The Concept of Biocompatibility
At the risk of being sentimentally romantic, the human body can be defined as a delicate shrine, and before introducing something into it, it is at least prudent to answer a few questions: Is the material implanted, injected or, no matter how, introduced compatible with the body? Is the whole object acceptable? Is the interaction between the foreign body and the organism components physiologically compatible? How long can it stay compatible?
When there is no sure answer, confirmed by in vitro and in vivo experiments, it is advisable not to use the product. The so-called precautionary principle states as much and is law in many countries, but the law is almost never applied.
The biomedical/pharmaceutical industries, but also most technologists, tend to underestimate or utterly overlook this basic, obvious concept which they consider contrary to progress.
Replacements for body parts lost through injury, amputation or disease have been in use for millennia. In 1998, some archaeologists unearthed what is believed to be the most ancient artificial eye in the world, a prosthesis made of bitumen paste dated to about 5000 years ago, discovered at the necropolis of Shahr-i-Sokhta in the Sistan desert on the Iran-Afghan border. A prosthetic big toe composed of leather, moulded and stained wood, and thread was discovered near
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Luxor, belonging to a female mummy dated between 950 and 710 BC. A prosthesis which certainly was not functional but, in a certain way, was to be considered aesthetic. Then, arms, legs, dentures, even a silver nose worn by the sixteenth-century Danish astronomer Tycho Brahe (who lost his in a duel). None of them, however, was inserted into the body. For this to be done, knowledge and technologies were needed, then and for a very long time not available and, it must be admitted, even today not exactly absolutely certain.
The first ‘modern’ definition of biocompatibility is dated 1982.
Already at that time many prostheses were implanted in the human body to substitute an organ or part of it, to replace a tissue or to make up for a function which, for any reason, had gone lost.
Starting from years long before the eighties, probably the most common prostheses were those replacing bones or joints. A great impulse was done by the wars, since the wounds and mutilations prompted by projectiles, bombs and explosions in general caused ‘not normal' lesions and orthopaedists had to ‘invent’ prosthetic tools, in some cases made especially for that particular case.
Most of the prostheses were manufactured according to the general indications given by an orthopaedist and were a sort of compromise between the anatomical location they were meant to occupy, the function they had to accomplish and the mechanical stresses they had to endure. Because of that, when mechanics was the main concern, it was rather customary that those materials were selected by technicians with great experience in mechanics but very little or not so great in biology, physiology and pathology. Unfortunately, then, medical doctors and surgeons had a rather primitive knowledge of materials and the final result was not particularly satisfactory.
But it was not in the field of orthopaedics alone that prostheses showed problems. For years, heart pacemakers were encapsulated in plastic materials (silicone and epoxy resins) which were prone to absorb water and swelled, a problem in some cases aggravated by their permeability to the gases leaked and released by defective batteries.
Because of wear, prosthetic heart valves lost tiny fragments of their plastic ball or of their plastic disc(s), and in other models which enjoyed a relatively short-lived popularity, they lost silver particles of the coating meant to prevent the growth of pathological tissue.
The definition of biomaterial, where the prefix ‘bio’ means ‘compatible with a living organism’, was '. . . any substance, other than a drug, or combination of substances, synthetic or natural in origin, which can be used for any period of time, as a whole or as a part of a system which treats, augments or replaces any tissue, organ or function of the body' .
That was a definition specifically addressed to the specific activity and supposed durability of the material in contrast with other ‘similar’ materials used in other fields (in cars, in architecture, etc.). The definition included the concept of temporary implant.
In 1986 the definition was enhanced, adding 'non-viable material, used in medical device, intended to interact with biological systems’. This definition opened a new scenario, since it became necessary to assess when a material is actually fit for the human body. At that time, new tests considering the interaction of the candidate materials with cells, tissues and organs started to be developed and new parameters of compatibility had to be found. Most of the tests were initially borrowed from those used by toxicologists to assess the toxicity of substances in molecular, atomic or ionic form, but when particles were understood to be toxic, and toxic in a way that is not the same as that of atoms and molecules, those tests proved to be not only useless but misleading.
One of the toxicologist’s tenets, probably the main one, is Paracelsus's adage ‘sola dosis facit venenum' or, a little more in detail, translating literally from his Latin, ‘All things are poison and nothing is without poison. Only the dose makes a thing not a poison.’ From this, the concept immediately derived is that, below a certain dose, any substance can be tolerated by the body.
