The use of organic compounds of phosphorus in clinical dentistry

Biomoteriok SOl42-9612(96)00012-9 PII ELSEVIER zyxwvutsrqponmlkjihgfedcbaZY 17 (1996) 2023-2030 Elsevier Science Limited Printed in Great Britain. All rights reserved 0142.9612/96/$15.00 0 1996 REVIEW zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA The use of organic compounds of phosphoru .s in clin .ical dentistry John W. Nicholson* and Gurdial Singh+ ‘Dental Biomaterials Department, London SE5 9RW, UK; +School 3BA. UK Organic These compounds include ingredients bonding of phosphorus dentine bonding in anticaries coverage for this application. have been developed agents, compound functional of recent restorative The review A characteristic clinically Keywords: Phosphorus, organic feature useful at preparing that this remains dental compounds, Received 13 June 1995; accepted 28 November materials. clinical bonding applications agents is the good and cements, field of chemistry Science dentistry. that has been organophosphorus 1996 Elsevier Hill, TSI such as active the progress improved a promising 0 in clinical agents, of all of these highlights organophosphorus work aimed of applications and therapeutic to the tooth. This review concludes for improved, for a range materials and durable synthetic the search College School of Medicine and Dentistry, Denmark University of Teeside, Middlesbrough, C/eve/and, and Technology, mouthwashes. of the phosphorus made to date in preparing includes Dental Institute, King’s of Science and molecules to explore in Limited dentistry 1995 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIH organophosphorus compounds have been used in clinical dentistry only rarely, although some of the more recently developed dental materials have employed compounds containing a direct C-P bond. Phosphorus is also capable of forming organic compounds via oxygen, i.e. in compounds containing C-O-P groupings. These have been much more widely studied for clinical use, for example as dentine bonding agents or as dental cements, and these compounds take up the bulk of the current review. This type of organic compound of phosphorus includes simple monofunctional molecules, polyfunctional molecules, e.g. phytic acid, and polymers with a multitude of phosphorus-containing functional groups, e.g. poly(vinylphosphonic acid). In each of these substances, the phosphorus moiety provides a number of features, for example polarity, chelation or acidity, which in turn confers the necessary chemical reactivity and durability to form functional biomaterials. The sections of this review which follow cover the topics of dentine bonding agents, dental cements and recent synthetic advances in the subject of organic compounds of phosphorus in clinical dentistry. Phosphorus is an element, atomic number 15. It is in Group V of the Periodic Table, as reflected in the fact that it forms compounds in which it shows valencies of 3 and 5. In terms of overall abundance, it is the eleventh most common element in the earth’s crus?. Phosphorus is a highly reactive element, and hence occurs only in combined form in nature, most commonly as phosphates of various metalsl. It also occurs in a number of physiologically important organic compounds, and is thus essential to plant and animal life. It was first obtained in the free state by Brand in 1669’ and independently by the same procedure (distilling evaporated urine) by Kunckel in 16763. Phosphorus is capable of forming true organophosphorus compounds, i.e. those containing a C-P bond. Such bonds are formed from overlapping s-orbitals, consequently are sigma bonds, and in general are stable with respect to thermal decomposition and hydrolysis at room temperature. Compounds of this type have been used as insecticides and have also been prepared for use as nerve gases in chemical warfare. Typically they have two effects, inhibition of cholinesterase following transmission of a nerve impulse, and delayed neurotherapy4. The latter manifests itself as the dying back of the nerves with degradation of the central axon followed by loss of the myelin sheath. Depending on which site in the body is affected, the resulting symptoms may include twitching, convulsions and respiratory failure. True DENTINE BONDING AGENTS The aesthetic filling materials most widely used in modern dentistry are the so-called composite resins5. There are a variety of materials within this class, and Correspondence to Dr J.W. Nicholson. 