In the last 70 years or so, our understanding of dental materials has progressed from the more or less purely pragmatic to a more structure–function design‐based science. This process is not yet complete. That is, despite the currency of ‘evidence‐based dentistry’ – which has its own Wikipedia entry and an eponymous journal – there remains much work to be done to make everyone appreciate the value of the science of those materials. Inadequate teaching and dogmatic schools of thought are also manifest in endodontics to no lesser extent. It is my understanding that this book represents an attempt to begin the essential process of modernization in this field. Accordingly, I shall attempt to provide some foundations for the necessary insight.
Once the vitality of the dental pulp becomes compromised, endodontic intervention is necessary to preserve a functional natural dentition, with natural alveolar (as opposed to ankylosed) bone attachment, and thus the preservation of that very bone. More, perhaps, than in some other areas of dentistry, the materials used in endodontic work have an intimate relationship with tissues. Most obviously, the dentine is subject to exposure to a variety of more or less aggressive irrigants as well as fillers and (putative) sealers, often involving calcium hydroxide. Another possibility is of a strong oxidizing agent in the form of hypochlorite. Whilst the need for microbial elimination is not disputed, it is appropriate to be aware of the implications of such treatments: the chemistry demands that if a reaction is possible, it will occur, whether you like it or not, whether you meant it or not, and whether you are aware of it or not. Of course, apical extrusion of almost all materials can have very unfortunate consequences. Such intimacy is quite undesirable. At the least, a foreign body reaction will be elicited; at the worst, destruction of periapical bone – but the risk of infection is always high, with potentially wider implications.
1.2 The Substrate
Dentine has a complex composite structure whose matrix is largely proteinaceous, but it also has an inorganic component, biological apatite. As such, it is vulnerable to hydrolysis (whether acid‐ or base‐catalysed), even at pH 7 – although this may then be at a very low rate . Since the mechanical properties of a composite structure are dependent on the integrity of the matrix, any such hydrolysis must be considered detrimental. In this light, the frequent finding that root fracture is associated with the use of calcium hydroxide, or materials containing it, is a predictable outcome for inevitable chemistry. The increased risk has to be treated as a necessary sequela of such a treatment, with the unhappy implication that the life of the remaining tooth may be limited (bearing in mind that the loads experienced by such teeth depend on a number of circumstances). Indeed, the use of oxidants such as sodium hypochlorite (which also deliberately has a high pH) must likewise contribute to such deterioration, because all organic material must be subject to oxidation, and indiscriminately. Add to this the penetration and diffusion of fluids and the effect can be seen to be not necessarily local. We therefore need to recognize that all such treatments involve compromise, a trade‐off between immediate benefit and longer‐term failure risk.
Disruption of the dentine matrix has further implications. As is discussed in Chapter 3, many biologically important molecules become bound within it during its development. Should these molecules be released through matrix breakdown, they may become once again biologically active and thus be important in reparative or regenerative processes. Such release through mechanical processes has little implication for that activity. Likewise, demineralization under mild conditions, such as with ethylene diamine tetra‐acetic acid or ‘EDTA’ (what is used in dentistry is actually closer to the trisodium salt, in order to provide enough solubility at around pH 7–8), may be considered in the same context. Such demineralization can be presumed to offer an easier diffusive path through the now much more porous tissue, and so may release these molecules without detriment to them, although perhaps the larger ones – proteins, for example – may emerge more slowly. It is, however, worth considering whether the more aggressive media at high pH cause any destruction of such molecules: proteins of whatever kind are still subject to hydrolysis. Are any of the other important matrix components capable of reaction, and thus damage and inactivation, under those conditions? Naturally, this is not necessarily an all‐or‐nothing kind of event – the kinetics of the reaction determines how much survives. It would follow, though, given that these molecules are believed to be of value in the course of treatment, that finding more benign means of release than the presently documented range of products would be of value for a more reliable effect of full efficacy. It would be wrong to assume, again, that the chemical reaction that destroys the matrix and releases these substances is selective. For example, urea may solubilize (that is, make soluble, as opposed to merely releasing) the matrix protein, but at the risk of unfolding, and therefore inactivating, enzymes of interest. There will probably not be a perfect resolution of this problem, but the means may conceivably be designed or selected for specific targets. It should be apparent that oxidizing agents are liable to destroy any and all biologically active molecules more rapidly than high pH alone. What appear to be needed are assays of the sequestered substances for comparison with release rates and survival in an active form after the various possible treatments.
