Bioactive and biomimetic restorative materials: a comprehensive review. Part II.

REVIEW ARTICLE

Bioactive and Biomimetic Restorative Materials: A Comprehensive Review. Part II STEVEN JEFFERIES, MS, DDS, PhD

ABSTRACT This second part (Part II) of a two-part comprehensive review of bioactive and biomimetic restorative materials reviews the calcium aluminate-based restorative dental materials. Part II explores the development, composition, properties, and application of the bioactive calcium aluminate-based materials that have been developed for several indications in restorative dentistry.

CLINICAL SIGNIFICANCE Bioactive materials have evolved over the past three decades from relatively specialized, highly biocompatible, but low-strength dental materials to now emerge in product compositions for expanded clinical uses in restorative dentistry. Further developments to meet additional restorative clinical needs are anticipated in the newly emerging category of dental materials. (J Esthet Restor Dent 26:27–39, 2014)

CALCIUM ALUMINATE CEMENTS Similar to the calcium silicate cements (CSCs), the calcium aluminate cements (CAC) are also derived from the class of cements called “hydraulic” or natural cements. Their hydrating solution is water with 30 to 90 ppm lithium to accelerate the hardening process. A typical CAC contains prereacted constituents as follows: Al2O3 = 43%; CaO = 19%; H2O = 15%; ZrO2 = 19% (silicon, iron, magnesium, titanium, and alkali oxides less than 10%). The calcium aluminate undergoes very rapid hydration with a setting reaction at a pH of 11.4 to 12.5 and the formation of the reaction products Katoite and Gibbsite. The chemical reaction forming the CAC is depicted as follows:1

3CaO Al 2 O3 12H 2 O + Calcium Aluminate Water Ca [ Al (OH )4 ]2 (OH )4 4 Al (OH )3 + → Gibbsite Katoite Mechanistically, water dissolves the calcium aluminate powder with the subsequent formation of calcium ions calcium ions (Ca2+), aluminum hydroxyl ions (Al(OH)4-, and hydroxyl ions (OH-). This activity is then followed almost immediately by precipitation of new solid phases (Katoite and Gibbsite) as the solution reaches saturation. These precipitates grow until they meet, and a connected cluster of hydroxide particles is formed continually. Crystallization of the phases proceeds and the hydrates grow in size from nanometers (nm) to microns (μm).1

Professor, Kornberg School of Dentistry, Temple University, Restorative Dentistry, Philadelphia, PA, USA This segment is the second part (Part II) of a two-part comprehensive review of bioactive and biomimetic restorative materials. Part I considered the calciumsilicate-based dental materials. Part II will now review the calcium aluminate-based restorative dental materials.

© 2013 Wiley Periodicals, Inc.

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Journal of Esthetic and Restorative Dentistry

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BIOACTIVE AND BIOMIMETIC RESTORATIVE MATERIALS Jefferies

There have been two specific restorative dental products that have appeared to date based on calcium aluminate chemistry: one as a direct restorative material (Doxadent [DD], Doxa Dental AB, Uppsala, Sweden),2 and one as a luting cement (Ceramir [CM] Crown & Bridge, Doxa Dental AB).3 The luting cement is actually a hybrid composition combining both calcium aluminate and glass ionomer chemistry.3,4 The glass ionomer component contains both polyacrylic acid and a reactive glass, which in the presence of the water available in the liquid component, permits a classical glass ionomer reaction. The manufacturer claims that the glass ionomer component contributes to a low initial, short-duration pH, improved flow and setting characteristics, early adhesive properties to tooth structure, and early strength properties. In contrast, the calcium aluminate component in the cement is reported to contribute to: increased strength and retention over time; biocompatibility; sealing of tooth material interface; bioactivity-apatite formation; stable, sustained long-term properties and lack of solubility/degradation; and ultimate development of a stable basic cement pH. Nevertheless, this review will first consider another calcium aluminate material for dentistry that preceded the introduction the calcium aluminate—glass ionomer luting material, CM.

USE OF CALCIUM ALUMINATE AS A DIRECT DENTAL RESTORATIVE MATERIAL Clinical use of predominantly CACs appear approximately 8 to 10 years after the first documentation of mineral trioxide aggregate (MTA)/calcium silicate/Portland-type cements use in dentistry. DD was a powder-liquid two-component CAC composed of a powder component containing calcium aluminate powder and other components described later, and a liquid component containing water and an accelerator comprising a lithium salt. The material is inorganic and nonmetallic, and the main components are CaO, Al2O3, SiO2, and water. DD was described in its 510-K approval to market document from the Federal Food and Drug Administration as a “dental ceramic composed of CAC and oxides that is intended to restore carious lesions or structural defects

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in teeth.”4 More specifically, this restorative cement was described as composed of CAC and oxides, i.e., silica and zirconium oxide (as well as iron oxide as a colorant), as a filler material, and a blend of fine, irregularly shaped particles ranging from 0.5 to 5.0 μm in diameter, and microfine particles having a diameter from 0.02 to 0.2 μm. DD was intended for use as a restorative dental material for the permanent restoration of Class I, II, and V cavity preparations. The product was presented in a two-component form comprising a tablet that was saturated in a plastic well with a specific amount of the liquid component. The wet tablet was then condensed into the cavity preparation. Physical properties of this material have been described by several researchers. The first published research report dealt with some important mechanical properties (hardness, dimensional stability, compressive and flexural strength) of an experimental version of a translucent calcium aluminate dental restorative material.5 All samples investigated have been made from prepressed tablets, with a compaction degree of approximately 60%, hydrated using a 0.15 wt% Li salt solution as an accelerator. The samples were stored in water at 37°C between the measurements. As reference materials, one composite, Tetric Ceram, and one glass ionomer, Fuji II, were used with specimens prepared according to the manufacturer’s recommendations. For the reference materials, some of the properties were published data. Vickers hardness for this novel material ranged from 87.1 HV for a coarse filler to 102 HV for a fine filler, and compared with Tetric Ceram (a composite resin) at 71 and 59 HV for Fuji II (a glass ionomer). Compressive strength (CS) using specimen rods 7.5 mm in length and 4 mm in diameter yielded a mean value of 182 ± 12.5 MPa as compared with 300 MPa for Tetric Ceram and 160 MPa for Fuji II (based on technical documentation cited by the authors). Flexural strength was reportedly measured according to ASTM F394 standard for ceramic materials using a circular plate of the material supported on three balls and loaded in the center of the plate by a fourth ball on the opposing side until fracture occurs. Specimens were stored in distilled water at 37°C for 14 days prior to testing. Using this method, mean