2023 Biomaterials 1996. Vol. 17 No. 2.1 2024 Organic compounds they are generally based on bisGMA, as patented by Bowen in January 1959. This substance is the reaction product obtained from bisphenol A and glycidyl and cures by an addition process methacrylate, involving the terminal methacrylate groups6. The is highly viscous and practical bis GMA liquid formulations are produced by adding liquid diluents comprising monomers of lower molar mass. These include diethyleneand triethylene-dimethacrylates. Being methacrylate terminated, these molecules react in much the same way as bisGMA at the cure stage. As an alternative, urethane dimethacrylate has been developed as a choice of principal monomer for dental composite resins7. For clinical use, composite resins are supplied as either one- or two-paste systems. The one-paste system is cured by exposure to visible light, typically blue light at 470nm. Initiation in such formulations is effected by an a-diketone, such as camphorquinone, with an amine reducing agent. The two-paste systems, by contrast, undergo self-cure as a result of the interaction between typically benzoyl peroxide in one paste with a tertiary amine accelerator in the other. This yields the free radicals required to effect polymerization of the monomer moleculess. A major disadvantage with composite resins is their lack of adhesion to dentine” . Unless appropriate steps are taken, this may result in microleakage, leading to postoperative sensitivity, and eventually to complete loss of the restoration. Bond failure in these systems stems from lack of wetting of the tooth surface owing to their hydrophobic character. Failure is made worse by the high polymerization shrinkage of the matrixlo, which may also cause cuspal distortion in the tooth” . There may be long-term hydrolytic breakdown at the filler-matrix or tooth interface, resulting in degradation and wear of the restoration. To overcome the problem of lack of adhesion, two main approaches have been explored, namely mechanical retention and chemical modification. The latter approach uses the so-called dentine bonding agents. Mechanical retention is mainly used for the enamel and is based on the work of Buonocore. He developed the acid-etch technique for increasing the roughness of the enamel surface using moderately concentrated solutions of phosphoric acid, typically 37%“ . This approach, however, is not suitable for bonding to dental lesions’“ . For this reason, the bonding agents that have been developed have been aimed specifically at improving the bond to dentine14. A large number of systems have been described, and the subject is evolving rapidly15. What follows is a brief description of those bonding agents that are based on compounds of phosphorus. Adhesion to dentine presents different problems from adhesion to enamel. The latter substance has a higher inorganic content, and is not connected to the pulp, the vital and soft inner section of the toothI’. Unless care is taken, bonding to dentine can cause adverse pulpal reaction17, and possibly enlargement of the tubules running through the structure of the dentine” ,‘“ . Dentine represents a dynamic substrate in which physiological activity causes continual changes” . In addition, cavity preparation typically leads to the Biomatcrials of phosphorus in clinical dentistry: J.W. Nicholson zyxwvutsrqponmlkjihgfedc and G. Singh development of a layer of disordered dentine known as the smear layer. Generally, clinicians recommend that this smear layer be removed prior to bonding in order to leave a clean surfacezl,“ . This may be readily accomplished, for example by washing with aqueous solutions of either citric acid or ethylenediaminetetraacetate, EDTA. However, in the late 1980s Douglas argued that the smear layer is not simply debris, but deranged dentine that retains its attachment to the underlying structurally sound dentinez3. As a result, for a while clinical opinion changed towards the view that the smear layer was an assetz4, and that this was the surface to which bonding should be made. However, studies such as those of Davidson et al.” have shown that those bonding systems that left the smear layer intact were more prone to premature failure than systems which removed it, and opinion is shifting back to the view that the smear layer should be removed to develop maximum bond strength and durability. Modern dentine bonding agents are assumed to act, partly at least, by micromechanical attachment. A small proportion of the bonding agent is able to follow into dentinal tubules, and to harden to form a tag which holds the layer in placez6. At the same time, a resin-dentine hybrid zone is formed” , which also reinforces the bonding zonez7. This hybrid zone has been shown to be typically some 2-5 pm wide, and to form through the infiltration of liquid bonding agent into tubules with widened orificesz8. The formation of such a hybrid layer has been shown to be important in creating a clinically durable bond between the composite resin and the toothzg. A number of organic compounds of phosphorus have been considered for use as bonding agents. One interesting example was the very first dentine bonding agent of all, developed by Hagger in the early 1950s. This was based on glycerophosphoric acid dimethacrylate (I)3o and sold under the name of Sevriton Cavity Seal. Like many molecules employed in dentine bonding agents, glycerophosphoric acid dimethacrylate has a non-polar tail and a strongly polar head. It was thought to bond to the calcium of the dentine via the phosphate groups3’, though this was never demonstrated conclusively. Whatever its method of action, it did not prove very effective, since it was hydrolytically unstable and bond