Shahbaz Khan1 , Muhammad Amber Fareed2 , Muhammad Kaleem3 , Shahab Ud Din3 , Kefi Iqbal4
1. M.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” firstname.lastname@example.org
How to CITE:
Khan S, Fareed MA, Kaleem M, Uddin S, Iqbal K. An Updated Review of Mineral Trioxide Aggregate Part-2: Biological Properties, Clinical Applications And Alternate Materials. J Pak Dent Assoc 2015; 24(1):02-10
The aims of Part-2 updated review are to present biological properties, clinical applications and comparisons of Mineral Trioxide Aggregate (MTA) with other alternate materials. MTA is a bioactive material that does not possess any cytotoxicity, neurotoxicity and mutagenicity. Clinically MTA performs better compared to other endodontic materials therefore, advocated as material of choice for various endodontic applications such as, pulp capping, pulpotomy, apexification, perforation repair, repair of root resorption and root end filling. MTA holds excellent sealing ability, biocompatibility, alkalinity and good interaction with mineral tissue forming cells to induce mineralization.The ability of MTA to induce mineral tissue formation is similar to calcium hydroxide however is more fast, thick and with uniform structural integrity. Difficult handling characteristics extended setting time, discoloration and higher cost are main shortcomings of MTA therefore, number of modified MTA products have been introduced (MTA Angelus, MTA Bio, Biodentine, DiaRoot Bioaggregate and MTA Plus). These alternate materials do possess some improvements over MTA however; considerable evaluation in laboratory and in clinical trials is required to improve clinical practices.
Mineral trioxide aggregate, biological properties, clinical applications, calcium silicate cements.
One of the major cause of death throughout the world remains the cancer1,2. Carcinogenesis is a multifactorial phenomenon with a complex interplay between genetics and environmental factors; mainly related to healthy habits and lifestyle3,4. Cancer may also be caused by oxidative stress in addition to these factors5,6.In the recent past though exponential progress in the prevention and management of cancers have taken place but as mentioned already its incidence is increasing at an alarming rate day by day due to the reasons already mentioned7,8. However, over a quarter of the incidence may be preventable by just adjusting the diet7. Diet in the recent past has been given too much importance because of its anti-oxidant and anti-cancer effects. “Let food be thy medicine and medicine be thy food”, as said by the father of medicine, Hippocrates in 431 B.C. Nature has provided us with a variety of treatment modalities in the form of fruits and vegetables9. Many of them consist of ingredients with hidden pharmaceutical qualities ranging from anti-inflammatory to anti-carcinogenic agent. They not only boost our innate immunity but also act as an adjunct to medicines for specific treatment9.
In a review of 200 papers on anti-cancer effect of vegetables Block et. al. reported that a significant proportion of studies found a positive relationship10. In another review of 206 studies, the similar relationship was examined and it was found that cruciform vegetable reduces chances of cancer occurrence11. Amjad Al et al in their study found an anti oxidant to anti-cancer effect of Sulforaphane (SFN) a metabolic by product of cruciferous vegetables12. Awasthi S, Saraswathi NT in another study found a potent anticancer effect of glucosinolate found in cruciferous vegetables13. Ahmadi A, Shadboorestan A in their study found that flavonoids one of the most important ingredients in vegetables and fruits exhibits an anti-cancer effect14. Michaud DS et alin theirstudy found that 20% increase in vegetable intake generally corresponds to a 20% decrease in cancer rates, and a 20% increase in cruciferous vegetable intake corresponds to a 40% decrease in cancer rates15. Cohen JH et al in another study found that 28 servings of vegetables per week decreases prostate cancer risk by 33%, moreover just 3 servings of cruciferous vegetables per week decreased prostate cancer risk by 41%16. It is worth mentioning here that cruciform vegetables includes: Bok Choy, Broccoli, Broccolini, Cabbage, Cauliflower, Mustard green, raddish and turnip etc17.
Though research have shown the importance of diet and physical activity in preventing cancers and awareness programs have been introduced and reported but still studies available on awareness programs regarding anti-cancer impact of vegetables are limited. Yong-chuan Wang et al in their study found that strategies for cancer prevention and control implemented in the USA can be valuable models for China18. The same can be over extended for other countries.Ken Yamaguchireported cancer prevention programs in Japan19. These can be valuable modes for cancer control.Fotedar V et al in their study concluded that though the mean knowledge of the population about cancers is good but the knowledge and practices about risk factors had to be reinforced20. Altin C et al in their study concluded that limited cancer literacy instruments are available21. Aim of this study is thus to assess the base line knowledge of Dental Graduates about the anti-cancer vegetables with the aim that their knowledge will have an impact on the awareness of the community.
2. Biological properties
Endodontic materials are often placed in direct contact with periodontal tissues therefore they are required to be biocompatible13. MTA is a non-mutagenic14 and non-neurotoxic material15 which does not exert adverse effects on microcirculation16 therefore, it is considered as the least cytotoxic dental materia8,17-20. 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 Kohetal., 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 tissues 27. Moreover, intraosseous implantation studies also revealed mild reaction to MTA with only minor inflammation22,28.
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 characteristics2,10,32. 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 material38,39. It should be emphasized that cellular adhesion and spreading is dependent on specific interactions between integrins and extracellular matrix 40 . These interactions control intracellular signals and significantly influence a number of cellular functions such as, proliferation, differentiation and apoptosis41,42. 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 cells43,44.
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 ability 45. 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, zincoxide 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 bacteria 46. Whereas, Estrela et al. Reported superior antibacterial activity for calcium hydroxide paste compared to MTA against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Bacillussubtilis 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 capping 3, pulpotomy4, perforation repair6, apexification5 and root end filling 7. 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 months 48 . Moreover, successful treatment of either mechanically or cariously exposed pulps of permanent teeth by MTA is also reported49,50. Bogen et al., reported clinical and radiographic success rate of 97.96% in permanent teeth capped with GMTA or WMTA after carious exposure51.
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 perforation of 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.
Calcium hydroxide is considered as the material of choice for apexification and its use has been advocated for many years 59 . However, calcium hydroxide apexification procedures require multiple visits and are also susceptible to root fractures59,60. Several studies have reported successful effects of MTA for the treatment of teeth with necrotic pulps and open apexes61-63. 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 outcomes65,66. Main et al., reported no clinical and radiographic pathological changes in teeth with various types of perforations treated with MTA after 12-45 months 6. Likewise, 90% teeth healed after treatment of perforations in furcation or cervical third of root with MTA 66 . 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 cost 2 . 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 GMTA2,70. The basic difference between the two variants of MTA was exclusion of iron from WMTA’s composition71-73. 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.
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 sulphate78,79. 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 identicalindications as for MTA and stimulate biomineralization86 and have low cytotoxicity88.
4.3 Biodentine89 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 Biodentine 92 . 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 capping 94, pulpotomy95 and retrograde filling96.
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 byXRD analysis of powder as well as set form of the material70,78,97. Moreover, unlike MTA, Bioaggregate diffraction patterns showed strong peaks of tantalum oxide added by the manufacturer for radiopacity70,97. 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 material70,93. 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 bio compatibility 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.
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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