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flexural strength for the calcium aluminate material was 106 ± 28.8 MPa as compared with 142 and 41 MPa for Tetric Ceram and Fuji II, respectively. Expansion values for the material ranged from 0% to 0.1%, to 0.1% to 0.2% for the fine and coarse filler grain materials, respectively. The authors concluded that “the results showed that the calcium aluminate material has sufficient mechanical properties to be used as a permanent dental restorative taking as a reference the International Standard Organization (ISO) 9917 and the ISO 4049 as well as the reference materials. In addition the results indicate that the mechanical properties are controlled by the microstructure, which is mainly determined by the grain size of the filler.” In another research paper describing the physical properties of the calcium aluminate restorative material (now termed a CBC), Lööf et al. report on the diametral tensile strength (DTS). flexural strength, and CS of this calcium aluminate material (believed to a DD) compared directly with dental amalgam (Disperalloy, DeTrey Dentsply, York, PA, USA) and a glass ionomer restorative (Chemflex, DeTrey Dentsply).6 In contrast with the method for CS cited in the study described previously in this review, the CS method in this report was conducted according to ISO 9917; 1991 (cylinder specimen dimensions of 6-mm length by 4-mm diameter). Strength values for were obtained at a variety of time points ranging from 1 hour to 4 weeks. Diametral tensile and flexural strength values, in this study, were in a similar range for both the CBC material (calcium aluminate-based) and the glass ionomer material (Chemflex) but lacked a corresponding comparison with Disperalloy, having only data at 1-hour time frame. CS values for the CBC-calcium aluminate were reported as 139.7 ± 20 MPa at 24 hours but increased significantly to 197.1 ± 17 MPa at 1 week and 258 ± 12 MPa at 4 weeks. Sunnegårdh-Grönberg et al. also evaluated the physical properties of DD in a series of publications.7–9 The aim of the first study was to compare a new ceramic restorative cement for posterior restorations, DD, with other types of tooth-colored materials for direct use as regards to hardness and in vitro wear.7 Four hybrid resin composites (RCs)—one polyacid-modified RC,


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one resin-modified glass ionomer (RMGI) cement, one conventional glass ionomer cement (GIC), and one zinc phosphate cement, an experimental version as well as the marketed version of the ceramic restorative cement—were investigated. Hardness of the materials was tested with the Wallace indentation tester, and wear was tested with the Academic Centre for Dentistry Amsterdam wear machine. All tests were carried out on 2-week-old specimens. DD was as hard as the zinc phosphate cement and the hardest RC. The ceramic restorative cement wore significantly more than the RCs, the same as the zinc phosphate cement, and less than the GICs. No correlation between hardness and wear was found. It was concluded by the authors that the ceramic restorative cement (DD) is a rather hard material but with a relatively low wear resistance. Another study was concluded to determine the surface roughness of a novel CAC (DD) intended for posterior restorations after treatment with different polishing devices in vitro.8 Forty-eight CAC specimens were polished with diamond burs at 15,550 or 27,000 rpm, Sof-Lex discs, Jiffy points, Shofu silicone points, and Aaba universal polishers. Amalgam specimens were polished with Shofu silicone points and used as reference. Roughness was measured using a profilometer. The smoothest CAC surface was observed after use of the fine Sof-Lex disc (roughness average [Ra] 0.26 μm). Diamond burs at higher speed, points, and polisher gave rather similar results (Ra 0.58–0.72 μm). An increase in surface roughness was seen from using diamond burs at lower speed (Ra 2.3 μm). Polished amalgam showed the smoothest surface in the study (Ra 0.17). It was concluded that the smoothest CAC surfaces were obtained with the fine Sof-Lex discs. Different polishing points and diamond burs at higher speed, which are suitable polishing devices for posterior restorations, also gave relatively smooth surfaces. An additional study by this group was conducted to compare this new restorative cement intended for posterior restorations, DD, with other types of tooth-colored materials with regards to flexural strength and flexural modulus.9 Four hybrid RCs—one


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polyacid-modified RC, one RMGI cement, one conventional GIC, one zinc phosphate cement, and an experimental version as well as the marketed version of DD—were investigated. Flexural strength and flexural modulus were tested according to ISO standard 4049 and determined after 1 day, 1 week, and 2 weeks. Together with the zinc phosphate cement, DD had the lowest flexural strengths (13–22 MPa). The strongest materials were the RCs and the polyacid-modified RC (83–136 MPa). The highest flexural modulus was found for DD (17–19 GPa). The flexural strength of DD decreased significantly from 1 to 2 weeks, whereas flexural modulus remained unchanged. The other materials reacted in different ways to prolonged water storage. It can be concluded that the restorative cement DD had significantly lower flexural strength and significantly higher flexural modulus than today’s materials used for direct posterior restorations. Another group also investigated the physical properties of the CAC, DD.10 This study compared in vitro the mechanical properties of a directly placed ceramic restorative material (DD) to glass ionomer (Fuji IX), hybrid composite control (Z250), and amalgam control (Tytin). DTS, CS, and Vickers hardness number (VHN) were measured for 10 specimens per group (N = 480 total) with time (1 hour, 24 hours, 1 week, 4 weeks). CS and DTS specimens were loaded to failure (Instron, Rate of Strain = 0.5 mm/minute). VHN discs were indented. Data were analyzed using analysis of variance (ANOVA) and Tukey’s test (p < 0.05) for pairwise comparisons of group means at each time. The CS of DD, in this in-vitro study, ranged from 44 ± 6 MPa at 1 hour to 63 ± 10 MPa at 24 hours, yet increased significantly at 1 week to 118 ± 9, and appeared to level at 4 weeks at a CS of 120 ± 11 MPa. DTS for DD ranged from 7 ± 1 at both 1 and 24 hours, and also increased significantly at 1 and 4 weeks to 14 ± 3 MPa and 15 ± 3 MPa, respectively. Vickers hardness values increased progressively from 52 ± 4 at 1 hour to 95 ± 2 at 4 weeks. The investigators concluded from their findings that for CS and DTS, DD was weakest (p < 0.05) for all testing times except Fuji IX DTS at 1and 4-week intervals. For VHN, DD was harder than glass ionomer, better than composite except at 1hour and less than amalgam. Except for VHN for Z250, all

