REVIEW Mineral trioxide aggregate as a pulpotomy medicament: A narrative review F.K. Ng, L.B. Messer Paediatric Dentistry, School of Dental Science, The University of Melbourne, Melbourne, Australia. Abstract Background: Several medicaments have been used to devitalize remaining pulp or maintain pulp vitality and promote healing. Based on pulpal biocompatibility and good sealing ability, a growing interest in more biocompatible materials promotes mineral trioxide aggregate (MTA) as an alternative to traditional medicaments. Uniquely, MTA can preserve pulpal health predictably and promote healing with pulp regeneration. Methods: Using electronic search all papers published since 1993 on the use of MTA in paediatric dentistry were identified. This paper provides a narrative review of the current literature on MTA, formocresol, ferric sulphate and calcium hydroxide with particular reference to primary teeth pulpotomy medication. Conclusion: The use of formocresol or formaldehyde-based medicaments should be replaced with more biocompatible medicaments possessing antimicrobial and pulpal regenerative properties. Of the four pulpotomy medicaments discussed, mineral trioxide aggregate is recommended as the medicament of choice.

Introduction A pulpotomy is performed in a tooth with a deep carious lesion adjacent to the pulp [AAPD, 2007-8]. The procedure is indicated when caries removal results in pulp exposure in a primary tooth with a normal pulp or reversible pulpitis or after a traumatic pulp exposure [AAPD, 2007-8]. Histologically, most primary molars with proximal caries have inflammation in the pulp horn, even in small lesions extending less than half the intercuspal distance, and manifesting well before clinical pulp exposure [Duggal et al., 2002]. A healthy radicular pulp is required for healing after coronal pulp amputation [Fuks, 2000]. Signs or symptoms of inflammation extending beyond coronal pulp, such as swelling, excessive mobility not due to physiological root resorption, furcal or periapical radiolucency, pathologic root resorption and excessive bleeding from amputated radicular stumps are contraindications [Fuks, 2000]. The diagnosis and subsequent management of pulp pathology in carious primary molars remains challenging and clinical guidelines written by various bodies can assist dentists. The UK National Clinical Guidelines in Paediatric Dentistry recommend formocresol (FC), ferric sulphate (FS), calcium hydroxide (CH) or mineral trioxide aggregate (MTA) for direct application to vital radicular pulp [Rodd et al., 2006]. The

American Academy of Pediatric Dentistry recommends the use of FC, FS or electrocautery to treat radicular pulp stumps [AAPD, 2007-8]. The Australasian Academy of Paediatric Dentistry addresses FC, CH and FS to treat amputated pulps, noting a more biocompatible medicament should be used in preference to FC where available given the potential toxicity issues [AusAPD, 2002]. The medicaments used for primary tooth pulpotomy may be classified by treatment objectives: devitalization, preservation or regeneration (Table 1) [Ranly, 1994]. Formocresol and glutaraldehyde are associated with pulp devitalization and fixation due to cross-linkages with pulp protein [s-Gravenmade, 1975]. Electrocautery devitalizes pulp by carbonization and coagulation necrosis [Ranly, 1994]. Ferric sulphate appears to preserve vital tissue with minimal damage, but has limited ability to induce reparative dentine [Ranly, 1994; Ranly and Garcia-Godoy, 2000]. Calcium hydroxide can promote pulp regeneration by inducing reparative dentine formation [Doyle et al., 1962; Ranly, 1994]. Interest in more biocompatible materials with regenerative potential has promoted MTA as an alternative pulpotomy medicament. This paper is a narrative review of literature on MTA, FC, FS and CH with particular reference to primary teeth pulpotomy, providing recommendations on medicament selection.

