Vital pulp therapy using calcium-enriched mixture: An evidence-based review.

Worldwide, casecontrol studies have revealed that the treatment outcomes of root canal therapy (RCT) are generally favorable; however, the overall epidemiological success rate of RCT in the general population is relatively low. On the other hand, vitality of dental pulp is a key factor in the long-term prognosis of permanent teeth; in recent years, vital pulp therapy (VPT) has received significant consideration as it has been revealed that the inflamed pulp has the potential to heal. In this review article, the current best evidence with regard to VPT using calcium-enriched mixture (CEM) cement in human permanent/primary teeth is discussed. A strategy based on a search using keywords for CEM cement as well as VPT was applied.

INTRODUCTION

Dental caries is still one of the most challenging infectious diseases worldwide; it affects oral/general health as well as the quality of life. Toothache and infection as the main sequelae of untreated caries/irreversible pulpitis are the main reasons for performing root canal therapy (RCT).[1] Permanent mature teeth with irreversible pulpitis/carious pulp exposure with/without clinical/radiological findings of apical periodontitis should be treated by RCT;[2] management of such teeth is the most common treatment carried out by dentists.

RCT has been shown to have a good success rate when carried out correctly.[3] Casecontrol studies have indicated that the pooled proportion of teeth surviving over 2–10 years following RCT ranged between 86–93%.[4] However, such studies are mainly carried out under controlled conditions; therefore, it is not valid to generalize such results. Moreover, the survival rate of endodontically treated teeth in comparison to vital teeth, especially molars, is very low.[5]

Results of epidemiological studies, which comprise<1% of endodontic literature, are necessary for the evaluation of treatment outcomes of RCT in the general public.[6] Review of these studies indicates different success rates of RCT in various countries, ranging from 35% (Spain)[7] to 70–80% (Sweden, Portugal),[89] although the majority of developing/developed countries (i.e., Iran, Brazil, Turkey, Denmark, Scotland, and Canada) have reported success rates of around 50%.[10-15] As an imaginary scenario, by assuming that one root-treated tooth exists in the mouth of every adult in a country with an adult population of 100 million, it is estimated that on an average, ≈100 million endodontically treated teeth are present, of which ≈50 million require nonsurgical endodontic retreatment (NSER). Results of a systematic review have revealed that the pooled estimated success rate of NSER, if carried out by endodontists/experienced clinicians, is 77%.[16] Assuming that in an optimal scenario, this country has 2,000 endodontists, all of whom carried out the necessary NSER treatment on the failed 50 million teeth, the problem would still remain in ≈11.5 million teeth. The next option for these teeth is surgical endodontic retreatment (SER), which has a success rate of ≈60%.[17] As a result, the final treatment option of teeth with failed SER (≈4.5 million) is extraction. This imaginary scenario is representative of the inefficiency of (non)surgical endodontic (re)treatments worldwide, which may be related to inefficient clinical skills as well as the complex nature of RCT.

Serious multidimensional (inter)national effort is necessary for the improvement of the quality of RCT to increase success rates;[710-15] therefore, suggestions of treatment options that are simpler/less costly with a higher success rate are a main priority in dentistry/endodontics.

Many patients are unwilling/unable to pay for necessary dental treatments; this is directly related to the cost and inversely related to their level of income/education and social status.[1819] It is clear to policy makers of oral health care that financial difficulty is the main factor preventing the general population from utilizing oral health-care services. According to the authors, an attempt should be made to provide less costly treatment options that are applicable in the above circumstances. For patients requiring expensive RCT, if possible, vital pulp therapy (VPT) can be provided as a less expensive, simple/ethical treatment option.

Biological properties of human dental pulp

The biological roles of pulp tissue consist of nutrition/sensory/defensive roles, although the most significant is dentinogenesis (maintenance of physiological vitality of the dentin).[20] Production of primary dentin occurs during initial tooth formation, secondary dentin throughout life, and tertiary dentin in response to various stimuli/irritations.[21] The pulp is a vascularized connective tissue consisting of various cells such as fibroblasts/stem cells.[22] Therefore, the damaged pulp tissue of permanent teeth has a healing potential similar to other connective tissues. Weaker stimuli cause stimulation of odontoblasts, which in turn induces the production of reparative dentin, and the choice of treatment in such cases is maintenance of vitality of the damaged odontoblasts. However, odontoblasts lose their vitality in cases of severe damage; as the adjacent differentiated odontoblasts cannot replace them, the stem cells differentiate into odontoblast-like cells.[23]