All that science elaborated in the field of toxicity was verified in order to find tests and already developed standards and adapt them to biomaterials. What we want to emphasise is that atoms and molecules do not behave the way that particles, though made of the same components, do, and all prostheses, bulky as they are, behave in a still different way.
Now, let us consider two toxicological parameters: LD50 and LC50.
LD50 (lethal dose fifty) is defined as the amount of a material, administered all at once, which kills 50% of a group of test animals. LD50 measures acute toxicity, that is, the short-term poisoning potential, of a certain material.
'LC50' stands for lethal concentration fifty' and refers not to the quantity but to the concentration of a substance in air or in water which causes the death of half the animals used for the test .
The actual LD50 value may be, and often is, different for a certain substance, depending on the route of exposure (e.g. ingestion, transdermal, inhalation, etc.). These different values are obtained testing the chemicals on laboratory animals. Special calculations are used when translating animal LD50 values to possible lethal dose values for humans. Safety factors of 10,000 or 1000 are usually included in such calculations to allow for the variability between individuals and how they react to a chemical, and for the uncertainties of experiment test results.
The limits of the two parameters are self-evident. Among others, a given substance can be toxic for a certain tissue or organ without affecting others. An organ can be affected by a substance without it causing death. Another problem hard to solve is the comparison between different kinds of damage: How can one determine objectively whether a damage is more or less serious than another? What with a substance which is objectively noxious but does not cause death? How can one scientifically cope with the obvious difference existing among different test animals, and how can one scientifically translate the results to humans without being ready to accept a huge margin of error? Answers are not lacking, but understandably, none of them is totally reliable.
As far as substances is concerned, the key point is that particles, particularly nano ones, can enter freely into cells, and interact chemically - that is, through the substances in question - with other biological substances impairing or destroying the local metabolism. From a purely theoretical point of view, it is sufficient that a single cell is attacked and that, as will be seen later, its defenses are made unable to function, to trigger a very serious biological reaction.
For that reason, it was necessary to study ad hoc tests identifying suitable parameters.
Then, another definition of biocompatibilify (1991) came to consider biomaterial as ‘a material intended to interface with biological system to evaluate, treat, augment or replace any tissue, organ or function of the body'. It is only obvious that this implies that there is a tolerance on the part of the organism in respect of that material and tolerance must be evaluated by appropriate tests considering the actual acute, long-term and chronic effects of this interaction.
First of all, it is necessary to remember that the body invariably reacts to the entrance of something which does not belong there and is not recognised as self, with something which can vary from a complete rejection to a mild reaction to a temporary acceptance to, in the best of circumstances, full acceptance.
If a more or less quick rejection and a mild reaction are easy to understand, temporary acceptability needs some explanation. Biocompatibility may not be an eternal property of a certain material. In fact, a material, once implanted, can induce a slow, low-degree biological reaction, which, as a final result, can lead to discomfort, mild pathologies or even full rejection.
The material used to replace a function of the body (orthopaedic prostheses, cardiac valves, etc.) or a tissue (skin, tooth, bone, blood) inside the body is subjected to stress and to chemical and biological interactions with what is present in the body. It works, it ages and it can wear. A well-known case is that of hip joint prostheses losing surface debris due to the friction between counterparts. In this occurrence, the debris invades the neighbouring tissues and, as a rule, induces a biological reaction. Figure 2.1 presents schemes and X-ray images of hip joint prostheses.
The bulk material may have passed all tests and be declared biocompatible, but that is not the case with its debris. As a matter of fact, they are generally attacked by macrophages and moved to other parts of the body. Generally speaking, and with some exceptions, biological materials (bone, cells, etc.) can reconstruct themselves, but synthetic materials are always unable to do so. What they do is degrade, or due to the surface interaction with body fluids, they can change some of their properties as happens, for example, in the case of corrosion, an oxidation process which occurs also inside the body at 37°C in an aqueous environment full of chemicals and crossed by weak electric currents. As a rule, degradation and oxidation products are not compatible, and a relatively frequent example of that incompatibility is represented by the release of iron hydroxide, a quite common event when iron-based matter is for any reason inserted into the body. Besides having grown incompatible, the prosthesis becomes so more and more useless. In some circumstances, a prosthesis may remain relatively biocompatible but stops functioning as it should. This is the case, for example, of the formation of bacterial biofilms or a so-called pannus on heart valve prostheses, that is, an ingrowth of tissue.