Physical properties of mineral trioxide aggregate Developed at Loma Linda University, USA in 1993 for rootend obturation, MTA is now used in procedures such as direct pulp capping, pulpotomy, apexification and repair of root and furcal perforations [Torabinejad and Chivian, 1999]. Marketed as ProRootTM (Dentsply Tulsa Dental, Tulsa, OK, USA) and AngelusTM (Industria de Produtos Odontologicos Ltda, Londrina, Brazil), MTA comprises fine hydrophilic particles containing tricalcium silicate, tricalcium aluminate, tricalcium oxide and silicate oxide [Torabinejad et al., 1995a]. Tetracalcium aluminoferrite from iron ore impurities imparts a grey colour. Bismuth oxide, a water-insoluble powder, is added for radioopacity [Torabinejad et al., 1995a] without appearing to affect the biocompatibility of MTA [Camilleri et al., 2004]. Powder hydration forms a colloidal calcium sili-

Key words: Pulp therapy, dental materials, mineral trioxide aggregate, formocresol, ferric sulphate Postal address: Prof. L. Brearley Messer, Paediatric Dentistry, School of Dental Science, The University of Melbourne, 720 Swanston St, Carlton 3010, Australia. Email: [email protected]

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Table 1. Summary of pulpal outcomes, histological findings, and clinical and radiographic outcomes of four primary tooth pulpotomy medicaments. Plpotomy medicament

Pulpal outcome

Histological findings in pulp

Clinical and radiographic outcomes

Normal pulp architecture and odontoblastic layers [Agamy et al., 2004]; little/no inflammation in most samples [Dominguez et al., 2003] MINERAL TRIOXIDE AGGREGATE

Regeneration

Less necrosis in contact with pulp than calcium hydroxide [Dominguez et al., 2003] Thicker dentine bridges, fewer showing tubules than calcium hydroxide bridges [Aeinehchi et al., 2002; Dominguez et al., 2003] Necrosis and inflammation; healing with granulation tissue [Berger, 1965; Alacam, 1989]

FORMOCRESOL

Devitalisation

Clinical and radiographic success rates 94-100% at 12-74 months [Rocha et al., 1999; Agamy et al., 2004; Jabbarifar et al., 2004; Farsi et al., 2005; Holan et al., 2005] Many cases show pulp canal obliteration [Agamy et al., 2004; Holan et al., 2005; Maroto et al., 2005]

Success rates generally decline with time [Rolling and Thylstrup, 1975]

Some hard tissue apposition [Salako et al., 2003]; dentine bridges poorly calcified [Agamy et al., 2004] Internal resorption [Rolling et al., 1976]

Clinical success 97% at 36-48 months [Papagiannoulis, 2002; Ibricevic and Al-Jame, 2003] Radiographic success 78-94% at 36-48 months [Papagiannoulis, 2002; Ibricevic and Al-Jame, 2003]

Clinical success 90-96% at 36-48 months [Papagiannoulis, 2002; Ibricevic and Al-Jame, 2003]

FERRIC SULPHATE

Preservation

Necrosis and inflammation [Cotes et al., 1997; Fuks et al., 1997; Salako et al., 2003]

Radiographic success 67 – 92% at 36-48 months [Papagiannoulis, 2002; Ibricevic and Al-Jame, 2003; Casas et al., 2004]

Some calcific changes [Salako et al., 2003]

Internal resorption common but not statistically different from formocresol pulpotomies. Many teeth with internal resorption stable over 36 months; resorptive process may arrest with calcific repair of defect [Papagiannoulis, 2002]

Various degrees of necrosis and/or inflammation (depends on formulation pH) [Subay et al., 1995] CALCIUM HYDROXIDE

Regeneration

Disorganized tissue with inflammation, healing with bridging [Schroder and Granath, 1971; Mjor et al., 1991] Tunnel defects in bridge [Cox et al., 1996]

cate gel which sets in about 15 minutes (AngelusTM) or under 3 hours (Loma Linda University) [Torabinejad et al., 1995a]. The pH of MTA immediately after mixing is 10.2, rising to 12.5 after 3 hours and remaining constant over 22 hours [Torabinejad et al., 1995a]. The pH values of 11-12 were maintained in vitro in the aqueous environment of MTA even after 78 days [Fridland and Rosado, 2005], conferring anti-