Classification of human dental pulp diseases

The conditions of the pulp that can be identified/described by using a systematic review include: Clinically normal pulp, reversible pulpitis, irreversible pulpitis, pulp necrosis, hyperplastic pulpitis, internal resorption, and pulp calcification. However, the best diagnostic terms that represent pulpal health/disease are clinically normal pulp, pulpitis, and necrosis.[24] The most appropriate term to use for a dental pulp with inflammation is pulpitis, although the generally accepted subterms are reversible and irreversible pulpitis. Irreversible pulpitis is a pulpal state that is theoretically characterized by mild/severe pain that lingers after removal of a stimulus, whereas reversible pulpitis refers to a pulpal state that implies the presence of mild pulpal inflammation.

Currently, there are no accurate metric methods for determining the diagnosis of reversible versus irreversible pulpitis; however, some researchers have tried to correlate the results of diagnostic tests with types of pulpal inflammation.[25] As the gold standard is histological evidence, determination of reversible versus irreversible pulpitis by using cold testing has low sensitivity, specificity, and predictive values.[26] Nowadays, differentiating between reversible/irreversible pulpitis is carried out on an empirical basis; there is no definitive evidence to support or refute the use of these terms.[24]

From a clinical point of view, the exposed pulp may be in one of the following three conditions: Normal pulp without inflammation (following trauma), reversible pulpitis (after mechanical exposure), and irreversible pulpitis (following carious exposure); however, a recent important review stated “It is also not known whether pulps with irreversible pulpitis are ever truly irreversibly inflamed, that is, could all pulps with inflammation recover if conservative treatment strategies were used? This question requires further research to establish an answer”.[24]

Definition/aims of VPT

The aims of VPT include maintenance of vitality of the dental pulp and stimulation of the remaining pulp tissue for adequate structural/functional healing of the pulp-dentin complex.[27] The response of the pulp to direct capping involves the formation of fibrodentin/reparative dentin and remineralization of the existing dentin, resulting from the recruitment of odontoblasts and/or proliferation of undifferentiated mesenchymal cells, which maybe either stem cells or dedifferentiated and transdifferentiated mature cells.[28] Therefore, by the creation of a biological seal, connection between the pulp and the oral environment is eliminated and re-entry of pathogens is prevented.

Indications for VPT

Vital primary/permanent teeth with complete/incomplete root formation after traumatic/mechanical/carious pulp exposures are suitable candidates for VPT. The most important factor in success is vitality of the pulp and in particular the presence of adequate vascularization, which is necessary for active formation/function of odontoblasts.[29] In addition, suitable candidates for VPT include teeth in which an appropriate coronal seal can be provided, as the prognosis of VPT is significantly reduced in cases of inadequate coronal seal formation and subsequent bacterial microleakage.[30] Restorations that require retention from radicular structures should be treated by RCT. The presence of a healthy periodontium is necessary for success of the treatment, as teeth with moderate to severe periodontal disease are not suitable candidates for VPT.[31]

Factors effective in the success of VPT

Several factors such as an adequate blood supply, severity of inflammation, obtaining hemostasis, disinfection of the exposure/cavity preparation, antibacterial/biocompatibility properties of pulp-covering agents, provision of an adequate seal, and the skills of the clinician may affect the success of VPT.[233233]

The presence of an adequate blood supply as the most important factor is required for the maintenance of vitality of the pulp,[23] which is, in turn, necessary for successful outcomes via repair/regenerative mechanisms.

Although previous evidence indicates that direct pulp capping (DPC) may be effective in the treatment of vital inflamed pulps,[34] it has been reported that the success rate is reduced in these cases.[35] Therefore it is recommended to carry out pulpotomy (partial/complete) to create a wound in an uninflamed location;[3336] however, this is not achievable clinically. Alternatively, inflammation of tissue and healing of pulpal tissue seem to be tightly interlinked; the inflammatory reaction may be a prerequisite for the burst of progenitors implicated in pulpal repair/regeneration.[28]

Control of hemorrhage (to achieve a clot-free pulpal wound) is necessary for the success of VPT.[37] In addition, sterilization/disinfection protocols should be followed as a main principle.[38] Various options available for the achievement of pulp hemostasis include light mechanical pressure using a sterile cotton pellet which may be soaked in saline/hydrogen peroxide/sodium hypochlorite solutions, although the use of chlorhexidine as an antibacterial/hemostatic agent is currently suggested.-[32]

Another important factor in the success of VPT is the provision of an adequate seal against bacterial (re)entry, as a bacterial attack is the cause of failure;[39] if a pulp exposure is adequately sealed, successful healing with the formation of a dentin bridge may occur.[3840]

Pulp-covering agents should provide a suitable environment and allow regeneration of the pulp-dentin complex. Such materials should be biocompatible, noncytotoxic, and antibacterial[41] to induce differentiation of odontoblast cells.

