A New Word to Describe the Nanoparticle-Human Body Interaction

Nanotechnologies are rampant disciplines, exponentially growing beyond any intelligent expectation. Discoveries once unimaginable, based on new properties of matter at nanoscale are appearing at a rapid rate, driven by the enthusiasm of the scientists working in new directions at the border of the knowledge.

While nanotechnology is still at its infancy, an increasing number of every-day items, from clothes to washing machines, from drugs to food are appear in the market. Even though consumers are being increasingly exposed to them, there is no general knowledge readily available to the public of the new technology applied. A worldwide concern is arising among experts about the toxicity of nanoparticles. Their size as tiny as that of protein, enzyme, DNA, etc. is suspected to play an important role in so far unknown toxic effect at cellular level.

Nanotechnology, in particular nanomaterials, are often used by manufacturers to improve the properties and performance of a product. However, very little information is known regarding the consequences when those nanomaterials or nanoparticles come into contact with biological organisms. Also, very little is known about the long-term impact that these nanotechnology-enhanced products can have on the environment and on human and animal life and we know virtually nothing about the fate of the nanoparticles at the end of the life cycle.

A new word was invented in 2002: "Nanopathology", and that name was used as the title of an FP5 European Commission Project coordinated by Dr. Antonietta Gatti, shared with the Universities of Cambridge (UK) and Mainz (Germany) and FEI Company (The Netherlands) aimed at verifying the "impact of micro and nanoparticle in inducing pathologies". At the beginning the word had a simple meaning "the branch of learning that deals with how the organism reacts to the presence of micro- and nano-particles".

Now, after a 10-year study, the word has taken other aspects and implications and probably, in the next future, Nanopathology will mean a new approach to patients and their symptoms: a sort of customized Medicine.

The research work of Nanopathology started from simple axioms:

1. engineered and non-engineered nanoparticles are already present in the environment, released by nanotechnological activities and by uncontrolled (in terms of release) high-temperature combustive processes like car engines, power plants, incinerators, explosions, etc.;
2. man and animals are already in contact with them;
3. nanosized particles can negotiate the physiological barriers thanks to their tiny size, reaching the deeper parts of the body.

The project developed a novel type of ultramicroscopic investigation to check possible exposures to inorganic micro- and nanoparticles suffered by patients. The analyses carried out were meant to identify those foreign bodies remained trapped in biological tissues.

After having examined more than 1,200 biological samples, mostly pathological ones, we came to a definiteve conclusion: "inorganic micro- and nanoparticles, whether they are inhaled (with contaminated air) and/or ingested (with contaminated food), can be found virtually in any organs". No known biological mechanism exists capable of getting rid of those nano-invaders.

Foreign inorganic micro- and nanoparticles can be spotted and analyzed in bioptic, autoptic or surgical samples via a novel ultramicroscopic technique which uses a Field-Emission-Gun Environmental Scanning-Electron Microscope. The exposure the patient underwent must be traced in the patient’s life. So, a focused anamnestic work is conducted with the fundamental aid of the patient and, if the collaboration works, it is not rare that the source of pollution can be identified and, if still present, eliminated from the patient’s life. The detective work is far from simple but sometimes the combination of chemical composition of the particles, their size and shape is like a finger print of a specific pollution.

Before being able to understand the mechanism of pathogenicity, we had to look for the possible entry points of pollutants leading to the internal organs and their mechanism of dispersion inside the human body.

It is widely known that, like a gas, nanoparticles can be inhaled and, when they are small enough, reach as deep as the alveoli. According to the University of Leuven's research¹, it takes just a few tens of seconds for 100 nanometer-sized particulate matter to pass from the alveoli to the blood stream. If those particles are insoluble, they act as a trigger for transformation of fibrinogen into fibrin, the insoluble serum protein which acts as a form of scaffold that allows thrombus to form. In most cases, the organism can counter that process by producing urokinase, but there are instances where, for a number of reasons, no efficient defense mechanisms are available.

In those cases, a thrombus actually forms without being attached to the vascular wall and, being free to float, can migrates along the veins, if the phenomenon has taken place in the venous system, to reach the lung circulation and be the cause of pulmonary thrombo-embolism. If this occurs in the arteries, the outcome can be a stroke or a myocardial infarction. It is clear that these nanoparticles cannot be considered biocompatible.

