Metastable Biocompatibility: A New Approach

MATERIALS

The concept of metastability

Stability is a concept often used in materials science (and in other physical sciences and engineering) to denote a state or condition of permanence or equilibrium. A corrosion-resistant alloy may be said to be stable under defined environmental conditions, as could a degradation-resistant polymer. An unreactive chemical may be described as stable in the context that it will not cause an explosive interaction with other chemical species, and so on. However, stability may not always be absolute and we may have to think of it in terms of degrees of stability. The corrosion resistance mentioned above may not be guaranteed under all circumstances. Changes to environmental conditions such as through variations in pH, temperature or ionic concentrations may reduce that stability. Often, a correlation between the susceptibility to corrosion and a particular environmental variable can be determined experimentally and be expressed by some mathematical relationship; for example, there could be a linear relationship between pH and the corrosion rate or an exponential relationship between temperature and corrosion rate. The mechanisms involved are usually easy to understand and corrosion rates relatively easy to predict.

In other situations, however, the deviations from stability may be profound and catastrophic, caused by minor variations in conditions or, indeed, not readily explained by any obvious environmental cause. Under these circumstances we may have to invoke the concept of metastability. The easiest way to look at this is to consider stability as an illusion, where its apparent existence results from a spurious combination of circumstances that yield structures that appear to defy normal scientific laws.

Metallurgists make good use of metastability. Titanium is one of the most chemically reactive of all metals, yet it is also one of the most corrosion resistant because of the nonreactivity of the oxide film that forms on its surface under some circumstances. Many steels have crystal structures that defy the laws of thermodynamics because metallurgical treatments such as quenching deny the ability of atoms to move to their equilibrium positions; without metastability there would be no high performance steels. Any metastable structure, however, can be profoundly altered by a subtle change to its conditions, which can lead to remarkable changes in its properties. This possibility was dramatically demonstrated in a medical device not long ago. The metastable structure of a transformation-toughened zirconia ceramic used in a variety of total hip replacement was altered during a production process and resulted in much poorer mechanical properties and catastrophic clinical performance.

We should bear this concept of metastability in mind when considering the current status of biomaterials and their biocompatibility.

Biocompatibility in long-term implants

A perception has developed over the last decade that the evolution of biomaterials for medical devices has been following a pattern in which so-called bioinertness has been displaced by new concepts of bioactivity. Indeed, much has been written about the development of second and third generation biomaterials on the basis of the desirability of intentional interactivity of the material with the host to assist in incorporating the device into the host or to achieve some specific functional activity.  The introduction of bioactivity into biomaterials’ specifications must be predicated on mechanisms whereby specific biomaterials characteristics control specific host responses, and that modulation of the former should lead to modification of the latter and the production of better biocompatibility-based performance.

The actual evidence, however, would suggest otherwise. This may be considered from two perspectives: clinical experience and experimental observation. An analysis of the performance of clinical devices over several decades leads unequivocally to the conclusions that the best performances are experienced with the use of materials that are as inert as possible, and that most attempts to induce bioactivity or to intentionally or unintentionally deviate from inertness have led to poorer clinical performance. Over the years, most significant developments in biomaterials’ specifications have been concerned with improvement to inertness or the optimisation of functional properties (for example, mechanical or physical properties) without decreasing inertness.

Thus, the successful long-term implantable devices of today use a smaller group of acceptable biomaterials than twenty years ago, and similar materials have emerged as the preferred options for several and varied applications. The majority of total joint replacement prostheses utilise cobalt–chromium alloys, titanium alloys, ultrahigh molecular weight polyethylene and alumina. A minority will have some component with a surface layer of hydroxyapatite. The majority of mechanical heart valves involve the same alloys with a polyester or a sewing ring based on polytetra-fluoroethylene (PTFE) and a carbon or carbon-coated leaflet or disc. Synthetic vascular grafts use the same polyester and PTFE. Implanted microelectronic devices use titanium for the can and cobalt-chromium alloys or platinum-group alloys for the leads and electrodes, with silicone elastomer or polyurethane insulation. Intraocular lenses and other ophthalmological devices use polymethylmethacrylate or silicones. Breast implants still only use silicone polymers. Almost every time a material with less than optimal chemical or biological inertness has been introduced, it has produced poorer performance.

From an experimental point of view, there have been many attempts to correlate material or material–surface variables with host–response variables. Almost without exception these correlations have been elusive. Parameters involved with surface chemistry, surface energy, surface topography, hydrophilic/hydrophobic balance, electrical and mechanical properties and many others do not generally correlate with protein, cellular or tissue responses except under a few sets of narrow conditions.

Metastable biocompatibility

The fact that we know how to control biocompatibility for long-term implantable devices by optimising the balance between inertness and mechanical/physical functionality does not mean that there are no biocompatibility failures. Indeed, there are far too many of them. A few are caused by a crass disregard of the basic principles of biocompatibility. Most, however, are associated with the inherent metastability of biocompatibility. The environment of the human body is so aggressive in its ability to deal with invading substances, for example, through cellular or enzymatic degradation processes, yet it is so sensitive to the presence of foreign substances. Thus, it seems impossible that biomaterials and tissues should be able to co-exist harmoniously in a stable relationship. The answer to this conundrum, I suggest, is that biocompatibility is not a stable state, but as a metastable state.

The control of the host response through the control of material stability is dependent on the maintenance of a dynamic equilibrium in a series of separate phenomena within material and host systems. The disturbance of any one of these equilibrium conditions has the potential to disrupt the progression of the host response. In some cases, there may be a threshold value for a reaction parameter that is associated with unacceptable behaviour. But it many cases it may be a subtle single event that triggers a cascade process and the rapid evolution of a clinically disastrous outcome. This is metastable biocompatibility.

The phenomena associated with metastable biocompatibility may become apparent as soon as the material comes into contact with the tissues, or may not occur until years after contact, triggered by some randomly occurring event. It may well be that the trigger is associated with the metastability of the surface of the material itself. Or it could result from the stimulation of some autocatalytic biological process such as the formation of a blood clot or the triggering of a hypersensitivity response such as complement activation and anaphylaxis. The successful use of mechanical heart valves is predicated on metastable biocompatibility, because there is no reason why any of the materials we use should be able to co-exist in a stable relationship with blood without causing a thrombus. We induce metastability through pharmacological means with anticoagulants. I have never seen a case of a fatal thrombus associated with a valve unless the patient has been transiently suboptimally anticoagulated.

I believe that the majority of cases of poor, unacceptable, clinical biocompatibility can be traced to the inherent metastability of biomaterials–tissue systems and that this metastability can be challenged by extraneous triggers, often related to issues of clinical variability, patient compliance and activity and variations in manufacturing conditions. By definition, no metastable system is guaranteed to be stable under all conditions and accidental triggers are always lurking and ready to pounce. That really does sound like biocompatibility.