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Particles in the Tissues

As occurs in all circumstances with foreign bodies, macrophages, the phagocytic cells of the innate immune system, are quickly attracted to the spot, their main function being that of engulfing foreign agents which, for any reason and no matter how, had managed to enter the body. This includes particulate matter. Macrophages have also the capacity to secrete in a very short time a wide range of inflammatory mediators, among which cytokines, small proteins influencing the development and extent of the inflammatory response. Inflammation, a mechanism of innate immunity, serves to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the insult they underwent and start the process of tissue repair. If the inflammatory reaction is not big enough, the condition could lead to progressive tissue destruction by the original damaging agent (e.g. bacteria) and put at risk the very survival of the whole organism. Chronic inflammation is characterised by the presence of mononuclear cells, mainly macrophages, and by phenomena of simultaneous destruction and healing of the tissue involved, a combination which can lead to a host of pathologies, including cancer. Inflammation by particles is both relatively mild and, if particles are not degradable, chronic, thus representing an impending danger to the organism.

Once the foreign bodies have been engulfed by macrophages, their function is that of digesting them: apoptotic cells, microbes and other organic foreign bodies. But solid, inorganic, insoluble particles are not digestible. So, when those particles are involved, macrophages, though actually engulfing them, are useless and can only do as much as secreting substances inducing inflammation.

Particularly when a fair number of particles are grouped in a limited volume, an inflammatory, granulation tissue grows, wrapping and isolating them from the surrounding cells.

In all cases, the presence of foreign bodies induces a biological reaction of the tissues. The consequent inflammation can achieve various effects: from becoming a cancer, normally a slow process, to modifying the patient's behaviour when it affects the brain or, as it looks more and more likely, modifying the intestinal microbiota, through a range of other pathological effects.

In the texts of laws and regulations in force worldwide, particles are often mentioned, when they are mentioned at all, as ‘inert’. Incinerator bottom ash is an example. If the classification, even though far from irrefutably correct, may be accepted from a chemical standpoint, it is thoroughly wrong if biological activity, that is, what is really important from people’s health's point of view, is considered. In most cases, the particles we deal with are crystals or amorphous structures with a poor or a completely not appreciable chemical reactivity, but in all cases, they are foreign bodies with an enormous biological reactivity, initially as inflammation inducers, and lawmakers and their advisers should take this into due account

Biocompatibility and Nanotechnologies

As can be seen, nowadays the concept of biocompatibility has changed dramatically.

But now we have a new challenge to face: the biocompatibility of nanoparticles and nanobiosafety, that is, the degree of safety of particles when they enter the body, always taking into account the enormous variety in which particles exist.

Through nanotechnologies, a lot of objects with unique, often surprising, characteristics are being produced and they are introduced also in medicine, with a view to solve old problems by using novel materials or nanotechnological devices.

Nanoparticles are called ‘magic bullets’ for their ability to cross any physiological barriers. In single form or in clusters, nanoparticles can enter cells and interact with organelles, proteins and enzymes at the nanolevel. For reasons which have to do both with science and the ‘bureaucratic’ convenience of placing numbers as limits, to be nano, a particle, be it crystalline or amorphous, must not exceed a 0.1 pm size. Particles that size have very peculiar properties which become more and more evident as the ratio between external surface and volume increases or, which is the same thing, as their size grows smaller. So, particles like those are more and more often produced in laboratories with steric properties and chemical compositions studied depending on the use to which they are intended. In fact, they are used in growing applications which can be found in nanotechnology textbooks, constantly trying to keep up with the continuous, faster and faster innovations and applications of engineered nanoparticles.

Nanobiointeraction is the key point to be checked to assess the biocompatibility of nanoparticles. That implies their behaviour when in touch with cells, proteins, enzymes, etc. The evaluation of the relationships between cellular uptake and a toxic response (Trojan horse effect) is a new frontier, difficult to deal with both for the limited knowledge we have of it and for the difficulties of investigations we face. We do not know well enough what processes determine the toxic potential necessary, for instance, to a prooxidant activity. We do not know that there is the possibility for the cell to excrete those nanosized foreign bodies and get rid of them the way it happens with non-biocompatible implants or devices [7].

What will matter for what we are dealing with in this chapter is that particles that size, be they engineered or, much more commonly, the product of unintentional pollution, have a toxicity which, as already pointed out, is quite different from that shown by bulkier material with the same chemistry.