Several studies conducted on thrombi extracted from coronary arteries in the first day after a myocardial infarction reveals the presence of inorganic foreign bodies inside the thrombus, similar results were also obtained from the analyses of venous thrombi captured by vena-cava filters. But in the majority of circumstances, the particles that travelled in the blood reached virtually any organ and those organs, behave like a mechanical filter, capturing that matter². We discovered micro- and nano-sized particles in all the organs: the liver, the kidney, the spleen, the brain, the gonads, the thyroid, the lymph-nodes...

Most particles are not biodegradable, i.e. they are bio-persistent and, once they have been imprisoned by a tissue, they cannot be expelled, as no such mechanism exists. Their permanence in the tissue can activate physico-chemical reactions that, over time, are likely to induce adverse effects.

Those particles are perceived like foreign bodies - as they actually are - and the classical foreign-body reaction begins: formation of a granulation tissue and the establishment of a chronic inflammatory condition. According to the current medical literature and to our experience, a chronic inflammation with such characteristics can be the cause of a cancer.

The microphotograph shows a particular of a liver sample affected by cancer. Inside a cell, in the nucleus, a submichronic particle of Titanium is present.

This hypothesis was verified through in-vivo tests on rats³. Five different materials (Cobalt, Nickel, Silica, Zirconia, PVC) were selected in a bulk and nanoscaled form and implanted in the rats’ back. The Cobalt and Nickel nanoparticles, but not the bulk material, induced rabdomyosarcoma, a rare cancer of soft tissues.

The presence of micro- and nanosized foreign bodies in the seminal fluid can be the cause of male sterility and of what is known as "burning-semen disease", a condition affecting the partner of the carrier: After unprotected sexual intercourse, bleeding, painful sores develop in the vaginal channel tissue of the female partner, and those sores cannot be advantageously treated either surgically or pharmacologically.

We verified also a possible passage for these nanoparticles from mother to fetus, a situation that can give rise to miscarriages when the particulate matter gets to the embryo at an early stage of gestation. When the phenomenon occurs at a later stage, these foreign bodies induce a damage compatible with life and the result can be a malformed baby.

All those pathological forms, apparently so mutually distant if considered in the light of the Medicine of the past, have been classified under the common name of Nanopathologies, i.e. the diseases deriving from nano - (and micro-) particles. The Nanopathology concept allows us to perform ad-hoc investigations especially in the cases of what are referred to as cryptogenic diseases. This results in a customized form of Medicine, to our opinion one of the positive aspects of Nanotechnologies, offering the possibility to discover pathological mechanisms at nanolevel.

Again in our opinion, it is mandatory to protect not only nanotechnological workers but also end-users and consumers with greater vigor because the inhalation or ingestion of nanoparticles can trigger Nanopathologies. At present, at the laboratory Nanodiagnostics of Modena (Italy), we analyze biopsies or surgical samples of patient in some instances affected by "mysterious" diseases, i.e. conditions never reported in medical literature⁴.

References

1. A. Nemmar, PH. Hoet, B Vanquickenborne, D Dinsdale, M Thomeer, MF Hoylaerts, H Vanbilloen, L Mortelmans, B. Nemery Passage of inhaled particles into the blood circulation in humans. Circulation. 2002 Jan 29;105(4):411-4
2. A. Gatti, S. Montanari, A. Gambarelli, F. Capitani, R. Salvatori " In-vivo short- and long-term evaluation of the interaction material-blood" Journal of Materials Science Materials in Medicine, 2005, 16, 1213-19.
3. T. Hansen, G. Clermont, a. Alves, R. Eloy, C. Brochhausen, J.P. Boutrand, A. Gatti, J. Kirkpatrick, " Biological tolerance of different materials in bulk and nanoparticulate form in a rat model: Sarcoma development by nanoparticles" J. R. Soc. Interface (2006) 3, 767-775
4. A. Gatti., S. Montanari "Nanopathology: The health impact of nanoparticles" book, ed by PanStanford Publishing Pte.Ltd Singapore, ISBN -10981\-4241-00-8, 2008, 1-298