failures occurred during clinical testing6. A few years later, another phosphate-based material was reported, this time by Buonocore et a1.32. However, the bond strengths obtainable for this material were low, typically of the order of 2-3 MPa, compared with bond strengths to acid-etched enamel of 15-20 MPa. A number of other phosphorus-containing bonding agents have been developed in the years since these early reports, and materials generally have much improved properties. An organic derivative of phosphoric acid, 2-methacryloxyethyl phenyl phosphoric acid (II), has been used with some success33. Like a number of other bonding agents, this material, available under the name ‘Clearfil’, is essentially a methacrylate derivative with both a hydrophilic and a hydrophobic functional group. There is considerable doubt that it undergoes any 1996, Vol. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 17 No. 21 Organic compounds of phosphorus in clinical dentistry: J.W. Nicholson leave and G. Singh the smear 2025 layer intact and was used in two Chemical zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA structures: layers. Polymerization occurred once the composite ii zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 0 resin was placed over the top of the system, and gave 0 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA good bond strengths, i.e. of the order of 8MPa35*36. carrier was also helpful towards bonding since it displaced surface b H zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA bound water, thus assisting efficient dentine wetting. Another organic compound of phosphorus that has been used as the active ingredient for enhanced bonding is the chlorophosphate ester of hydroxyethyl methacrylate (III)37. Bonding seems to be achieved in the same way as for other materials of this type, i.e. with a mixture of micromechanical interlocking and hybrid layer formation, and copolymerization of the organic tail with the composite resin of the main restoration. Among organic phosphorus compounds for dentine bonding, one of the most carefully studied has been 2hydrogen phosphate, methacryloxyethyl phenyl known as phenylP, and its derivatives. These substances were first described for dentine bonding by Yamauchi in 198638, and shown to give good bond strengths. In a subsequent study, phenyl-P was used for bonding resin to bovine enamel, and the resulting interfaces examined by scanning electron microscopy (SEM)3g. It was dissolved at a level of 5% in methyl methacrylate monomer, which was then polymerized. The dentine had been pretreated with an aqueous solution of 10% citric acid/ s% ferric chloride, and the resulting bond strength was 10.5MPa3’. The SEM results showed that the monomers of the bonding and interpenetrated the agent had impregnated demineralized dentine surfaces, a feature made P possible by removal of the smear layer. The study also concluded that the formation of resin tags is not essential for good dentine bonding. The presence of ethanol as catalyst H0- b\ zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Me P = OPO sH2 ANTICARIES AGENTS (W chemical reaction at the dentine surface34, though this was suggested originally33. However, the bonding agent becomes incorporated into the setting composite resin too rapidly to allow much in the way of surface reaction, which is anyway made unlikely by the presence of moisture on the surface. On the contrary, there is evidence that this particular derivative assists the liquid composite resin to penetrate the dentinal tubules, thereby enhancing the development of resin tags to assist micromechanical attachment. An alternative organic derivative of phosphorus used in clinical bonding has involved the halophosphorus ester of bisGMA. This was used in a successful system, known as ‘Scotchbond’ in conjunction with triethylene glycol dimethacrylate diluent and benzoyl peroxide. This system was a two-component one comprising a resin and an ethanol solution. The ethanol solution amine plus sodium aromatic contains tertiary benzenesulphonate. The phosphate esters appear capable of substitution into the hydroxyapatite lattice, and are stabilized against hydrolysis by the sulphonate part of the system. This adhesive was designed to Phosphorus compounds have been employed from time to time as ingredients for mouthwashes. For example, over 20 years ago polyphosphonates were shown to have pronounced anticariogenic activity4’. Topical treatment with solutions of these polymers led to adsorption of the polymer at the tooth surface, which caused a reduction in caries activity. These substances are of low toxicity when ingested41 and they have been proposed as additives for dentifrices, though they still have little or no use for this purpose. An alternative polymer, this time containing phosphonyl fluoride functional groups, is the basis of a patent for a cariostatic mouthwash. The mechanism of action again involves adsorption of the polymer at the tooth surface, this time followed by gradual hydrolysis to provide a local application of fluoride4’. DENTAL CEMENTS The