The use of demineralizing and matrix‐destroying agents has an important implication. If bonding to collagen is intended, it must be left intact. If interaction with the calcium or phosphate of the mineral is contemplated, that must remain available. It is clearly illogical to use a treatment that removes an essential component of a subsequently intended process.
The preceding discussions are essentially of simple chemistry. It is curious then that in the historical focus on sterility and its maintenance in the present context, there has been little consideration of the inevitable effects of some of the agents used. Ignorance of the chemistry is no excuse, and to claim, for example, that a particular effect is not required is a chemical absurdity: as already stressed, if a reaction is possible, it will occur; if a pathway exists, it will be taken. The only debate is about relative rates. Materials science – and no less in endodontics than anywhere else – must recognize the chemistry of systems and design accordingly. The dogma mentioned must be designed out of dentistry. Again, though, compromise is inevitable; perfection is – at best – unlikely. Rational assessment is not optional, it is essential.
1.3 Nomenclatural Hype: ‘Bioactivity’, ‘Bioceramics’
It is clear that substances released unaltered from the dentine matrix must retain their biological function and activity, although whether the balance that originally obtained during development in the many complex interacting pathways is effectively and usefully maintained remains a matter for investigation. Nevertheless, it is proper to argue that this is indeed biological activity – bioactivity, to use the current jargon – because these are natural substances involved in entirely normal biological processes. Unfortunately, the field of dentistry is heavily trampled and muddied by the indiscriminate use of the term in any context where a biological response is elicited. That is, in the absence of those natural biological substances, any action, process, or material that provokes a response of any kind is automatically labelled ‘bioactive’. Such responses fall for now into just two classes: simple chemical and challenge defence.
Simple chemical responses typically involve the provision of a species that perturbs a chemical equilibrium, such as by changing the local pH. To take an ordinary example, adding sufficient calcium ions to a tissue fluid (by dissolution of a component of a material, say) must locally drive the precipitation of a calcium phosphate, assuming nucleation can occur. Because this is inevitable simple chemistry, with no sign of the involvement of a biological process, there is no logic or sense in labelling the source material ‘bioactive’, yet this is commonplace. We may note in passing that a frequently‐used test of ‘bioactivity’ involves immersing the test material in a metastable supersaturated solution of calcium and phosphate, the criterion being the appearance in due course of an apatitic precipitate on that material. The fact is that almost everything produces that effect, due to the ease with which apatitic material nucleates under those circumstances – there are many papers reporting such an outcome. It is worth remembering that tissue fluids are not, in general, supersaturated with respect to apatites. Simplistic calculations based on analytical values without taking into account speciation (and, especially, binding by many specialized protein systems) fail to give sensible results. Whilst hypercalcification (heterotopic ossification) is a real and distressing disease, we do not as a matter of course calcify promptly and locally in response to cuts and bruises, which effect would otherwise be expected. To make this point more clearly, highly supersaturated calcium phosphate solutions can be prepared that can stand for days without doing anything. Yet, merely shaking the flask can result in the prompt and massive precipitation of the excess: any seed is enough. There is no discernible chemical difference between such a system and the ‘bioactivity’ test. There is simply no biology involved.
Challenge defence responses are elicited by anything that represents a foreign body, toxicity, osmotic imbalance, boundary layer disturbance (via zeta potentials or surface chemistry), pH change, or merely an unusual ion – that is, a chemical challenge, an insult to the tissue. The body’s natural reaction is to mount a defensive response such as encapsulation and immune reactions, if outright apoptosis and necrosis does not occur. When calcification (e.g. dentine formation) is involved, it is greeted with pleasure. But then, such an effect occurs with low‐level challenges such as caries anyway. It does not seem to be sensible to label materials that provoke a defensive response, however natural or normal, as ‘bioactive’. On that basis, formaldehyde is bioactive, zinc oxide‐eugenol is bioactive, and calcium hydroxide is bioactive.
By extension, then, it is a puzzle how materials that cause disruption or degradation of the dentine matrix can be labelled ‘bioactive’ simply because in the course of that damage some truly biologically active substances happen to be released, and quite regardless of the fact that such substances may have local beneficial effects. What we see is a creeping inflation of titular importance that bears no relation to underlying processes. It is one of the worst examples of the hijacking of a term to make the products it is attached to seem more valuable and useful. There are many such in dentistry. The problem is that, in the absence of understanding by the general user of the products’ actual chemistry, their use and effects are misunderstood. We do not serve patients’ best interests by such exaggeration and misinformation.