Similar to all clinical procedures, the skills of the clinician in carrying out VPT correctly are important. Familiarity with the principles of clinical decision making, diagnosis, case selection, access/cavity preparation, and mixing/applying the capping agent are necessary.

Healing mechanisms of the exposed dental pulp

Exposure/amputation of a section of the normal pulp is a process which results in at least short-term inflammation; in an inflamed pulp, an exposure may well add to the injury burden of the dental pulp. Initially, in the tissues adjacent to the exposure site, various amounts of necrotic tissue, inflammatory cells, and extravascular erythrocytes can be observed. The initial damage results in the production of fibrinogen, formation of blood clot, and an acute inflammation accompanied by the presence of polymorphonuclear leukocytes (PMNs).[42] The production of mediators by PMNs/macrophages is a significant event in the successful humoral immune response of the host.[43] Some particles from the pulp-covering material/dentin chips may also enter the underlying pulp tissue;[42] hard tissue formation occurs around dentinal chips. Although the hemostatic, inflammatory, proliferation, and repair phases occur in a specific order, it is not possible to specify clearly the beginnings and ends of these overlapping phases.[44] The evidence with regard to pulp defense reactions is similar to the reactions which occur during damage to other connective tissues with their associated specific/nonspecific defense mechanisms.[44] Successful elimination of the causes of pulpitis using VPT results in the successful treatment of the pulpal wound and creation of a dentin bridge by regeneration of the pulp-dentin complex.[3945] Nowadays, various important studies are being carried out in the field of pulp-dentin regeneration using molecular biology and stem cells.[46] Although clinical application of such techniques is not yet widespread, it appears that the science of tissue engineering will have highly significant effects in clinical treatment.

VPT methods

The topic of VPT has received considerable attention in recent years, in particular with regard to being the most suitable technique/material.[2747] In clinical practice, VPT is categorized as DPC/IPC (IPC: indirect pulp capping) and miniature/partial/complete pulpotomy.[47-50] Recent developments in technique/(bio)materials have emerged in the evolution of the management of caries from G.V. Black's ‘extension for prevention’ to ‘minimally invasive dentistry’ (MID).[51] In MID during IPC, carious infected dentin is removed and a pulp-covering (bio)material is placed onto the remaining affected dentin. Sealing the lesion with adhesive restorative materials allows healing of the underlying pulp.[52] During DPC, a pulp-covering (bio)material is placed directly onto the exposed pulp, which protects it from further damage and allows healing of the pulp-dentin complex.[5354] During a large pulp exposure/severe pulp inflammation, pulpotomy (miniature/partial/complete) is carried out. This involves the removal of a small part/all of the coronal pulp tissue, followed by direct coverage of the remaining coronal/radicular pulp.[4955]

CALCIUM-ENRICHED MIXTURE CEMENT

Calcium-enriched mixture (CEM) cement was introduced to dentistry as an endodontic filling material (USPTO number: 7,942,961). The major components of the cement powder are calcium oxide (CaO), sulfur trioxide (SO3), phosphorous pentoxide (P2O5), and silicon dioxide (SiO2), different from mineral trioxide aggregate (MTA) and Portland cement (PC).[5657] The physical properties of this biomaterial, such as flow, film thickness, and primary setting time are favorable.-[56]