Figure 2.1 (a) Images show examplesof hip joint prostheses made of metallic, ceramic and polymeric materialsand (b) Rx images of different types of hip joint prostheses. Reproduced with permission from OrthoInfo © American Academy of Orthopaedic Surgeons (http://orthoino.aaos.org).
This behaviour suggested the opportunity of developing temporary implants (when it was the case) like those used, for instance, in case of bone fracture when helping the edges of the fracture to be in touch with each other is necessary in order to facilitate healing (intramedullary nail, osteosynthesis plate and nail, etc.). When the fracture is recovered, those devices are no longer necessary, so they can be removed. Of course, no temporary implants can be used in the case of physical impossibility by the body to heal or reconstruct itself.
On the other side, biodegradability can be a very useful property. In fact, surgical sutures are the oldest example, so that, once they have done their job, removal is no longer needed as they ‘disappear’. 11 is the case of the so-called catgutsuture (although cats have nothing to do with it). Connective tissue is taken from the small intestine of sheep, cattle, horses or pigs, after having undergone a chemical treatment, and now synthetic materials are used for internal sutures which have the peculiarity to be absorbed in a time longer than that it takes to the wound to heal.
As a matter of fact, non-degradable prostheses can wear during their use, and after a certain time they must be replaced in order to maintain their function. It is the case of hip joint prostheses which can wear and release wear debris which cause an inflammatory body reaction. In conclusion, bulk material can be biocompatible, but not its debris, and generally speaking, metal debris are more dangerous than ceramic or plastic ones.
An example of such a reaction is that caused by the metal-metal hip joint prosthesis called McKee-Farrar and a similar one produced, decades after, by DePuy (J&J) (Fig. 2.2a,b).
Figure 2.2 Images of two metal-metal hip joint prostheses: (a) the more recent one by DePuy and (b) the old McKee-Farrar one.
The studies on biomaterials and biocompatibility led to new concepts like that of the ‘sandwich materials’. Since it is hardly possible to make an artificial material with all the properties requested (according to each case, strength, non-wettability, elasticity, softness, durability, etc.), researchers devised materials made of different layers, with every layer corresponding to a specific property. The new materials have a mechanically resistant core and their surface is coated with molecules as similar as possible to the biological matrix they have to match (biomimetic coating). There are also coatings which can be bioactive, meaning that they change over time (biodegradation process) in order to generate an osteointegration, that is, a direct bonding with the bone. That is the case of bioglasses [3, 4].
The concept is that the prosthesis is coated with something which ‘cheats’ the biological host which recognises it as self, and in some products the molecules are ‘powered’ in order to determine an intimate, close contact with the biological tissue. In some cases, that technology succeeds in developing structures (scaffolds) which can host cells of the patient As far as material is concerned, these organic-inorganic devices are fully biocompatible, since they contain part of the hosting body, and that part is in touch with the subject's tissues. The outlook seems to be in the hands of tissue engineering and synthetic biology .
A branch of implantology is related to tissue engineering. That involves the new concept of self-regeneration. In some particular cases of implantology, it is possible to stress the self-regeneration of a tissue or function. The scientist prepares a scaffold (a resistant armature) which is seeded (filled) with the previously explanted cells of the patient, which are cultivated and expanded. To maximise the expansion, growth factors can be added to the culture broth. In this case, the patient will receive something which is particularly biocompatible. For example, an ear has been reconstructed for aesthetic reasons (Fig. 2.3).
A big boost to prosthesis production comes from 3D technology. Born to reproduce small things such as toys, 3D printing is increasingly proving to be an exceptional tool to produce customised prostheses as well as in various specialties of surgery . This new method allows us to manufacture prostheses built exactly on the patient, with obviously better results than those obtained from industrial products, which can also be of the highest quality but, however, mass-produced without being able to take into account the individual case.
Figure 2.3 Ear prosthesis. Image of a head without one ear (left) and 3D reconstruction with a polymeric prosthesis made on a copy of the other ear (right). Figure courtesy of Professor L. Di Silvio.