Clinical success 50-87% at 24 months [Schroder, 1978; Gruythuysen and Weerheijm, 1997; Huth et al., 2005] Radiographic success 50-80% at 24 months [Schroder, 1978; Gruythuysen and Weerheijm, 1997; Huth et al., 2005] Failures not limited to internal resorption [Huth et al., 2005; Markovic et al., 2005]

microbial effects against some facultative bacteria [Torabinejad et al., 1995b]. The mean compressive strength of MTA at 21 days is 67.3 (±6.6) MPa, comparable to that of IRMTM and Super-EBATM but less than amalgam, hence it is not used in stress-bearing areas or as a permanent restoration [Torabinejad et al., 1995a].

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The grey colour of MTA is considered unaesthetic for pulpotomy and pulp capping [Naik and Hegde, 2005]. To overcome this, White ProRootTM MTA (Dentsply Tulsa Dental, Tulsa, OK, USA) and White MTA (Industria de Produtos Odontologicos Ltda, Londrina, Brazil) were developed by excluding iron compounds [Asgary et al., 2005; Camilleri et al., 2005]. Users of White ProRootTM MTA claim a creamier mix which is more difficult to manipulate than ProRootTM MTA but sets as hard [Kratchman, 2004]. In vitro, White ProRootTM MTA was similar to grey MTA in compressive strength at 21 days, but set faster [Spencer, 2004]. The differing compositions of grey and white MTA raise questions on whether the materials induce different cellular responses of clinical significance. A comparison of 72 human primary molar pulpotomies performed with (grey) ProRootTM MTA, White ProRootTM MTA and FC found lower clinical and radiographic success rates (80%) in the white MTA group after 12 months compared with a 100% success rate for molars in the grey MTA group [Agamy et al., 2004]. Used as apical barriers in 44 human incisors in vitro, (grey) ProRootTM MTA demonstrated better sealing against methylene blue than White ProRootTM MTA [Matt et al., 2004]. Directly capping 24 dog pulps, no differences were found in the degree of inflammation or production of hard tissue between both MTA formulations, and no signs of pulp necrosis [Parirokh et al., 2005]. These results support in vitro and in vivo animal studies which found the connective tissue response to, and the sealing ability of, grey and white MTA were similar, suggesting similar mechanisms of action [Ferris and Baumgartner, 2004; Al-Hezaimi et al., 2005; Shahi et al., 2006]. It should be noted that human studies typically assess clinical and radiographic outcomes whereas animal and in vitro studies use histological or laboratory analyses. Results of animal and in vitro studies cannot be extrapolated to humans without well-controlled clinical trials. Studies cannot be compared readily due to differing methodologies, durations, sample sizes and MTA thicknesses. Of note, animal studies are based on mechanical pulp exposures of noncarious teeth, whereas human studies are conducted on carious teeth with pulps likely already inflamed. White MTA must undergo extensive testing similar to grey MTA, including randomized clinical trials (RCTs), before both materials can be used confidently. Set MTA can be considered as calcium hydroxide contained in a silicate matrix; as a by-product of the hydration reaction MTA produces calcium silicate hydrate gel and calcium hydroxide [Camilleri et al., 2005; Camilleri and Pitt Ford, 2006]. Set MTA is insoluble in water after 21 days [Torabinejad et al., 1995a], exhibiting good in vitro and in vivo biocompatibility with cell lines, pulp and peri-radicular tissue in animal studies [Tziafas et al., 2002; Economides et al., 2003; Camilleri et al., 2004], better sealing ability than amalgam and IRMTM [Fischer et al., 1998; Tang et al., 2002], and stimulation of cytokine production [Mitchell et al., 1999;