Creation of a three-dimensional seal, acceptable antimicrobial properties, and biocompatibility are highly significant in the success of VPT.[5859] The sealing ability of CEM is similar to MTA[60] and improves by storage in phosphate-buffered saline solution.[61] The particle size of CEM is smaller than MTA;[62] this may be related to its acceptable sealing properties. It has the ability to promote hydroxyapatite formation in saline solution[63] and might promote the process of differentiation in stem cells and induce hard tissue formation, that is, cementogenesis.[6465] Antibacterial properties of CEM, calcium hydroxide (CH), MTA, and PC have been compared in a number of studies; the results have shown that CEM has antibacterial properties similar to CH.[6667] Comparison of antifungal properties of CEM and MTA on Candida albicans has shown that both biomaterials induce complete death of fungal cells after 24 hours.[68] CEM has an alkaline pH of ~11, which is important in the antimicrobial properties of this biomaterial.[56] Several animal studies have shown that in various forms of VPT treatments, the induction of dentin bridge formation in CEM was comparable with that in MTA and superior to that in CH.[6970] Studies of complete pulpotomy treatment using CEM, MTA, and CH have shown that compared to CH, samples in the CEM group exhibited lower inflammation, improved quality/thickness of calcified bridge, superior pulp vitality status, and morphology of odontoblast cells. However, no significant differences were identified in comparison to MTA.[70] In a study using the MTT assay on L929 as well as a scanning electron microscope (SEM) study on human gingival fibroblast (HGF), the cytotoxicity of CEM was compared with MTA and intermediate restorative material (IRM); the results indicated that the cytotoxic potentials of CEM and MTA are both insignificant and comparable, and both biomaterials were significantly superior to IRM.[71-73] A recent study comparing the subcutaneous tissue response to CEM and MTA in rats showed that unlike MTA, CEM did not induce any cellular necrosis after one week. After 60 days, levels of inflammation in the CEM group were significantly lower than the white/gray MTA groups. Another significant finding was the presence of dystrophic calcification adjacent to the biomaterials, which is an indication of their osteo-inductive potential.[74]

Evidence for VPT with CEM cement

Evidence-based dentistry/endodontics (EBD/EBE) is based on the best available scientific evidence; the strength of evidence-based clinical recommendations is classified according to the existing level of evidence.[75] Randomized clinical trials as well as systematic reviews (SRs) and meta-analyses provide the highest quality of evidence, followed by cohort studies, case control studies, case series, and case reports.[76] Numerous methods/materials have been proposed for the treatment of exposed dental pulps; however, many have not been based on current best evidence, and are unreliable for generalization into the current clinical practice of dentistry.

FULL/COMPLETE PULPOTOMY WITH CEM CEMENT

Deciduous molars

Complete pulpotomy treatment of human deciduous molars is a well-known treatment procedure, which is carried out following coronal pulp exposure caused by caries/cavity preparation/trauma. It involves amputation and removal of the inflamed coronal pulp and maintenance of uninflamed vital radicular pulp tissue using an appropriate pulp-covering (bio)material.[77] Recently, a randomized clinical trial study on the success rates of MTA and CEM in pulpotomy of deciduous molars with a two-year follow-up period was published. The results of this trial, which is of level 1 quality of evidence, indicated that only one tooth in the CEM group presented with failure, whereas three teeth in the MTA group were extracted due to pathologic resorption; however, this difference was not statistically significant. It was concluded that pulpotomy treatment of deciduous molars using CEM is an advisable/successful treatment modality.[78]

Permanent teeth

Open apex

Apexogenesis is considered as the treatment of choice in vital permanent teeth with incomplete root formation.[7980] A rare case of a maxillary incisor with an open apex and traumatic pulp exposure has been reported; the tooth was left untreated for one month and then treated by pulpotomy using CEM. Acceptable clinical/radiographic results were achieved, including formation of a dentin bridge beneath CEM and closure of the tooth apex.[81] Another case report of a permanent molar with an open apex and signs of irreversible pulpitis showed that complete pulpotomy using CEM resulted in successful clinical outcomes of pain relief and radiographic success including apical root closure.[82] A randomized clinical trial study of permanent molars with open apices which presented with extensive caries and signs of reversible/irreversible pulpitis was carried out on 51 subjects. Results of a follow-up after one year[85] indicated that complete pulpotomy of the teeth using MTA and CEM were 100% successful.[83]

Mature molars

A case report of a mature mandibular molar with irreversible pulpitis and condensing apical periodontitis indicated that two years after pulpotomy, acceptable clinical/radiographic results such as formation of normal trabecular bone structure around the root apices had occurred.[84] In a case series study of 12 permanent mature molars with irreversible pulpitis, CEM was used for pulpotomy, and resulted in complete success at a follow-up after16 months. It was also shown that to enable improved regeneration, the pulp-dentin complex had isolated itself by forming a calcified bridge.[45] In a multicenter randomized clinical trial in 23 medical centers linked to five medical universities in Iran, pulpotomy treatment of mature permanent molar teeth with irreversible pulpitis using CEM and MTA were examined. The results of this trial indicated that pulpotomy treatment carried out by trained dentists can result in successful control of pain[85] and high rates of clinical/radiographic success (> 92%) during a follow-up after oneyear.[8687]