All that said, there is a conceptual class of material that can truly be described as bioactive, and although there is nothing at present on the market, it has been demonstrated in principle. That is, the incorporation of a naturally occurring biological substance or substances that may stimulate or trigger a natural process that leads to a suitable outcome, such as bone growth or dentine deposition. By definition, this is a substance that is normally involved, but whose artificial provision enables, facilitates, or amplifies the pathway. One would expect that the vehicle for such a delivery would be otherwise benign, not representing a challenge in itself – for example, a resorbable, noninflammatory material.
We must be careful, though, not to stray into the realm of pharmaceutical products (which incidentally has all kinds of implications for marketing and promotion, never mind supply and use). That is, pharmaceuticals are intended to be biologically active in that they may, for example, modulate or trigger natural processes. The question is whether a material that is the vehicle for a substance not normally involved in the usual biochemistry of repair can be considered ‘bioactive’. Imagine a material carrying, say, aspirin: it would be wrong to say this is bioactive. Thus, salicylate‐based cements and liners are not. Whether the provision of a normal, human, biological substance in such a fashion is pharmaceutical is for others to debate and decide. Ponder the taking of vitamin D, or melatonin, for example. Antibiotics clearly cross the line.
Overall, then, the key is that we must inspect the chemistry to ascertain what is going on. If it is a simple chemical effect that does not involve any biology as such, or if it is a chemical challenge that results in a defensive (albeit normal) response, it is quite improper to apply the term ‘bioactive’: it is an advertising malfeasance. If – or, perhaps, when – materials are available that are the vehicles for any of the many biologically active substances that offer the possibility of true reparative or regenerative responses, the label will be fully justified and accurate. Until then, it is suggested that much more careful thought is required, which goes beyond the allure of advertising hype and wishful thinking. Mere repetition does not make it so. Believing one’s own propaganda is not scientific.
A similar abuse occurs in the term ‘bioceramic’. A ceramic material is, in simple chemical terms, anything that is not metallic or organic polymeric. The prefix ‘bio’ only seems to refer to the context in which it is used: in a medical or dental application. This is pretentiously misleading. It does not automatically confer special properties on the material in question, which has in any case been chosen (one hopes) on grounds of its general inertness and suitable mechanical properties. There are no classes of materials that in any sense earn the label, except possibly those of bone, dentine, and enamel – natural hard tissues – and even then, it serves no real purpose. Can it be applied to mollusc shells? Quite possibly. But how does that help us understand the value of marketing hype? Its extension to setting cements and sealers is incomprehensible .
Chemistry is frequently a weak point in other areas. Take ‘MTA’ as perhaps the most egregious example: this is the trade‐name abbreviation for what is described as ‘mineral trioxide aggregate’. Try as one might, this phrase makes no sense whatsoever: it does not inform in any way at all – it does not even describe the material itself – yet it is bandied about as if it were a meaningful label. It is inorganic, admittedly, but as the Oxford English Dictionary has it: ‘Mineral: A naturally occurring substance of neither animal nor vegetable origin; an inorganic substance. (Not now in technical use.)’. MTA plainly does not qualify.1 The only ‘mineral’ present as such is gypsum, possibly – but not originally. Then again, ‘mineral aggregate’ is a term for ‘rock’ that has fallen out of fashion. This kind of product is not a rock, nor derived as such from one. Otherwise, ‘aggregate’ ordinarily means the rough granular material used in concrete, for example, such as pebbles, crushed rock, slag, and so on – the first thing that springs to mind – but that is clearly not what is meant (where it is in fact the core or filler in that composite material).
The first publication to refer to ‘MTA’ claims that one of the ‘principle [sic] compounds present’ is ‘tricalcium oxide silicate oxide’ . This is not an identifiable substance; indeed, it is chemical nonsense. There are no details given whatsoever of provenance, processing, or analysis. The next paper says, ‘The principle compounds present . . . tricalcium oxide, and silicate oxide’, which speaks of a lack of understanding and an earlier failure to proof‐read (and of very poor reviewing on both occasions), but quite simply neither compound exists, nor can the labels be parsed in a chemically meaningful fashion . Later, we find: ‘All MTA was divided into calcium oxide and calcium phosphate’ – this was for the set material