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values improved from 1 to 24 hours. Based on current in vitro results, this novel restorative material does not yet equal composite or amalgam CS or DTS. The cytotoxic effects of DD were compared with several currently used direct restorative materials.11 Specimens of three composites (QuiXfil, Tetric Ceram, Filtek Supreme)—one zinc phosphate cement (Harvard Cement), one GIC (Ketac Molar), and the CAC (DD)—were used fresh or after 7-days of pre-incubation in cell culture medium at 37°C, pH 7.2. polyvinyl chloride strips for ISO 10993-5 cytotoxicity test were used as positive control and glass specimens as negative control. L-929 fibroblasts (5-mL aliquots, containing 3 × 104 cells/mL), cultivated in Dulbecco‵s Modified Eagle Medium with 10% fetal calf serum, 1% glutamine, and 1% penicillin/streptomycin at 37°C/5% CO2 and trypsinized were exposed to the specimens for 72 hours. The cells were harvested, centrifuged, and resuspended in 500 μL of DMEM and then counted in 500 μL of DMEM for 30 seconds with a flow cytometer at 488 nm. The ANOVA comparing the six materials showed different influences on L-929 fibroblast cytotoxicity (p < 0.0001). The cytotoxicity of all specimens diminished with increasing pre-incubation time (p < 0.0001). Fresh DD exhibited the lowest cytotoxicity, followed by QuiXfil. Ketac Molar showed the highest cytotoxicity. After 7 days of pre-incubation, Harvard Cement and Filtek Supreme demonstrated more cytotoxicity than the other materials (p < 0.005). The clinical performance of DD as a posterior restorative material was also evaluated up to a 3-year recall point.12,13 The aim of this study was to evaluate intra-individually the experimental CAC (DD) and an RC in Class II restorations. Each of 57 participants received at least one pair of restorations of the same size, one CAC and one RC (Tetric Ceram). Sixty-one pairs were performed. The restorations were evaluated clinically, according to slightly modified United States Public Health Service criteria, at baseline, after 6 months, and 1, 2, and 3 years. One hundred and twenty restorations were evaluated at 2 years.12 Postoperative sensitivity was reported for five restorations (2 RC, 3 CAC). Significantly better clinical durability was shown for RC. Five nonacceptable CAC restorations (8.2%)

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were observed at 6 months, 10 CAC (16.7%) and 2 RC (3.3%) at 12 months and 11 CAC (18.3%) at 24 months. This resulted in a cumulative failure frequency, at 24 months, of 43.3% for the CAC material and 3.3% for the RC material. Main reasons for failure for the CAC were partial material fracture (seven restorations), cusp fracture (five restorations), and proximal chip fracture (six restorations). The CAC showed a nonacceptable clinical failure rate for Class II restorations probably caused by its difficult handling and low mechanical properties. This trend continued at the 3-year recall, At 3 years, 62 out of 63 originally placed restorations were evaluated.13 At 6 months, 9.5% nonacceptable DD restorations were observed, 17.5% at 12 months, 24.2% at 2 years, and 21% at 3 years, which resulted in a cumulative failure frequency of 72.6% at the end of the 3 years for the new restorative material. Main reasons for failure were material or tooth fracture. The authors of this study concluded that DD showed a nonacceptable clinical failure rate as a posterior restorative, especially in Class II cavities. Clearly, based on this study, this calcium aluminate-based material appeared unacceptable as an amalgam replacement for posterior restorations. That said and in view of the observation that the in-vitro physical property performance of the DD material was closer to that of glass ionomer as opposed to composite resin or amalgam, it is interesting to speculate whether this CAC compares more closely in clinical performance with a high-strength glass ionomer restorative in posterior restorations. A 2-year clinical investigation of a high-strength glass ionomer in Class I and II posterior restorations was reported in 2009.14 In this controlled, prospective, clinical study, the highly viscous GIC Ketac Molar was clinically assessed in Class I and Class II cavities. Forty-nine subjects (mean age 32.3 years) received 108 restorations placed by six operators in conventional Black Class I and II type cavities with undercuts after excavating primary lesions or after removing defective restorations. At baseline and after 6, 12, and 24 months, restorations were assessed by two independent investigators according to modified USPHS codes and criteria. Recall rates were 83% after 6 months, 50% after 12 months, and 24% after 24 months. Failure rates after 24 months were 8% for Class I and 40% for Class II fillings mainly because of bulk fracture


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at occlusally loaded areas. This failure rate for this highly viscous glass ionomer is proportionally similar to failure rates for DD at 2 years recall reported by van Dijken and Sunnegårdh-Grönberg,12 namely 10% for Class I restorations and 43% for Class II restorations. One final point: This case study of the in-vitro and in-vivo performance of DD illustrates another critical object-lesson in the development of new dental devices, and more specifically new compositions or chemistries in dental restorative materials. Clinical evaluations of sufficient duration are still absolutely necessary prior to the introduction of new dental restorative materials with new chemistries or significant changes in formulation prior to their introduction and marketing.

CALCIUM ALUMINATE—GLASS IONOMER LUTING CEMENT The most recent modification in bioactive chemically bonded cements with a predominant use in restorative dentistry has been the introduction of a calcium aluminate–glass ionomer luting cement (CM Crown & Bridge, originally named XeraCem). CM is a luting agent intended for permanent cementation of crowns and fixed partial dentures, gold inlays and onlays, prefabricated metal and cast dowel and cores, and high-strength all-zirconia or all-alumina crowns.15,16 The cement is a water-based composition comprising calcium aluminate and glass ionomer components, and has been demonstrated to be bioactive.15,17 The term “bioactivity” again refers to a property of this new cement to form hydroxyapatite (HA) when immersed in vitro in a physiological phosphate-buffered saline (PBS) solution.17 The introduction of any new cement chemistry necessitates assessment of its laboratory and clinical performance, and it should be noted that both laboratory and clinical investigations were initiated and findings were collected prior to commercial introduction of this material. The laboratory performance of this new cement has been assessed with respect to a number of performance criteria. Assessment of CS, film thickness, and setting time all conformed favorability to the ISO standard for water-based luting cements.18 Comparative in-vitro microleakage performance of this new bioactive cement