DPC WITH CEM CEMENT

There is controversy amongst pediatric dentists regarding DPC treatment of human deciduous molars with CH;[88] however, many investigations have found that postoperative pulpal pathosis can be attributed not to the capping agent, but to later microbial microleakage at the dentin/pulp interface.[89] A recent randomized clinical trial study has shown that CEM and MTA exhibit similar and acceptable outcomes in DPC treatment of human deciduous molars.[90]

DPC is one of the best known clinical treatments available, whereby connection between the exposed pulp and oral cavity is eliminated using appropriate materials.[47] A case report of a mature first mandibular molar with symptomatic irreversible pulpitis/apical periodontitis demonstrated favorable clinical/radiographic outcomes such as complete resolution of the apical lesion at a follow-up after 15 months.[91] Recent DPC outcomes of prospective randomized controlled/clinical trials carried out on 32 permanent teeth that were orthodontically planned for extraction have shown that under immunohistochemical examinations, thickness of dentinal bridge beneath CEM was higher than MTA at various time intervals; pulp inflammation was also lower in the CEM groups.[92] In addition, expression of fibronectin/tenascin in the CEM groups were higher than the MTA groups during both time intervals; however, the above differences were not statistically significant.[93]

IPC WITH CEM CEMENT

Currently, the concept of complete caries removal is being challenged for permanent teeth. IPC decreases the risk of pulp exposure, reduces the substrate for bacteria, prevents lesion development and promotes a physiological reaction in the pulp-dentin complex. Once cariogenic flora is isolated from their nutritional supply by an effective coronal seal, they perish/become inactive. An interesting case report of IPC treatment with CEM of a mature symptomatic first mandibular molar with irreversible pulpitis associated with apical periodontitis demonstrated favorable clinical and radiographic outcomes such as complete resolution of symptoms and healing of the apical lesion at 15 months follow-up.[94]

SUCCESS CRITERIA

The clinician can assess outcomes of the treatment by compiling the information collected from clinical/radiographic signs. Excluding low-level sensitivity and short-term pain during the initial 1-2 weeks after VPT, lack/relief of pain is one of the criteria for success.[53] In general, increased bone density is not a sign of failure,[95] although elimination of periapical lesions and a positive response to electric/thermal pulp testing after VPT are signs of success of the treatment.[87] Although the most accurate method of assessment is by histological examination of the pulp-dentin complex, it is apparent that this is only possible in laboratory/animal studies and cases of extraction of the human tooth.[40]

Prognosis

There is general consensus that in pulp exposure of mature/immature permanent teeth, VPT by DPC/pulpotomy (complete/incomplete) is an alternative treatment for healthy uninflamed pulps (normal pulp or reversible pulpitis).[9697] Results of a number of recent histological studies have shown that even in cases of irreversible pulpitis, VPT using endodontic biomaterials has a satisfactory success rate.[404598] An interesting recent systematic review revealed that the success rate of VPT was up to ≈99%; this provides an important evidence that permanent teeth with cariously exposed pulps can be successfully managed by VPT.[47]

The success of VPT is based on the healing capacity of the normal/inflamed dental pulp; it has been reported that aging of the pulp reduces the chance of success.[99] However, recent studies have revealed the weakness of evidence regarding the effects of age and status of the root apex on treatment outcomes of VPT.[47]

Placement of an adequate coronal seal is necessary for ensuring success of most endodontic treatments.[1030] Prognosis of VPT is reasonably high if a bacteria-tight coronal restoration is placed.[100]

Policy making

Based on the best current evidence[85-87] , VPT treatment of teeth by complete pulpotomy using CEM has been introduced by the Iranian Ministry for Health and Medical Education in public health-care centers; this has resulted in saving many teeth which would otherwise be unnecessarily extracted. Oral health-care policy makers have officially announced that nearly2 million teeth are extracted annually in public health-care centers in Iran. Therefore, it is believed that by the generalization of this technique, it is possible to save many of these teeth.

CONCLUSION

Results of epidemiological studies demonstrate that the success rate of RCT is alarmingly low worldwide.

Maintenance of vitality of the pulp with the aim of extending the lifespan of vital teeth is a proven concept.

Carrying out VPT (apexogenesis) in vital immature teeth with open apices is an inevitable choice of treatment.

Carious pulp exposure/irreversible pulpitis can be treated by VPT; therefore, carrying out VPT in mature/immature permanent/primary vital teeth is a logical priority in modern dentistry.

The highest level of current best evidence has revealed that CEM cement is a suitable endodontic biomaterial for VPT treatments of primary molars as well as mature/immature permanent teeth with reversible/irreversible pulpitis.