, which was introduced by the manufacturers of original gray formulation⁷⁰. WMTA was introduced to overcome the potential discoloration associated with the use of GMTA^2,70. The basic difference between the two variants of MTA was exclusion of iron from WMTA’s composition^71-73. Over the years a number of modified or alternate materials with similar composition to MTA have been introduced. Some of these alternate materials includes: gray MTA Angelus (AGMTA) and white MTA Angelus (AWMTA) (Angelus Solucoes Odontologicas, Londrina, PR, Brazil)⁷⁴ MTA Bio (Angelus Solucoes Odontologicas, Londrina, PR, Brazil), Biodentine (Septodont, Saint-Maur-Fosses Codex, France)⁷⁵, DiaRoot Bioaggregate (Innovative bioCeramix, Vancouver, BC, Canada)⁷⁶ and MTA Plus (Avalon Biomed Inc., Bradenton, FL, USA)⁷⁷.

4.1 MTA-Angelus

According to manufacturer, MTA-Angelus contains calcium silicates (PC) and bismuth oxide⁷⁴. Compositional comparison of MTA-Angelus and PC have shown similar constituents and both materials contained an aluminate phase⁷⁸ and no detectable amount of sulphate^78,79. The absence of calcium sulphate and presence of aluminate phase in MTA-Angelus was aimed at reducing setting duration⁷⁸ to 10-15 minutes⁸⁰ which was significantly less than reported setting duration of MTA⁸¹. Although similar loading of bismuth oxide in MTA-Angelus and MTA has been reported⁷⁹ however, Song et al., have shown less amount of bismuth in MTA-Angelus compared to MTA⁸². The release of heavy metals (arsenic) for both MTA-Angelus and MTA was similar and at values that do not harm human tissues⁸³. Clinical studies have shown successful results for MTA-Angelus in the treatment of internal resorption⁸⁴ and root perforations⁸⁵.

4.2 MTA Bio

MTA Bio is a white variant of calcium silicate material which is similar in composition to ‘white MTA Angelus’ instead and introduced by the same manufacturer⁸⁶ which claims its synthesis in a specially controlled laboratory environment to ensure it free from undesirable contaminants, especially arsenic⁸⁷ MTA Bio has identica indications as for MTA and stimulate biomineralization⁸⁶ and have low cytotoxicity⁸⁸

4.3 Biodentine

Biodentine like MTA, is based mainly on tricalcium silicate⁸⁹ however, in contrast to MTA it contains zirconium as a radiopacifying agent and does not contain tricalcium aluminate⁷⁸. The compositional analysis of Biodentine shows 15% loading of calcium carbonate which acts as nucleation site and improves the microstructure as well as setting characteristics of Biodentine^90,91. The liquid of Biodentine consists of calcium chloride and a water reducing hydro-soluble  polymer (polycarboxylate)⁷⁸ for ease of handling and faster setting reaction. However, the surfactant effect of hydrosoluble polymer is responsible for unfavorable washout characteristics of Biodentine⁹². Moreover, addition of zirconium instead of bismuth oxide resulted in low radio-density of Biodentine compared to other calcium silicate endodontic materials⁹³. Studies have advocated use of Biodentine for pulp capping⁹⁴, pulpotomy⁹⁵ and retrograde filling⁹⁶.

4.4 Bioaggregate

Bioaggregate is also a tricalcium silicate based reparative material with same indications as MTA⁹⁷. Resembling Biodentine, Bioaggregate also lacks the tricalcium aluminate phase which is verified by XRD analysis of powder as well as set form of the material^70,78,97. Moreover, unlike MTA, Bioaggregate diffraction patterns showed strong peaks of tantalum oxide added by the manufacturer for radiopacity^70,97. The MSDS indicates addition of calcium monophosphate (HA) and amorphous silicon oxide in Bioaggregate⁷⁶ which reduced the content of calcium hydroxide in the set structure of the material^70,93. The sealing ability of Bioaggregate is comparable to MTA⁹⁸ and is also shown to favor cell attachment and osteocalcin expression⁹⁹. Chung et al., showed that Bioaggregate was nontoxic to human pulp and periodontal ligament cells and its biocompatibility was comparable to MTA¹⁰⁰.

4.5 MTA Plus

MTA Plus was recently introduced and there are few studies regarding its material characteristics and properties. MTA plus is almost similar in composition to MTA and MTA-Angelus, but its particle size is finer in comparison to MTA and X-ray diffraction showed  similar mineral phases⁷⁰. Evaluation of specific surface area of MTA and MTA Plus indicated that MTA Plus have surface area (approximately 1.5 times that of MTA), which was attributed to its finer particle size⁹⁰.

5. Conclusions

This review systematically summarized the contemporary knowledge regarding biocompatibility, bioactivity and clinical applications of MTA. Cell culture studies indicated both gray and white variants of MTA are non-toxic, non-mutagenic, relatively inert and superior in maintaining cell viability. The precipitated HA surface layer on MTA provides an active substrate for adhesion and proliferation of mineral tissue forming cells. The ability of MTA to induce mineralization of dentin and cementum is relatively superior to calcium hydroxide and promotes comparatively homogenous and thicker dentinal bridges. Clinical studies documented best results for MTA and by the virtue of its excellent biocompatibility, sealing ability, marginal adaptation, and antibacterial effects indicated it to be the material of choice for pulp capping, pulpotomy, apexification, repair of root perforation and resorption and root end filling. The modified or alternate products for endodontic applications inspired from MTA can be employed in clinical practice if they overcome potential weaknesses of the predecessor and have generally superior properties. Indeed the aforementioned variants of MTA material were successfully modified from the original MTA however; considerable evaluation in laboratory and in clinical trials is required to improve clinical practices.

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1. Phil Student, Department of Dental Materials, Army Medical College, National University of Sciences and Technology, Islamabad, Pakistan. Department of Operative Dentistry, Bolan Medical College, University of Balochistan, Quetta, Pakistan.
2. Associate Professor, Department of Dental Materials Science, FMH College of Medicine and Dentistry, University of Health Sciences, Lahore, Pakistan.
3. Assistant Professor, Department of Dental Materials, Army Medical College, National University of Sciences and Technology, Islamabad, Pakistan.
4. Professor, Department of Dental Materials Science, Baqai Dental College, Baqai Medical University, Karachi, Pakistan.

Corresponding author: “Dr Muhammad Amber Fareed ”<docamberfareed@hotmail.com >