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has also been assessed by two methodologies. Dye leakage analysis in cemented crowns concluded that CM demonstrated significantly less leakage than a conventional GIC, Ketac-Cem (KC).19 An in-vitro bacterial leakage model comparison of CM with a conventional glass ionomer luting cement, again KC, and an RMGI cement (Rely X Luting Plus, RX) demonstrated that the groups cemented with CM and RX showed no significant difference in microleakage patterns (p > 0.05), whereas both recorded significantly lower microleakage scores (p < 0.05) than the group cemented with KC.19,20 Biocompatibility ranks as one of the most important properties of a final luting cement, and as such, a number of in-vitro and in-vivo tests (as recommended by American National Standards Institute/American Dental Association (ANSI/ADA) Spec. 41 and ISO 10993) were conducted prior to the clinical investigation to evaluate the biocompatibility of CM Crown & Bridge cement.21 Results for the Ames test for mutagenicity indicated that this new cement formulation did not induce gene mutations. In-vitro cytotoxicity testing indicated cell responses ranging from none to mildly cytotoxic, an acceptable response. The skin sensitization test (in guinea pigs) indicated that this cement is not a skin sensitizer, whereas testing for mucous membrane irritation (hamster pouch test) indicated that it produced no local irritation.21 Pulpal testing in Rhesus macaques, according to ANSI/ADA Spec. 41, indicated a virtual absence of pulpal inflammation at both 30- and 85-day evaluation periods after CM was used to cement composite resin inlays in a Class V preparation.21 Retention is perhaps the most critical factor in the performance of a final luting cement. A comparative, in-vitro crown retention study was conducted (also prior to the clinical evaluation) to assess the retentive properties of this new cement with noble metal (gold) crown-copings.22 Results of this test indicated that it demonstrated retentive values equivalent (no statistically significant difference) to a self-adhesive resin cement, Rely X Unicem, but were significantly higher than a conventional glass ionomer, KC, and zinc phosphate cement.

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A clinical investigation was initiated approximately 2 years prior to the introduction of CM.23–26 The aim of this pilot clinical study (a prospective, consecutive case series clinical study) was to assess the clinical performance of a new bioactive cement as a luting cement for cast high-gold alloy and noble metal porcelain-fused-to-metal restorations. This clinical study was conducted to determine the multiyear clinical performance of this new bioactive dental cement (CM Crown & Bridge) for permanent cementation. A total of 38 crowns and bridges were cemented in 17 patients. Thirty-one of the abutment teeth were vital and seven nonvital. Six (6) restorations were bridges with a total of 14 abutment teeth (12 vital/2 nonvital). One fixed splint comprising two abutment teeth was also included. Preparation parameters were recorded, as well as cement characteristics such as working-time, setting-time, seating characteristics, and ease of cement removal. Baseline data were recorded for the handling of the cement, gingival inflammation, and precementation sensitivity. Postcementation parameters included postcementation sensitivity, gingival tissue reaction, marginal integrity, and discoloration. All patients were seen for recall examinations at 30 days and 6 months.23 Fifteen of 17 subjects and 13 of 17 patients were also available for subsequent comprehensive 1-24 and 2-year recall examination,25 and 13 patients were available for a 3-year recall examination.26 Two-year recall data yielded no loss of retention, no secondary caries, no marginal discolorations, and no subjective sensitivity. All restorations rated “alpha” for marginal integrity at the 2-year recall.25 Restorations available for the 3-year recall examination included 14 single-unit full-coverage crown restorations, four three-unit bridges comprising eight abutments, and one two-unit splint. Three-year recall data yielded no loss of retention, no secondary caries, no marginal discolorations, and no subjective sensitivity. All restorations rated excellent for marginal integrity. Average visual analog scale scores for tooth sensitivity decreased from 7.63 mm at baseline to 0.44 mm at 6-month recall, 0.20 mm at 1-year recall, 0.00 mm at 2- and 3-year recall. Average gingival index scores for gingival inflammation decreased from 0.56 at baseline to 0.11 at 6-month recall, 0.16 at 1-year recall, 0.21 at 2-year recall, and 0.07 at 3-year recall. After

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periodic recalls up to 3 years, CM Crown & Bridge thus far has performed quite favorably as a luting agent for permanent cementation of permanent restorations.26 At the time of reporting the 3-year recall data, additional in-vitro crown-coping retention data were presented using CM and crown-copings utilizing various all-ceramic crown and bridge materials. Mean laboratory retentive forces measured for CM Crown & Bridge were comparable with other currently available luting agents for both metal and additionally all-ceramic indirect restorative materials, specially all-zirconia and lithium disillicate.26 Figure 1 depicts a lithium disillicate e.Max crown (Ivoclar Vivadent, AG, Bendererstrasse 2, 9494 Schaan, Principality of Liechtenstein) cemented on a mandibular left second premolar with a calcium aluminate/glass ionomer luting cement (CM Crown & Bridge) at 6 months postcementation. An excellent gingival soft-tissue gingival response can be noted in this digital photograph.

BIOACTIVITY AND INTERACTIONS WITH DENTIN AND THE PULP The preceding review has provided a broad overview of the major calcium silicate- and calcium aluminate-based dental materials that originated within

FIGURE 1. Lithium Disillicate e.Max Crown (Ivoclar Vivadent) cemented on a mandibular left second premolar with a calcium aluminate/glass ionomer luting cement (Ceramir Crown & Bridge, Doxa Dental AB) at 6 months postcementation.