Their most evident feature is their capability of crossing virtually any physiological barrier without being perceived, and it is for that reason that they are called not only magic but also ‘invisible bullets’. They are so good at penetrating everywhere that they can enter cell nuclei and interfere with proteins, with chemicals like, for instance, enzymes, with organelles and even with the DNA. This cross-relationship (nanobiointeraction [8]) is crucial in assessing biocompatibility, and chemistry is but one of the parameters to be considered, not the most important, size and shape being more determining though not the sole.

With nanoparticles, dose keeps being important a la Paracelsus, but other parameters need be considered. As a matter of fact, we don’t know what the exact circumstances are to allow particles to enter cell nuclei, nor do we know why very often they stay outside cells, but, again as a matter of fact, when particles cross a cell membrane they can cause dramatic consequences, and dose becomes just a minor actor, being that only a parameter which can increase or decrease the degree of likelihood which makes the phenomenon occur. In short, in this case, Paracelsus's concept of dose becomes a variation of probability. Anyhow, at least from a theoretical point of view, a single cell into which a particle has penetrated and has interfered with the DNA can be the trigger for an extremely important pathological reaction. It should be kept in mind that the DNA attacked in that way loses the ability to repair itself and the cell loses its apoptosis capacity. So that the daughter cell is the result of modified genetic information and reproduction with the inherited, modified DNA will continue as long as the tissue receives its nourishment.

Again, as size is concerned, the smaller it is and, as a consequence, the higher is the outer surface/volume ratio, the more energy is contained in the particle (a feature which nanotechnologists widely exploit). That energy exerts an influence on the surrounding cells, an influence which needs to be explored in detail and which is far or, in any case, different from the old dose concept

Another parameter which has nothing to do with dose is the shape particles have. For merely mechanical reasons, spherical particles like those generated at high temperature, for example, when melting metals, are less capable of moving across tissues than many irregularly shaped particles or needle-shaped ones. And size and shape combined together are also critical. In addition to being richer in energy due to the large surface/volume ratio, a particle with a particularly jagged surface offers a large contact to tissues and that must necessarily have a significance.

(a) In vitro tests of cells with iron oxide nanoparticles

Figure 2.4 (a) In vitro tests of cells with iron oxide nanoparticles. A fibroblastic cell is shown in contact with iron oxide nanoparticles (white arrow). Some nanoparticles remain outside the cell, but others can enter and interact with mitochondria (black arrows), inducing alteration and the ensuing damage in the cell metabolism. They do not induce cell death, and the cell can go into mitosis. When the nuclear membrane disappears, the particles (black arrow) are very likely to interact with DNA (see panel b), which acquires erroneous information, becoming unable to remedy it and becoming unable to die from apoptosis, (b) Iron oxide nanoparticles (black arrow) close to chromatin (DNA).

Incidentally, it must also be remembered that some particles, especially those produced by high-temperature processes like those typical of foundries and incinerators, are often hollow inside with a very fragile surface. That surface gets easily crumbled into very tiny fragments, besides having an increased number of particles following the breakup.

But particles can also be electrically charged, and that is obviously important when they get in touch with tissues or with chemicals like, for example, proteins. In the latter case, proteins can be altered either chemically or sterically by unfolding processes, thus changing their characteristics. Just as a theme suggested to researchers for further studies, enzymes have a protein nature and altering them can be a cause of consequences hard to predict.

Finally, chemistry has an influence on how particles behave. Their surface is obviously made of chemical elements and those elements keep, at least in part, their toxicity, if any. But even here, not all is so simple. We may take steel here as an easy example. Steel, an alloy of iron atoms with varying amounts of carbon and other elements, is usually a crystal with an internal structure made up of neat rows of atoms. In addition to iron, which is the main component, and carbon, the most common elements present in steel are generally chromium and nickel. When a stainless-steel implant is inserted in the body, the reactions which tissues show to it are not those they would deploy against iron, chromium or nickel alone. The same thing occurs with particles.

As can be easily deduced, it is impossible to establish simple rules for the behaviour of particles, these being very different from each other for a set of dimensional, steric, electrical, radiological and chemical characteristics. So, the toxicology of particles is much more complex than Paracelsus’s one, simplistically applying which is an endless source of misunderstanding and blunders.

Only when doctors have acquired these fundamental notions in their cultural background, the more and more numerous health problems caused by the particles which we keep introducing into our lives will get a hope to be remedied.

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