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Huang et al., 2005]. The insoluble silica matrix probably maintains the MTA integrity [Camilleri et al., 2005]. The superior seal at the dentine-MTA interface may be due to chemical bonding following calcium ion release [Sarkar et al., 2005]. Reacting with phosphate and hydroxide ions, hydroxyapatite precipitates as an adherent layer on the MTA surface [Sarkar et al., 2005]. Water absorption and subsequent expansion promotes dentinal adaptation [Shipper et al., 2004], enabling the sealing ability of MTA to be unaffected by blood [Torabinejad et al., 1994]. In vitro leakage studies of root-end fillings have demonstrated the superior sealing ability of MTA. Using endotoxin or dyes such as methylene blue as tracers, MTA leaked significantly less than amalgam, Super-EBATM and IRMTM [Torabinejad et al., 1994; Martell and Chandler, 2002; Tang et al., 2002]. Bacterial tracers such as Serratia marcescens showed MTA specimens leaked less rapidly than amalgam, Super-EBATM and IRMTM, or not at all after 120 days [Fischer et al., 1998]. With orthograde filling of the root canal, both grey and white MTA were more resistant to human saliva leakage than vertically-condensed gutta-percha after 42 days [Al-Hezaimi et al., 2005]. These laboratory findings need cautious interpretation. Dye tracers are smaller than bacteria, and may not simulate microleakage. Methylene blue hydrolyses to thional after contact with alkaline materials such as MTA, complicating dye detection around restorations since thional is colourless [Wu et al., 1998]. While clinically relevant, bacterial models have limitations. Most in vitro studies use a single bacterial type but a mixed flora is found in vivo. Most in vitro bacterial models are unable to indicate the titre of bacteria leaked. Bacterial contamination may occur and sampling time may affect bacterial quantitation. Radioactive-labelling of bacteria has been used to quantitate leaked bacteria [Mangin et al., 2003]. The thickness of MTA and the placement method affect sealing ability. Using a protein-dye complex in vitro to identify leakage, a 4mm thickness of MTA showed significantly superior sealing to a 3mm thickness [Valois et al., 2004]. Orthograde MTA apexification resulted in more leakage than surgical placement of MTA as a root-end filling, due to difficult access and condensation associated with minimal resistance of an open apex [Hachmeister et al., 2002]. Hand condensation allowed better adaptation than ultrasonic condensation to plastic tube walls simulating root canals, attributed to excessive ultrasonic tip vibration [Aminoshariae et al., 2003]. Physical changes in dentine of extracted teeth must also be considered. Pertinent variables in vivo include dynamic interactions of root canals with periradicular tissues and body fluids, bacterial leakage, operator skill, and host response. Therefore, significantly different laboratory findings may be clinically irrelevant.

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Biocompatibility of mineral trioxide aggregate Biocompatibility is defined as the ability of a material to perform with an appropriate response in a specific application [Williams, 2003]. The excellent biocompatibility of MTA is supported by studies of cytotoxicity, subcutaneous and intraosseous implantation, and direct contact with periradicular or pulpal tissues in vivo [Camilleri and Pitt Ford, 2006]. Cell line studies suggest MTA induces cytokine expression in vitro, in particular of interleukins 4, 6, 8 and 10, stimulating formative cell attachment and bone turnover [Mitchell et al., 1999; Huang et al., 2005]. In vitro, superior cementoblast adhesion to MTA compared with amalgam and IRMTM, and expression of genes for cementogenesis, led investigators to label MTA as cemento-conductive [Thomson et al., 2003]. The levels of osteocalcin, a protein marker suggestive of biomineralization, increased in the presence of MTA [Thomson et al., 2003]. On subcutaneous implantation in rats, MTA showed dystrophic calcification and moderate inflammation which resolved by day 90 [Yaltirik et al., 2004]; implantation into guinea pig mandibles showed minimal inflammation and bony apposition [Saidon et al., 2003]. While 6/6 root canal apices filled with amalgam in a monkey model showed moderate to severe periradicular tissue inflammation and cementum formation at the cut dentinal root ends, 5/6 apices filled with MTA showed no periradicular inflammation and a complete cementum layer over the root end and root-end filling [Torabinejad et al., 1997]. In contrast, concerns exist over the toxicity, mutagenicity and carcinogenicity of FC [Swenberg et al., 1980; Goldmacher and Thilly, 1983; Ranly and Horn, 1987; IARC, 2004]. The International Agency for Research on Cancer has stated that there is now “sufficient evidence that formaldehyde causes nasopharyngeal cancer in humans, limited evidence for cancer of the nasal cavity and paranasal sinuses, and ‘strong but not sufficient evidence’ for leukaemia” [IARC, 2004]. Although cancer is highly unlikely with judicious use of FC in pulpotomies [Milnes, 2006], the availability of effective alternatives indicates routine FC use is no longer justified [Rodd et al., 2006; Srinivasan et al., 2006].