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the field of endodontics and have increasingly expanded into the area of other, non-stress-bearing indications in restorative dentistry. This review will now conclude with some more recent research findings concerning the property of bioactivity, and the interaction of these bioactive materials with dentin and pulpal tissue, which have particular clinical significance in the areas of adhesive and restorative dentistry. In order to better clarify the form of bioactivity specifically associated with these calcium-based dental materials, this author suggests the use of the term “bioactive CBCs” (BCBCs) to differentiate this type of material, specifically one displaying apatite-forming bioactivity, from phenomena associated with other device or drug actions. That said, an important question concerning the bioactivity of BCBCs is how this phenomenon impacts the interaction of these materials with both enamel and dentin. MTA and Portland cement, in the presence of PBS, promote a biomineralization process that leads to the formation of an interfacial layer with tag-like structures at the cement-dentin interface.27 BCBCs, such as MTA or Portland cement, also appear to enhance their adhesion to dentin through their bioactivity. This increased adhesion to dentin was demonstrated by increased push-out strength of these cements when inserted into sectioned root segments and after contact with PBS for 72 hours, particularly the MTA groups.28 More in-depth analytical assessment of these BCBCs with dentin has also been reported. The interfacial properties of the tricalcium silicate-based restorative material (Biodentine, Septodont, St Maure des Foss′es, France) and a GIC with dentin were studied by a combination of advanced analytical techniques such as confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM), micro-Raman spectroscopy, and two-photon autofluorescence and second-harmonic generation imaging.29 Results of this study indicated the formation of tag-like structures alongside an interfacial layer called the “mineral infiltration zone,” where the alkaline caustic effect of the CSC’s hydration products degrades the collagenous component of the interfacial dentin. This degradation leads to the formation of a porous structure that


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facilitates the permeation of high concentrations of Ca(2+), OH(−), and CO(3) (2−) ions, leading to increased mineralization in this region. Comparison of the dentin-restorative interfaces shows that there is a dentin-mineral infiltration with the Biodentine, whereas polyacrylic and tartaric acids, and their salts characterize the penetration of the GIC. A new type of interfacial interaction, “the mineral infiltration zone,” was suggested by these investigators for these calcium-silicate-based cements.

the bonding agents containing the bioactive microfillers tested in this study showed stable bond strengths at 6 months of storage, an evident reduction of nanoleakage, and mineral deposition after SBS storage. A second study employed additional modifications to these bioactive microfillers also yield similar favorable results.32 Resin bonding systems containing specifically tailored Portland cement microfillers may promote a therapeutic mineral deposition within the hybrid layer and increase the durability of the resin-dentin bond.

As was noted earlier in this review, degradation of denuded collagen within adhesive resin-infiltrated dentin is a pertinent problem in dentin bonding. Utilizing a remineralization medium consists of a Portland cement/simulated body fluid (SBF) that includes polyacrylic acid and polyvinylphosphonic acid biomimetic analogs for amorphous calcium phosphate dimension regulation and collagen targeting; this research report describes the remineralization of incompletely infiltrated resin-dentin interfaces created by etch-and-rinse adhesives.30 The objective of this study was to remineralize resin-free, acid-etched dentin, with evidence of intrafibrillar and interfibrillar remineralization. Using this concept that the authors termed “biomimetic remineralization,” both interfibrillar and intrafibrillar apatites became readily discernible within the hybrid layers after 2 to 4 months. In addition, intraresin apatite clusters were deposited within the porosities of the adhesive resin matrices. Thus, the use of BCBCs or their derivatives, as part of a “biomimetic remineralization” scheme, may provide an alternative strategy to extend the longevity of resin-dentin bonding.

The effect of smear layer removal on the push-out bond strength between radicular dentin and three CSCs in comparison with gutta percha and sealer has recently been examined.33 Two major groups: (1) smear layer preserved, and (2) smear layer removed using irrigation with 17% ethylenediaminetetraacetic acid were examined. Roots within each major group were further divided into four subgroups according to the obturation material used: (1) ProRoot MTA, (2) Biodentine, (3) Harvard MTA, and (4) gutta percha and AH-plus sealer (Dentsply DeTrey, Konstanza, Germany). Obturated roots were stored in synthetic tissue fluid for 7 days to allow maximum setting of the root filling materials. Three 2-mm-thick slices were obtained from each root at different section levels (coronal, middle, apical). The canal diameters and slice thickness were measured, and the adhesion surface area for each slice was calculated. Push-out bond strength test was carried out using a universal testing machine. The bond failure mode was assessed under an optical microscope at 40×. The mean push-out bond strength in groups 1A, 2A, and 3A were 7.54 (±1.11), 7.64 (±1.08), and 8.79 (±1.55) MPa, respectively, whereas those for groups 1B, 2B, and 3B were 6.58 (±1.13), 6.47 (±1.08), 7.71 (±1.81) MPa, respectively. In the gutta percha and sealer groups, the push-out bond strength means were 1.98 (±0.48) and 2.09 (±0.51) MPa in the preserved and removed smear layer groups, respectively. The push-out strength values were significantly reduced when the smear layer was removed in the CSC groups (p < 0.05), whereas no significant difference was detected in the gutta percha and sealer groups. Based on the conditions of this ex-vivo study, it was concluded that smear layer removal is detrimental to the bond strength between CSCs and dentin.

This concept of hybrid-zone dentin remineralization using BCBCs (or their components) has been extended most recently to novel experimental formulations for dentin bonding agents.31,32 One study aimed at evaluating the therapeutic bioactive effects on the bond strength of three experimental bonding agents containing modified Portland cement-based microfillers applied to acid-etched dentin and submitted to aging in SBF solution (SBS). The analysis of the material-dentin interface was utilized CLSM and SEM morphological analysis.31 All the resin-dentin interfaces created using

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Several investigators have attempted to capture the in-vivo tooth/material ultramorphology of BCBC materials. The aim of one in-vivo study was to evaluate the interfacial marginal adaptation of a CAC, DD, and to compare it intraindividually with an RC, tetric ceram/syntac single-component (TC/SS), in Class II cavities.34 Sixteen Class II box-shaped, enamel-bordered cavities were prepared in eight premolars scheduled to be extracted after 1 month of service for orthodontic reasons. The interfacial marginal adaptation (internal surfaces) of the restorations was evaluated by a quantitative SEM analysis using a replica method. DD showed a statistically significant, lower degree of gap-free adaptation to enamel compared with TC/SS: 84% versus 93%. To dentin, DD showed a significantly better adaptation than TC/SS: 72% versus 49%. A high frequency of enamel fractures perpendicular to the margins was observed for the DD restorations, which may be explained by an expansion of the calcium-aluminate cement. It can be concluded that DD showed a better adaptation to dentin, whereas TC/SS showed a better adaptation to enamel. Another research paper investigated the interface formed in vivo between the calcium aluminate-based dental filling material (DD) and teeth.35 Class 1 occlusal fillings were made in wisdom teeth (3rd molars) and extracted after up to 4 weeks. Polished cross-sections of the teeth were studied with SEM, focused ion beam microscopy, and transmission electron microscopy. In order to analyze the distribution of elements at the interface elemental mapping was performed using scanning transmission electron microscopy and energy-dispersive X-ray spectroscopy. The results showed that a tight bond forms between the filling material and tooth, and no gap could be found even at high magnification. A 100 to 200 nm wide zone with an increase in oxygen was detected in the enamel next to the filling. The zone was denser than the rest of the enamel. Elemental mapping indicated an increase of silicon and a decrease of Ca at the interface. Dark field imaging and EDX mapping also showed that the calcium aluminate system formed apatite in situ during hardening through precipitation. Both of these investigations demonstrate the ability of a bioactive calcium aluminate filling material to form an intimate interface between both enamel and dentin tooth structure in vivo.