term ‘cement’ is slightly ambiguous, but in general, in dentistry, it is taken to mean the product of an acidbase reaction, formed by reaction of a solid, powdered base with an acidic liquid. The neutralization of the zyxwvuts Biomaterials 1996, Vol. 17 No. 21 Organic 2026 compounds acid by the base leads to the formation of a continuous hydrated salt phase, which forms the matrix of the Like all materials used in the hardened cement43. mouth, such cements must be compatible with the surrounding tooth structure in terms of colour, translucency and texture, and they should be bland and non-toxic. A number of materials fulfil these criteria, including zinc phosphate, zinc polycarboxylate and glass polyalkenoate cements, each of which finds distinctive application in modern clinical dentistry. Experimental dental cements derived from organic compounds of phosphorus have been reported from time to time. For example, Wilson in 1968 reported results from a study of alternatives to orthophosphoric acid as cement-formers with aluminosilicate glasses44. The glasses were of the type formerly employed in dental silicate cements, and they were capable of forming cements with a range of concentrated acid solutions, both organic and inorganic in nature. Among the acids studied was glycerol phosphoric acid, a substance which at quite high powder :liquid ratios gave a cement whose compressive strength at 24 h was a mere 38 MPa (see Table 2). By comparison, in the same study the dental silicate cement, formulated from orthophosphoric acid, was found to have a compressive strength at 24 h of 272 MPa. Modern glass polyalkenoates regularly give values in the region 180-220 MPa45. Another experimental cement of this type was that based on phytic acid (IV), a system studied in detail by Prosser et a1.4” in a paper published three years after the patent application which first described the system47. Phytic acid has the systematic name myo-inositol hexakis(dihydrogen phosphate), and is an abundant constituent of plants4s. It complexes strongly with metal cations, the strength of the complex increasing with cation valency. Most phytic acid complexes with polyvalent cations are insoluble in water, a feature which considerably assists phytic acid as a cement-former. Phytic acid cements set more rapidly than their glass polyalkenoate or dental silicate counterparts; their mechanical properties, though, are similar. Set phytic acid cements are impervious to attack by lactic acid at pH2.7, a unique attribute among acid-base cements. Their compressive strength at 24 h with glass, and other properties, are shown in Table I. One disadvantage of these phytic acid cements is that they do not form an adhesive bond to the tooth. This is a major drawback now that both zinc polycarboxylate Table 1 Properties compounds of cements Acid Glycerol phosphoric acid, 35% in water Powder : liquid ratio Setting time/min Compressive strength, 24 h/MPa Water-leachable material, % mass made from organic Phytic acid, 40% in water 4.0 4.0 3.2 38 2.7 201 3.3 phosphorus 0.88 of phosphorus in clinical dentistry: J.W. Nicholson and G. Singh zyxwvutsrq and glass polyalkenoate cements are available. Phytic acid cements also suffer from poor translucency, and as a result of this combination of less desirable properties have never found application in practical clinical dentistry. A few other cements have been prepared, based on organophosphorus precursors, as highly unusual described in this paper. The most widely studied of those based on cements, however, are these poly(vinylphosphonic acid), PVPA. This cement system has been developed as the phosphorus analogue of glass polyalkenoates, mainly driven by the expectation that such a system should show improved adhesion to the tooth, and possibly exhibit improved There have been a number of translucency. publications covering these materials, but they have not yet been used clinically. Like the polyalkenoate cements, PVPA cements are prepared by reaction of a concentrated aqueous solution of polymer with calcium aluminosilicate glasses4g. Cements have also been made from a variety of metal oxide?‘, including deactivated zinc oxide, to form a cement analogous to the zinc polycarboxylate dental cement51. The polymer itself, PVPA, has been prepared by the free-radical homopolymerization of the acid chloride, vinyl phosphonyl dichloride, using azobisisobutyronitrile as the initiator in a chlorinated solvent5’. The free acid is obtained by hydrolysis of the product. To date the molar masses of the polymer prepared by this route appear modest, considerably less than those of the poly(acrylic acid) used in dental cements4” . The low value of molar mass was assumed, by analogy with the glass polyalkenoates, to be the reason for the low compressive strength of the original system, the highest value of compressive strength obtained being 90 MPa4” . One attempt to overcome this involved the incorporation of potential cross-linkers during the polymerization reaction” “ . The addition of substances such as formaldehyde or buta-1,3-diene diepoxide at this