Mineral trioxide aggregate as a pulp medicament – laboratory studies As a pulp capping or pulpotomy medicament in both animals and humans, MTA preserved normal pulp architecture, caused little or no inflammation and maintained an intact odontoblastic layer in almost all samples (Table 1) [Dominguez et al., 2003; Agamy et al., 2004]. Mild inflammation associated with the procedure or medicament appeared to resolve as bridge formation continued [Aeinehchi et al., 2002; Salako et al., 2003]. Four weeks after MTA pulpotomy, a rat study showed complete bridging with normal pulp histology [Salako et al., 2003]. In contrast, the pulp responded with various degrees of inflammation to FC application,

depending on concentration and application time [GarciaGodoy et al., 1982; Fuks et al., 1983]. Subjacent to the amputation site a zone of necrosis is followed by a zone of fixation; apical to this an inflammatory infiltrate leads to normal pulp (Table 1) [Alacam, 1989]. Necrotic tissue may be replaced with granulation tissue [Berger, 1965] but internal resorption [Rolling et al., 1976]; poorly calcified dentinal bridges and few residual odontoblasts have been reported [Agamy et al., 2004]. Pulpotomy studies in animals showed similar pulp responses to FS and FC [Cotes et al., 1997; Fuks et al., 1997]. A histological study of FS pulpotomies in rats showed widespread necrosis, progressive pulpal replacement with blood clot, inflammation and calcific changes [Salako et al., 2003]. These studies used zinc oxide-eugenol or polycarboxylate cement over the amputated pulps, possibly confounding tissue changes as a previous histological study showed zinc oxide-eugenol directly contacting vital pulp caused persistent inflammation and internal resorption [Berger, 1965]. A 5year retrospective record audit of patients who received FS pulpotomies in a Texan private paediatric dental practice found the most common radiographic findings were internal resorption and calcific metamorphosis [Smith et al., 2000]. Internal resorption was attributed to chronic inflammation and necrosis due to placing eugenol directly over vital pulp, suggesting zinc oxide-eugenol may not be a suitable base for a FS pulpotomy [Smith et al., 2000]. Calcium hydroxide can promote pulp regeneration by inducing reparative dentine formation [Zander, 1939; Doyle et al., 1962]. But inflammatory changes including internal resorption can occur [Doyle et al., 1962; Schroder, 1978], due to a blood clot remaining prior to CH application [Schroder 1973], previous chronic inflammation [Schroder, 1978], or the inability of CH to maintain a long-term seal [Cox et al., 1996; Goracci and Mori, 1996], resulting in microleakage. Human studies have shown CH is associated with low-grade pulp necrosis and/or inflammation which stimulate healing (Table 1) [Doyle et al., 1962; Schoder and Granath, 1971]. High pH (over 12) CH formulations such as PulpdentTM (Pulpdent Corp, Watertown, Mass., USA), or pure CH are associated with severe pulp necrosis and inflammation [Subay et al., 1995]. With lower pH, hard-setting CH products (eg. LifeTM, Kerr, Portland, Oregon, USA, or DycalTM, LD Caulk Division, Dentsply International Inc., Milford, DE, USA), bridge formation occurs without an intermediate necrotic layer [Stanley, 1989]. Three monkeys were used to study the healing of mechanical pulp exposures capped with LifeTM [Mjor et al., 1991]. At 1-5 days, pulpal disorganization, haemorrhage and inflammation was seen at the wound site; at 2 weeks, bridging had occurred in the absence of necrosis between the CH and pulp [Mjor et al., 1994]. Bridge formation represents pulpal healing response and does not imply clinical success. A monkey model was used