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While the vast majority of in-vitro studies utilize an SBF, such as PBS, however, only a limited amount of research has been devoted to formation of HA in contact with actual biological fluids which contain inorganic phosphate sources. A recent research publication has documented the uptake of inorganic phosphate and the formation of apatite-like calcium phosphate on the surface of the calcium aluminate/glass ionomer luting agent (CM) in the presence of human saliva.36 The objective of this investigation was to study the surface reactions occurring in human salvia on a novel dental cement. CM Crown & Bridge, a bioceramic luting agent that has been discussed earlier in this review, was evaluated by immersing discs made from the cement in human saliva and PBS for 7 days, after which they were dried and analyzed. The analytical methods used in order to verify HA formation on the surface were grazing incidence X-ray diffraction, SEM, and X-ray photoelectron spectroscopy. All results showed that HA was formed on the surfaces of samples stored in saliva as well as on samples stored in PBS. The authors speculate about the possibility of a dental luting cement able to promote natural formation of HA at the tooth interface in order to increases the stability and durability of the system and could help prevent secondary caries. The adhesive shear bond strength of the calcium aluminate/glass ionomer luting agent, CM, to enamel, dentin, and various restorative materials, has been documented both by the manufacturer,37 Doxa Dental AB, and also an independent testing laboratory (The Dental Advisor).38 The manufacturer’s bond strength data (without pretreatment) was 11 MPa to dentin, 8.4 MPa to enamel, 10.2 MPa to gold, 7.5 MPa to aluminum oxide ceramic, and 8.2 MPa to zirconium oxide.37 The independent testing laboratories’ bond strength data (without pretreatment) was 8.6 MPa to superficial dentin, 16 MPa to gold alloy, 10.4 MPa to Ivoclar Porcelain System e.max ZirCAD ceramic, and 12.0 MPa to BruxZir zirconium oxide.38 Again, the evidence of adhesive strength to tooth structure and dental material substrates suggests the adhesive potential of both the calcium silicate- and calcium aluminate-based BCBC materials.


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Pulpal biocompatibility is a critical necessity for liners, bases, direct filling materials, and most importantly luting cements. Although evidence-based literature concerning the pulpal response to each of the bioactive materials and chemistries has been previously discussed in this review, some recent research reports have now provided even stronger guidance regarding the use of these bioactive materials in vital pulp therapies such as direct and indirect pulp capping. The recent availability of human clinical and pulp histology has provided a clearer picture on this topic. With regard to a comparison of the direct pulp capping performance of MTA versus calcium hydroxide Ca[OH]2, one research study was conducted on 90 intact first and second premolars of human maxillary and mandibular teeth.39 The teeth were randomly assigned into three groups of 30 each. Under local anesthesia, teeth were exposed and capped either with gray mineral trioxide aggregate, white mineral trioxide, or Dycal. After 30, 60, and 90 days, 10 teeth of each group were extracted and prepared for histological observation. The calcified bridge in teeth that were capped with GMTA was significantly thicker than that measured in the Dycal pulp capped teeth at 30 and 60 days (p = 0.015 and p = 0.002, respectively), whereas WMTA showed significantly thicker calcified bridge than Dycal at 90 days (p = 0.02). In addition, GMTA specimens showed significantly less inflammation compared with Dycal samples at 90-day interval (p = 0.019). No significant difference was found between GMTA and WMTA in terms of calcified bridge thickness and pulp inflammatory response to the capping materials (p > 0.05). Based on the result of this study, the authors state that both types of MTA can be suggested as the materials of choice for direct pulp capping procedure instead of Dycal calcium hydroxide cement. To assess the effectiveness of MTA used as an indirect pulp-capping material in human molar and premolar teeth, another human clinical study was conducted.40 Sixty teeth underwent an indirect pulp-capping procedure with either MTA or calcium hydroxide cement (Dycal). Calcium hydroxide was compared with MTA, and the thickness of the newly formed dentine

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was measured at regular time intervals. The follow up was at 3 and 6 months, and dentin formation was monitored by radiological measurements on digitized images using Mesurim Pro® software. At 3 months, the clinical success rates of MTA and calcium hydroxide were 93% and 73%, respectively (p = 0.02). At 6 months, the success rate was 89.6% with MTA and remained steady at 73% with calcium hydroxide (p = 0.63). The mean initial residual dentine thickness was 0.23 mm and increased by 0.121 mm with MTA and by 0.136 mm with calcium hydroxide at 3 months. At 6 months, there was an increase of 0.235 mm with MTA and of 0.221 mm with calcium hydroxide. A higher success rate was observed in the MTA group relative to the Dycal group after 3 months, which was statistically significant. After 6 months, no statistically significant difference was found in the dentine thickness between the two groups. The authors concluded that additional histological investigations are needed to corroborate these findings, but that these finding suggest a superior performance of MTA in indirect pulp capping. A recently published, large, randomized, controlled, clinical trial has provided pivotal information in the debate regarding use of a calcium silicate-based MTA material versus the traditional use of calcium hydroxide (CaOH) in direct pulp capping.41 This practice-based, randomized, clinical trial evaluated and compared the success of direct pulp capping in permanent teeth with MTA or CaOH. Thirty-five practices in Northwest Practice-Based Research Collaborative in Evidence-Based Dentistry were randomized to perform direct pulp caps with either CaOH (16 practices) or MTA (19 practices). Three hundred seventy-six individuals received a direct pulp cap with CaOH (N = 181) or MTA (N = 195). These individuals were followed for up to 2 years at regular recall appointments or as dictated by tooth symptoms. The primary outcomes were the need for extraction or root canal therapy. Teeth were also evaluated for pulp vitality, and radiographs were taken at the dentist’s discretion. The probability of failure at 24 months was 31.5% for CaOH versus 19.7% for MTA (permutation log-rank test, p = 0.046). This large randomized clinical trial appears to have provided confirmatory evidence for a superior performance with MTA as a direct