stage was found to lead to significant increases in compressive strength of the set cements at 24 h, values up to 138MPa being measured. These reagents were shown to be involved at the polymerization stage because they made no comparable difference if simply added to the completed polymer prior to cement fabrication. Moreover, there was an increase in molar mass of the polymer product, as demonstrated using viscometry. However, the increase in compressive strength obtainable by this route was not sufficient to render these cements acceptable for modern clinical use54. The key development that has enabled PVPA cements to be made having properties comparable with glass polyalkenoates has been the discovery that minor additions to the PVPA solution of zinc fluoride or zinc phosphate (at a level of approximately 10%) moderates the reaction and enables cements of higher powder to liquid ratio to be mixed. Thus, a cement having a compressive strength of 198MPa and a setting time of 2.75min has been prepared55, properties which comfortably exceed the minimum requirements of the current Standard and which are comparable with those of existing glass polyalkeno- Biomaterials zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 1996, Vol. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 17 No. 21 Organic compounds of phosphorus in clinical dentistry: J.W. Nicholson 2027 zyxwvutsrq and G. Singh ates56. The precise mode of action of these additives is unclear. Recently, a study has been published which has shown that these PVPA-based cements do not exhibit a simple increase in compressive strength with time5’. Such behaviour is typically encountered with glass polyalkenoates based on poly(acrylic acid), but not with all carboxylic acid polymers5e. In the case of the unmodified PVPA cements, compressive strength was found to reach a maximum, then gradually decline up to the end of the six months duration of the study. In contrast, cements prepared from PVPA modified with ZnFz showed no such decline, but gradually increased in strength up to approximately 3 months from the date of preparation, after which the value remained the same. The reason for these differences between the modified and unmodified PVPA are still to be established. In order to form cements with satisfactory handling properties, some alterations in the composition of the glass may be desirable. The original glass polyalkenoate cements employed glasses of greater basicity than those used in the parent dental silicate cements, in order to compensate for the reduced acidity of the polycarboxylic acid compared with phosphoric acid. In the same way, cements prepared from PVPA can employ glasses of lower basicity HO-(=-J-[/ CO,H because of the relatively increased acidity of PVPA compared with poly(acrylic acid). A study along these lines has been conducted5’. It was based on previous studies of Hill and Wilson” which showed that the basicity was controlled by the (WI ratio of alumina to silica in the glass. Hence ideal glasses for PVPA cements were found to be those with synthetic strategies that have led to alternative organic higher alumina : silica ratios than those used routinely derivatives of phosphorus are described, many of in glass polyalkenoate cements. Using such glasses which show promise for clinical application. enabled cements of improved handling characteristics Several monomers containing the phosphonic acid to be prepared, with compressive strengths of 24 h in functional group have been prepared and tested for the region of 200 MPa. use, for example as comonomers capable of aiding The biocompatibility of cements based on PVPA adhesion of the resulting polymer. The vinyl has been studied, and shown to be extremely good phosphonic acid (V) and vinyl benzyl phosphonic acid This study under the conditions employed6’. (VI) monomers gave rise to materials that exhibited employed a range of glass polyalkenoates, and significant adhesion, which proved to be persistent included some experimental cements based on when subjected to immersion in water. Incorporation PVPA. Acute cytotoxicity using contact techniques of these monomers into the acrylic monomer Epoxylite which cultured fibroblast cells was determined olymer that 8760 resulted in the formation of a new before and after extraction of the specimens with hot 6! showed strong adhesion to dental enamel . water. The effect of implantation was also studied, Among the organic compounds of phosphorus that using rods inserted into the femurs of adult hooded have been investigated for their potential as additives rats. The cements based on PVPA showed extremely in adhesive compositions for human hard tissues are good biocompatiblity, with more bone growth in the those which have been proposed for use in artificial direct contact test than any of the other cements joints as well as materials for dental fillings63. For studied, and good osseointegration in the in vitro dental restoratives, there have also been claims that experiments. Extraction with hot water made no adhesion is enhanced by the addition of polymerizable difference to the already excellent biocompatibility phosphoryl monofluoro compounds” 4. However, this of these cements. