to HCSCs.
2.4.5 Resin‐Based Hydraulic Calcium Silicate Cements
In an attempt to overcome the long setting time of HCSCs, command‐set light‐cured HCSCs have been developed. TheraCal LC (Bisco, Schaumburg, IL, USA) is one of the most researched. It consists of a mixture of Portland cement, strontium glass, fumed silica, barium‐based radiopacifier, and a light‐activated resin made up of Bis‐GMA and polyethylene glycol dimethacrylate [179]. Although it is claimed to be an HCSC, the reaction of the Portland cement component requires the imbibition of fluids from its surroundings, which may be limited [180]. TheraCal cures through photopolymerization, and the water‐based reaction is slow as the liquid required for the setting of the cement depends on the porosity of the resin. A number of organic components are not declared on the material safety data sheet [181]. Leaching of calcium hydroxide is negligible [182] or significantly less than that of other CSCs [183]. The alkaline pH of TheraCal is similar to that of Dycal [184] and significantly lower than that of ProRoot MTA at both short‐ and longer‐term intervals [185].
Several in vitro studies have been carried out comparing TheraCal to other VPT agents. It has been demonstrated to be cytotoxic with pulp cells [186, 187], and it shows more significant inflammation and less bioactive potential than Biodentine [187]. The authors of the latter study even suggested it should not be considered a candidate for direct interfacing with the pulp.
TheraCal does not perform as well as conventional water‐based HCSCs when interfacing with the pulp itself [188]. In a study of partial pulpotomies in dogs, it induced pulp inflammation in 90% of cases, compared with 18% of those treated with ProRoot MTA [188]. A histological study of partial pulpotomy of third molars in humans compared the use of Theracal, ProRoot MTA, and Biodentine. TheraCal treatment resulted in pulp disorganization beneath the material in 66.67% of cases and of the entire pulp in 22.2%. Discontinued dentinal bridge was noted in most cases treated, and the authors stated that Biodentine and ProRoot MTA were more reliable for long‐term protection of dental pulp [189].
Based on the limited research to date, it does seem that TheraCal is a poor candidate for VPT when directly interfacing with the exposed dental pulp. It may be that it is more suitable for use as an indirect pulp‐capping agent, but there is scant evidence for this indication.
2.4.6 Glass Ionomer Cements
GICs form as a result of an acid–base reaction between a weak polymeric acid and powdered glass, which is basic in nature. Curing occurs in concentrated solutions of water, and the final structure contains unreacted glass particles, which act as a filler, reinforcing the material. Resin‐modified glass ionomer cements (RMGICs) were developed to provide command set in an attempt to decrease setting time/moisture sensitivity [190]. Ostensibly, they are a hybrid of glass ionomers and resin composite.
These materials are not traditionally thought of as an option for directly interfacing with the vital pulp tissue, due to their cytotoxicity. Conventional glass ionomers tend to be less toxic than the resin‐modified formulations [191, 192]. Due to their ability to chemically bond to tooth structures, they provide an excellent bacterial seal [193] and show good biocompatibility when used in close approximation – but not direct contact – with the pulp [75].
When RMGICs were compared to calcium hydroxide in deep nonexposed cavities, a quantitative systematic review could not demonstrate superiority in terms of pulp response with either agent [194], and although histologically RMGICs showed more damage in the short term, this decreased over time, with both RMGICs and conventional GICs performing similarly [195].
Activa Bioactive base/liner (Pulpdent, Watertown, MA, USA) was launched in 2014. It has the mechanical strength, aesthetics, and physical properties of composites and the increased release and recharge of calcium, phosphate, and fluoride. Pulpdent suggests that it is a light‐cured resin‐modified calcium silicate, but this is misleading – it is much more indicative of an RMGIC [196]. The material has three setting mechanisms: glass ionomer (acid–base reaction), light composite resin, and self‐cure composite resin; however, there is a suggestion that the self‐cure reaction does not occur [197]. The bioactive properties of this material are based on a mechanism whereby changes in pH result in the release and recharge of significant amounts of calcium, phosphate, and fluoride [198]. Although this material is suggested for use in indirect and direct pulp therapies, there is insufficient evidence at this stage to support its placement directly against the pulp.
GICs are thus considered indirect pulp‐capping agents rather than as suitable for direct placement on to the pulp itself. A high‐quality randomized controlled clinical trial has shown them to be as effective as Biodentine in treating a deep carious lesion with reversible pulpitis when used in the former mode [27, 199]. Meanwhile, the European Society of Endodontology recommends either a glass ionomer or an HCSC be used as an indirect pulp‐capping agent [1].
2.4.7 Experimental Agents Used in Vital Pulp Treatment
In order to improve the clinical outcomes of VPT, several experimental therapies that have shown promise in tissue regeneration elsewhere have been explored. Bioactive glasses composed of silica, sodium oxide, calcium oxide, and phosphorus pentoxide are well studied in biomaterials [200]. Originally, such glasses were used to repair bone fractures in order to stimulate the body's own regenerative capacity. Bioactive glass dissolves in the normal physiological environment and activates genes controlling osteogenesis and growth factor production [201], leading to bone growth of equivalent quality to that of natural bone [202]. Attempts have been made to assess bioactive glasses as pulp‐capping materials [203], but they have never been significantly more successful than their controls [204].
Emdogain is an enamel matrix derivative originating from unerupted porcine tooth buds which contain amelogenins of various weights. It has proved successful in regenerating periodontal tissues when treating infrabony defects caused by periodontal disease [205]. However, the evidence is less convincing for pulpal tissues: the limited animal and human research conducted to this point shows that, at best, it is no better than calcium hydroxide or MTA [206].
There are several different growth factors and naturally occurring bioactive signalling molecules that are sequestered in dentine during tooth development [178] which have been considered for use as pulp‐capping agents [207]. Bone morphogenetic protein‐2 (BMP‐2), a member of the TGF‐β super family, has been approved by the US Food and Drug Administration (FDA) for clinical use in bone grafting [208] and is known to induce differentiation of DPSCs to an odontoblast phenotype [209]. However, very few other recombinant cytokines have made it past the animal research stage to become candidates for clinical trials. Fibroblast growth factor‐2 (FGF‐2)‐incorporated gelatin hydrogels with collagen sponge have been used on the amputated pulp surface of a rat upper first molar [210, 211]; controlled release of FGF‐2 from the hydrogel induced regeneration of pulp tissue and osteodentin‐like hard tissue in the defect area. In vitro research shows that there is huge promise in the use of these naturally occurring bioactive signalling molecules [38].
The therapeutic use of pharmacological inhibitors to modulate epigenetic ‘marks’ on cellular chromatin has also been shown to alter mineralization response, with inhibitors targeted at DNA‐methylation [212] and histone acetylation shown to promote odontoblast‐like cell differentiation and mineralized tissue formation [51, 213]. Acetylation of histone tails on chromatin is controlled by histone deacetylase (HDAC) and histone acetyl‐transferase enzymes, which if altered by HDAC‐inhibitors (HDACis) result in the promotion of gene expression and a change in cell phenotype [214]. Application of HDACis to rat and human DPSC cultures enhanced mineralization processes, accompanied by an upregulation of genes associated with odontoblast differentiation and mineralization, such as TGF‐β1, BMPs, and DSPP [213, 215, 216]. In addition to the direct regulation of cellular processes, HDACis also induced bioactive DMC release from