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pulp-capping agent as compared with CaOH when evaluated in a practice-based research network for up to 2 years. A concluding footnote on this topic of BCBCs and direct pulp capping comes with a recent human clinical study involving Biodentine and MTA.42 The purpose of the present study was to compare the response of the pulp-dentin complex in human teeth after direct capping with this new tricalcium silicate-based cement with that of MTA. Pulps in 28 caries-free maxillary and mandibular permanent intact human molars scheduled for extraction for orthodontic reasons were mechanically exposed and assigned to one of two experimental groups, Biodentine or MTA, and one control group. Assay of periapical response and clinical examination were performed. After 6 weeks, the teeth were extracted, stained with hematoxylin-eosin, and categorized using a histological scoring system. The majority of specimens showed complete dentinal bridge formation and an absence of inflammatory pulp response. Layers of well-arranged odontoblast and odontoblast-like cells were found to form tubular dentin under the osteodentin. Statistical analysis showed no significant differences between the Biodentine and MTA experimental groups during the observation period. Within the limitations of this study, Biodentine had a similar efficacy in the clinical setting and may be considered an interesting alternative to MTA in pulp-capping treatment during vital pulp therapy.

4. Recent animal and human pulpal histology suggest that a tricalcium silicate bioactive material, Biodentine, is equivalent to MTA in direct pulp capping. 5. Clinical indications for use of bioactive cements have expanded further into uses such as lining and bases (Biodentine) and luting cements for crown and bridge applications with the introduction and laboratory/clinical validation of a calcium aluminate/glass ionomer luting cement (CM Crown & Bridge). 6. Strength and physical properties of BCBCs have increased gradually and are now approaching the CS range of conventional, water-based GICs.

DISCLOSURE AND ACKNOWLEDGEMENTS The author’s institution has received research funding from Doxa Dental AB, Uppsala, Sweden, the company that markets CM Crown & Bridge Cement. The author also holds common stock in the company Dentsply International, the company that markets ProRoot MTA.

REFERENCES 1. 2.

CONCLUSIONS 1. MTA (gray MTA and white MTA) have demonstrated that efficacy and effectiveness are a variety of clinical indications, including pulp cap, pulpotomy, root ending filling, repair of root resorption, repair of root perforations, and apexification. 2. Additional materials with compositions similar to MTA have been introduced, including MTA Angelus, Bioaggregate, iRoot BP, and BP Plus. 3. In the area of vital pulp therapy, MTA appears to be clearly equivalent and possibly superior to classical CaOH in terms of direct pulp capping.


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Lööf J, Engqvist H, Gomez-Ortega G, et al. Mechanical property aspects of a biomineral based dental restorative system. Key Eng Mater 2005;284–286: 741–4. Sunnegårdh-Grönberg K, Peutzfeldt A, van Dijken JW. Hardness and in vitro wear of a novel ceramic restorative cement. Eur J Oral Sci 2002;110(2):175–8. Sunnegårdh-Grönberg K, van Dijken JW. Surface roughness of a novel “ceramic restorative cement” after treatment with different polishing techniques in vitro. Clin Oral Investig 2003;7(1):27–31. Sunnegårdh-Grönberg K, Peutzfeldt A, van Dijken JW. Flexural strength and modulus of a novel ceramic restorative cement intended for posterior restorations as determined by a three-point bending test. Acta Odontol Scand 2003;61(2):87–92. Geirsson J, Bayne SC, Swift EJ Jr, Thompson JY. Mechanical property characterization of a novel directly-placed ceramic restorative material. Am J Dent 2004;17(6):417–21. Franz A, Konradsson K, König F, et al. Cytotoxicity of a calcium aluminate cement in comparison with other dental cements and resin-based materials. Acta Odontol Scand 2006;64(1):1–8. van Dijken JW, Sunnegårdh-Grönberg K. A two-year clinical evaluation of a new calcium aluminate cement in Class II cavities. Acta Odontol Scand 2003;61(4): 235–40. Van Dijken JW, Sunnegårdh-Grönberg K. A three year follow-up of posterior Doxadent restorations. Swed Dent J 2005;29(2):45–51. Frankenberger R, Garcia-Godoy F, Krämer N. Clinical performance of viscous glass ionomer cement in posterior cavities over two years. Int J Dent 2009;2009:781462. doi: 10.1155/2009/781462. Doxa Dental AB. 510(k) Summary, XeraCem TM, K081405, August 21, 2008. Doxa Dental AB. 510(k) Summary, Ceramir® Crown & Bridge, K100510, March 25, 2010. Lööf J, Svahn F, Jarmar T, et al. A comparative study of the bioactivity of three materials for dental applications. Dent Mater 2008;24(5):653–9. Jefferies S, Lööf J, Pameijer CH, et al. Physical Properties of XeraCem™. IADR/CADR 86th General Session (July 3–5, 2008). J Dent Res 2008;87(Special Iss B). abstract number 3100. Available at: http://www.dentalresearch .org. (accessed August 20, 2013). Pameijer CH, Jefferies S, Lööf J, Heransson L. Microleakage Evaluation of XeraCem™ in Cemented Crowns IADR/CADR 86th General Session (July 3–5, 2008). J Dent Res 2008;87(Special Iss B): abstract number 3098. Available at: http://www.dentalresearch .org.