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA latter claim should be treated with caution, given the potentially highly toxic nature of compounds containing P-F bonds. In general, as we have already SYNTHESIS OF PHOSPHORUS COMPOUNDS seen, organic phosphorus compounds of much safer FOR DENTISTRY composition have been employed65. Analogously, phosphoric or phosphonic acid esters which contain Replacement of the acrylic acid functional group by one or more polymerizable functional groups have polymers that contain the phosphonic acid group has been found to exhibit excellent adhesion and are zyxwvutsr been described in the previous section. In this section, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Biomaterials 1996, Vol. 17 No. 21 Organic compounds 2028 of phosphorus in clinical dentistry: J.W. Nicholson and G. Singh G) zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA OH Me (XII) wide range of monomers that are capable of polymerization and we have incorporated these into cements that are formed with ion-leachable glasses. The early resistant to zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA hydrolysis. Examples of these monomers materials we investigated included thienyl phosphonic are illustrated (VII-XII). acid (XIII) and phenyl ally1 phosphinic acid (XIV), Reaction of glycerol derivatives with phosphorus both of which were mixed with aluminosilicate glass dihalides in thG presence o$ a tertiary amine results in and water. However, in both cases the products were the formation of cyclic phosphonite esters which cements of poor quality. However, the incorporation of undergo polymerization using aluminium trichloride, an adamantane counterion led to a salt (XV) capable of and on hydrolysis yield bisphosphonic acids that are forming a cement with very promising properties” 7, of interest (Scheme)66. including excellent water-stability. To date, however, In our laboratories we have investigated the use of a zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGF these approaches have not led to the complete R f + OH H OH m is X-ClorBr Ma3 6- 2 H,O R’ Scheme Biomaterials 1996, Vol. 17 No. 21 OH R’ R-p: R Organic compounds of phosphorus inclinical dentistry: J.W. Nicholson development of clinical materials. However, they serve to demonstrate the versatility of organophosphorus chemistry and we believe that further work in this area will lead to new materials of greater durability and biocompatibility. 16 CONCLUSIONS ia Organic compounds of phosphorus already have a number of uses in modern dental practice, and it is clear from the chemistry described in this review that they have the potential for even greater effectiveness in clinical applications. With the growing worldwide concern about the safety of amalgam fillings, the use of polymeric restoratives seems likely to grow considerably in the future, even against a background of an overall decline in dental caries. Under these circumstances, the use of organic phosphorus compounds may also be predicted to grow. The ability of certain acidic species to form cements of the acidbase type, analogous to the glass polyalkenoates and zinc polycarboxylates, has also been highlighted, and such materials may also have a role in amalgam-free clinical restorations. Against the background of these developments in dentistry, the future for the clinical use of organic compounds of phosphorus is bright. 15 17 19 20 21 22 23 Ali SAM, Williams DF. The characteristics and performance of dentine bonding agents. CIin M ater 1993; 14:243. Pashley D. Dentin: a dynamic substrate-A review. Scanning M icroscopy 1989; 3: 161. Stanley HR, Going RE, Chauncey HH. Human pulp response to acid pretreatment of dentin and to composite restoration. /Am Dent Assoc 1975; 91: 817. Brannstrom M, Nordenvall KJ. The effect of acid etching on enamel, dentine and the inner surface of the resin restoration: a scanning electron microscope investigastion. J Dent Res 1977; 56: 917. Gwinnett AJ. The morphologic relationship between dental resins and etched dentin. J Dent Res 1977; 56: 1155. Mjor L. Reaction patterns of dentin. In: Thylstrup A, Leech SA, Qvist V, eds. Dentine and Dentine Reactions in the Oral Cavity. Oxford: IRL Press; 1967: 27-31. Bowen RL. Adhesive bonding of various materials to hard tooth tissues, XIX. Solubility of dentinal smear layer in diluted acid buffers: Int Dent J 1978;28:97. Nordenvall KJ, Brannstromm M. In vivo resin impregnation of dentinal tubules. J Prosthet Dent 1988; 44: 630. Douglas WH. Clinical status of dentine bonding agents. J Dent 24 2029 zyxwvutsrq and G. Singh 1989; 17: 209. Tao L, Pashley DH. Shear bond strengths of dentin: effects of surface treatment, depth and position. Dent M ater 1988; 4: 371. Davidson CL, Abdulla AI, de Gee AJ. An investigation into the quality of dentine bonding systems for accomplishing a durable bond. JOml Rehab 1993; 20: 291. 26 Nakabayashi N, Kojima K, Masuhara E. 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