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to study bridging after direct pulp capping with hard-setting CH. Histological study of 235 mechanically-exposed pulps showed bridges in 192 samples; 172 (89%) of these contained multiple tunnel defects [Cox et al., 1996]. Some defects were patent from the pulp to the CH interface, putatively allowing bacterial microleakage on bridge exposure to the oral environment [Cox et al., 1996]. Due to poor dentinal adhesion of CH, polymerization shrinkage of an overlying resin composite restoration could detach CH, allowing microleakage and causing pulp inflammation and necrosis [Goracci and Mori, 1996]. Monkey and dog models showed teeth directly capped with CH had medicament particles dispersed into the tissue or macrophage cytoplasm, suggesting progressive resorption of CH [Cox et al., 1996; Faraco and Holland, 2001]. A histological study of direct pulp capping and pulpotomy in 15 dogs found MTA produced less necrosis than CH; most MTA specimens showing little or no inflammation [Dominguez et al., 2003]. After 150 days, only 1/10 MTA pulpotomies progressed to necrosis, compared to 8/10 CH pulpotomies; fewer MTA pulpotomy bridges showed tubule formation compared with CH bridges [Dominguez et al., 2003]. Comparing MTA and CH for direct pulp capping in non-carious human third molars, histological study at 6 months found no inflammation or necrosis, an almost regular odontoblastic layer and a thick dentine bridge (0.43 mm) in the molar capped with MTA [Aeinehchi et al., 2002]. The molar capped with CH showed pulp necrosis and chronic inflammation under a thin bridge (0.15 mm). This experiment cannot be extrapolated to carious teeth as small pulp exposures were created mechanically under rubber dam [Aeinehchi et al., 2002].

Mineral trioxide aggregate as a pulp medicament – clinical reports In cariously-exposed human first permanent molars, an RCT using MTA and CH for partial pulpotomies found 26/28 (93%) MTA molars and 21/23 (91%) CH molars were clinically and radiographically successful after 25-45 months, with bridging observed radiographically in 18/28 (64%) MTA molars and 12/23 (52%) CH molars [Qudeimat et al., 2007]. Similar results were found in a RCT comparing MTA and CH pulpotomies in 30 traumatized and carious immature permanent teeth where, after 12 months, all 15 MTA-treated teeth (100%) and 13/15 CH-treated teeth (87%) were clinically and radiographically successful [El-Meligy and Avery, 2006]. The small sample size precluded statistical significance. A study of MTA for direct pulp capping and pulpotomy in 21 carious primary molars reported success rates of 80% (8/10) in directly pulp-capped molars, and 91% (10/11) in pulpotomized molars after 6 months [Caicedo et al., 2006]. Although histology of teeth extracted at 6 months showed pulp necrosis, inflammation, bridging and intrapulpal calcifications, the clinically-favourable pulpotomy response was attributed to bacteria removal, sealing, and low toxicity of MTA [Caicedo et al., 2006].