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20. Pameijer CH, Zmener O, Alvarez Serrano S, Garcia-Godoy F. Sealing properties of a calcium aluminate luting agent. Am J Dent 2010;23(2):121–4. 21. Pameijer CH, Tena E, Jefferies S, et al. In vitro and in vivo biocompatibility tests of XeraCem™, IADR/CADR 86th General Session (July 3–5, 2008). J Dent Res 2008;87(Special Iss B): abstract number 3097. Available at: http://www.dentalresearch.org. 22. Pameijer CH, Jefferies S, Lööf J, Heransson L. A comparative crown retention tests using XeraCem™, IADR/CADR 86th General Session (July 3–5, 2008). J Dent Res 2008;87(Special Iss B): abstract number 3099. Available at: http://www.dentalresearch.org. 23. Jefferies SR, Pameijer CH, Lööf J, et al. Clinical performance with a bioactive dental luting cement—a prospective clinical pilot study. J Clin Dent 2009;20(7):231–7. 24. Jefferies SR, Pameijer CH, Appleby D, et al. One year clinical performance and post-operative sensitivity of a bioactive dental luting cement—a prospective clinical study. Swed Dent J 2009;33(4):193–9. 25. Jefferies SR, Pameijer CH, Appleby DC, et al. Prospective observation of a new bioactive luting cement: 2-year follow-up. J Prosthodont 2012;21:33–41. 26. Jefferies SR, Pameijer CH, Appleby DC. Boston D, Lööf J. A bioactive dental luting cement—its retentive properties and 3-year clinical findings. Compend Contin Educ Dent 2013;34(Spec No 1):2–9. 27. Reyes-Carmona JF, Felippe MS, Felippe WT. Biomineralization ability and interaction of mineral trioxide aggregate and white Portland cement with dentin in a phosphate-containing fluid. J Endod 2009;35:731–6. 28. Reyes-Carmona JF, Felippe MS, Felippe WT. The biomineralization ability of mineral trioxide aggregate and Portland cement on dentin enhances the push-out strength. J Endod 2010;36(2):286–91. 29. Atmeh AR, Chong EZ, Richard G, et al. Dentin-cement interfacial interaction: calcium silicates and polyalkenoates. J Dent Res 2012;91(5):454–9. 30. Tay FR, Pashley DH. Biomimetic remineralization of resin-bonded acid-etched dentin. J Dent Res 2009;88(8):719–24. 31. Profeta AC, Mannocci F, Foxton R, et al. Experimental etch-and-rinse adhesives doped with bioactive calcium silicate-based micro-fillers to generate therapeutic resin-dentin interfaces. Dent Mater 2013;29(7):729–41. 32. Sauro S, Osorio R, Osorio E, et al. Novel light-curable materials containing experimental bioactive microfillers remineralise mineral-depleted bonded-dentine interfaces, J Biomater Sci Polym Ed 2013;24(8):940–56. 33. El-Ma’aita AM, Qualtrough AJ, Watts DC. The effect of smear layer on the push-out bond strength of root canal calcium silicate cements. Dent Mater 2013;29(7):797–803.

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34. Sunnegårdh-Grönberg K, van Dijken JW, Lindberg A, Hörstedt P. Interfacial adaptation of a calcium aluminate cement used in class II cavities, in vivo. Clin Oral Investig 2004;8(2):75–80. 35. Engqvist H, Schultz-Walz JE, Lööf J, et al. Chemical and biological integration of a mouldable bioactive ceramic material capable of forming apatite in vivo in teeth. Biomaterials 2004;25(14):2781–7. 36. Engstrand J, Unosson E, Engqvist H. Hydroxyapatite formation on a novel dental cement in human saliva. ISRN Dent 2012;2012:624056. doi: 10.5402/2012/624056. 37. Facts About Ceramir® Crown & Bridge, Page 6. 2011. Available at: http://www.ceramirus.com/wp-content/ uploads/Ceramir_TechBro.pdf (accessed August 20, 2013). 38. Yapp R, Lööf J, Powers JM. Mechanical properties of a bioceramic luting cement. The Dental Advisor, 2012 Research Report. Number 45, March 2012. 39. Eskandarizadeh A, Shahpasandzadeh MH, Shahpasandzadeh M, et al. A comparative study on dental pulp response to calcium hydroxide, white and grey


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mineral trioxide aggregate as pulp capping agents. J Conserv Dent 2011;14(4):351–5. 40. Leye Benoist F, Gaye Ndiaye F, Kane AW, et al. Evaluation of mineral trioxide aggregate (MTA) versus calcium hydroxide cement (Dycal(®))in the formation of a dentine bridge: a randomised controlled trial. Int Dent J 2012;62(1):33–9. 41. Hilton TJ, Ferracane JL, Mancl L. for Northwest Practice-based Research Collaborative in Evidence-based Dentistry (NWP). Comparison of CaOH with MTA for direct pulp capping: a PBRN randomized clinical trial. J Dent Res 2013;92(7 Suppl):S16–22. 42. Nowicka A, Lipski M, Parafiniuk M, et al. Response of human dental pulp capped with biodentine and mineral trioxide aggregate. J Endod 2013;39(6):743–7.

Reprint requests: Steven Jefferies, MS, DDS, PhD, Kornberg School of Dentistry, Temple University, Restorative Dentistry, 3223 N. Broad Street, Philadelphia, PA 19140, USA; Tel.: 215-707-3751; Fax: 215-707-2840; email: [email protected]


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Bioactive and biomimetic restorative materials: a comprehensive review. Part I.

Esthetic smile rehabilitation of anterior teeth by treatment with biomimetic restorative materials: a case report.

The adverse effects of dental restorative materials--a review.

Chronic pancreatitis, a comprehensive review and update. Part II: Diagnosis, complications, and management.

Finishing composite restorative materials.

Long-Term Surgical Complications in the Oral Cancer Patient: a Comprehensive Review. Part II.

CAM restorative materials: part I--procedures and results.

Biomimetic and nanostructured hybrid bioactive glass.

Dental materials: 1974 literature review. Part I.

Dental materials: 1976 literature review. Part I.

Forced eruption: part II. A method of treating nonrestorable teeth--Periodontal and restorative considerations.

Microleakage of intermediate restorative materials.

Innovative materials processing strategies: a biomimetic approach.

Biological and biomimetic materials and surfaces.

Thermal cycling for restorative materials: does a standardized protocol exist in laboratory testing? A literature review.

Results of the initial administrations of the NBME comprehensive Part I and Part II examinations.

What's in those wonder(ful) restorative materials?

Creep behavior of glass-ionomer restorative materials.

Microleakage of five temporary endodontic restorative materials.

Endometrial cancer: a review and current management strategies: part II.

Color stability of temporary restorative materials.

Ultrasonic evaluation of anterior restorative materials.

Future needs for dental restorative materials.

Clinical Evaluation of Restorative Materials in Primary Teeth Class II Lesions.