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Mineral trioxide aggregate vs formocresol as a pulpotomy medicament – clinical findings In carious primary molars treated with MTA pulpotomy, success rates above 94% have been reported at 12-74 months follow-up (Table 1) [Rocha et al., 1999; Agamy et al., 2004; Jabbarifar et al., 2004; Farsi et al., 2005; Holan et al., 2005]. High clinical and radiographic success rates for FC pulpotomy (78% to over 90%) have been reported at 36-48 months follow-up (Table 1) [Papagiannoulis, 2002; Ibricevic and AlJame, 2003]. The differing success rates are attributed to intra-patient variations, clinician and assessment factors, FC concentrations and application times, and study durations. Caries control measures and a hermetic coronal seal improve success rates [Holan et al., 2002; Vij et al., 2004]. In RCTs comparing MTA and FC, MTA was clinically and radiographically more successful than FC, but without statistical significance [Agamy et al., 2004; Jabbarifar et al., 2004; Farsi et al., 2005; Holan et al., 2005]. This may be due to small sample sizes (19-38 molars per group) at analysis. In a well-designed RCT comparing MTA and FC in 62 primary molars, 32/33 (97%) MTA molars were clinically and radiographically successful after follow-up for 4-74 months (molars followed for less than 12 months were excluded except for one FC failure at 4 months). Although 24/29 (83%) FC molars were clinically and radiographically successful, no significant differences between the medicaments were found due to the small sample size. The MTA success rates remained stable with no new failures after 12 months while FC success rates declined with time (last failure detected at 30 months) [Holan et al., 2005]. In another RCT, radiographic success rates for MTA pulpotomy remained at 100% while those for FC declined from 100% to 87% (31/36 molars) over 24 months [Farsi et al., 2005]. Similar findings for the FC pulpotomy were reported in an earlier clinical trial showing a 3 month success rate of 91% declining to 70% at 36 months [Rolling and Thylstrup, 1975], suggesting fixatives do not promote pulp healing [Doyle et al., 1962]. Small clinical trials of 6 months duration have reported MTA success rates above 90% [Cuisia et al., 2001; Maroto et al., 2005; Naik and Hegde, 2005; Aeinehchi et al., 2007]. One of these was a RCT with a slightly larger sample size showing MTA molars (0/43) were significantly less likely to show pathologic root resorption than FC molars (6/57) [Aeinehchi et al., 2007]. Although the high dropout rate, brief study duration, and use of amalgam or glass ionomer cement as coronal seals necessitate cautious interpretation, the findings confirmed an earlier meta-analysis which found MTA pulpotomies had a significantly lower rate of internal root resorption than FC pulpotomies [Peng et al., 2006]. A recent systematic review by the present authors showed findings from 5 primary studies comparing MTA and FC were consistent and can be generalized across different patient groups [Ng, 2007; Ng and Messer, 2007]. Meta-analysis confirmed with statistical significance that MTA was clinically and radi-

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ographically more successful than FC as a primary molar pulpotomy medicament. However, these findings are limited by differing study methodologies and durations. Most primary studies followed MTA pulpotomized teeth for less than 24 months, limiting conclusions as brief studies preclude investigation of the full potential of a medicament. In another systematic review of primary molar pulpotomy medicaments, it was argued that although MTA appeared superior, most primary studies [except Holan et al., 2005] had faulty study designs and fulfilled few selection criteria in appraising the primary evidence [Fuks and Papagiannoulis, 2006]. Supporting the conclusion of others [Nadin et al., 2003], the authors stated that “no conclusion can be made as to the optimum treatment or technique for pulpally involved primary teeth” [Fuks and Papagiannoulis, 2006].

Mineral trioxide aggregate vs ferric sulphate as a pulpotomy medicament – clinical findings Reported clinical and radiographic success rates for FS pulpotomy are 67-96% at 36-48 months follow-up (Table 1) [Papagiannoulis, 2002; Ibricevic and Al-Jame, 2003; Casas et al., 2004]. A meta-analysis pooling data from 2 RCTs found no significant differences in the clinical and radiographic successes for FS and FC pulpotomies [Loh et al., 2004] but both RCTs used a zinc oxide-eugenol base after pulp amputation. In a recent systematic review, a metaanalysis by the present authors pooled 7 RCTs and reported a similar finding and suggested MTA pulpotomies were significantly more successful radiographically than FS pulpotomies [Ng, 2007; Ng and Messer, 2007]. The clinical success of FS appears dependent on pulp status, as FS is not antimicrobial and cannot fix pulp or stimulate pulp regeneration. Although meticulous pre-operative clinical and radiographic assessment is mandatory, accurate pulp diagnosis is challenging because clinicians rely on clinical assessment of bleeding to evaluate radicular pulp health following coronal pulp amputation. Uncontrollable pulp haemorrhage suggests irreversible pulpitis, indicating pulpectomy or extraction [Rodd et al., 2006].

Mineral trioxide aggregate vs calcium hydroxide as a pulpotomy medicament – clinical findings A small clinical trial comparing MTA and CH pulpotomies in 14 primary molars showed no significant differences in the clinical and radiographic successes after 12 months even though the MTA success rates were 100% [Rocha et al., 1999]. Reported success rates for primary molar CH pulpotomies are 50-87% at 24 months follow-up, but study comparisons are complicated by differing preparations and sample sizes (Table 1) [Schroder, 1978; Gruythuysen and Weerheijm, 1997; Huth et al., 2005]. Although CH pulpotomies may show signs of pulp healing with bridging and

intrapulpal calcifications [Waterhouse et al., 2000; Markovic et al., 2005], the radiographic success of CH pulpotomies appears significantly lower than MTA and FC pulpotomies [Ng, 2007; Ng and Messer, 2007]. Many failures are attributed to furcal and apical bony resorption, and internal or external root resorption [Huth et al., 2005; Markovic et al., 2005]. Although set MTA is considered CH in a silicate matrix, MTA may be more successful than CH as a pulpotomy medicament due to the presence of reaction by-products such as calcium silicate and calcium oxide, and MTA’s ability to elicit cytokine production [Camilleri et al., 2005; Camilleri and Pitt Ford, 2006].

Recommendations for selection of a primary tooth pulpotomy medicament Faced with a primary tooth requiring a pulpotomy, several medicaments are available to the clinician. Selection then depends on medicament properties, adequacy of the evidence base including likely outcomes, cost and ease of use. Based on current evidence, this narrative review recommends the following with reference to primary molar pulpotomies: 1. The empirical use of formocresol should be abandoned in favor of biocompatible medicaments which promote pulp healing and regeneration. 2. International guidelines should be revised to discontinue the use of formocresol and encourage the use of more biocompatible medicaments. 3. Prospective clinical studies on ferric sulphate are required to determine recommendations on selection of a suitable base material. 4. Calcium hydroxide is not recommended due to low radiographic success rates; failures are not limited to internal resorption. 5. Further research is required to understand the pathogenesis and significance of internal resorption and intrapulpal calcifications. 6. Of the four pulpotomy medicaments reviewed, mineral trioxide aggregate is the medicament of choice due to its pulpal biocompatibility and promotion of healing with pulp regeneration. 7. Well-designed and rigorously-reported randomized clinical trials with prior ethics approval and adequate sample sizes and follow-up times are required to confirm the superiority of mineral trioxide aggregate. 8. Further material development is required to improve the convenient use of mineral trioxide aggregate. 9. Collaborative, multi-centre prospective trials should be performed to draw conclusions from diverse populations and large sample sizes. Pivotal bodies within paediatric dentistry are encouraged to set up internet databases allowing clinicians to share experience and outcomes.

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Ng and Messer

In summary, the use of formocresol or formaldehyde-based medicaments should be replaced with more biocompatible medicaments possessing antimicrobial and pulpal regenerative properties. The use of mineral trioxide aggregate in pulp therapy is supported by laboratory and clinical reports of its biocompatibility and promotion of healing with regeneration. Direct and indirect evidence from randomized clinical trials suggests mineral trioxide aggregate is more successful than formocresol, ferric sulphate and calcium hydroxide but conclusions are limited by methodological differences in the primary studies. Of the four medicaments discussed, mineral trioxide aggregate is recommended as the medicament of choice.

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