Medical Device Link.

Conventional devices from traditional biomaterials

In my last column on different directions for the biological evaluation of biomaterials,1 I concluded that we should consider better methods for these types of evaluations, just as we are currently revising our views on what exactly is a biomaterial. I referenced a recent paper of mine on the subject of the nature of biomaterials to highlight this point.2 Because this discussion has major implications for materials in medical device technology in general, it seems appropriate to expand on the subject in this column.

For many years I have been concerned that the traditional concepts of materials science and engineering are becoming outdated when they are applied to the application of materials
in medicine. Being initially trained as a materials engineer, I held onto the view that materials were “substances useful for making objects.” This posed no problem when those materials were used for manufacturing what we now consider to be classical or traditional medical devices. A titanium alloy follows conventional laws of metallurgy and is used in total joint replacements, mechanical heart valves and implantable electronic devices. A silicone elastomer follows the laws of rubbery elastic solids and is used in implantable and nonimplantable medical devices. Polyetheretherketone (PEEK) complies with the conventional laws of thermoplastic polymers and is used in a wide variety of medical devices. In each case, we can see that they are substances and extremely useful. It is usual to consider those substances as solids because we do not normally make things out of liquids and gases, and by convention we assume that we can see them and hold them. Moreover, we usually consider that the objects are made by a top-down manufacturing process, in which bulk material is shaped by one of many moulding, extrusion, casting, machining or other engineering processes.

Changing requirements for biomaterials

Now let us consider the evolution of medical technology in the past decade. As I have noted in this column before, the science of biomaterials for implantable medical devices has matured. Rarely do we have to look outside a small group of materials, which combine chemical and biological inertness with mechanical and/or physical functionality, when selecting materials for those devices. Alongside titanium, silicones and PEEK mentioned above, there are cobalt- chromium alloys, stainless steel, carbon, polyethylene, acrylic polymers, textiles such as some polyesters and fluorinated hydrocarbon polymers, and a few others, which all generally give good performance. Because their performance is predicated on inertness, however, there is a limit to how far they can go to meeting the demands of other medical therapies. We may consider here, for example, tissue engineering scaffolds that are specifically designed to be interactive with cells and to be biodegradable. In gene therapy we are using polymeric particles that can deliver DNA to target cells. With contrast agents and in vivo diagnostic imaging systems we are using nanoparticles that can be targeted to specific receptors on cells and respond to interrogation systems such as magnetic resonance or ultrasound. The significant question asked of materials scientists here is whether these structures, which possess these types of functionality, can be considered to be materials.

I believe that it is now time to change our thinking on what constitutes a material, and therefore, on what constitutes a biomaterial. The boundaries between material classes such as the alloy, the elastomer and the thermoplastic polymer mentioned above are being eroded. Those “substances of which objects are made” are no longer simply derived from clear, chemically defined interatomic and inter-molecular bonds. They have been replaced by those of greater structural complexity that arise from different concepts, including those of nanotechnology and self assembly processes inspired by nature. For example, it is a basic concept of nanoscience and nanotechnology that materials produced by top-down manufacturing processes are being replaced by those derived from natural bottom-up synthesis. This is reflected in the new science of biomaterials. It is obvious now that we used to think of materials as being substances of which things were made simply because we visibly saw the objects being made by classical manufacturing or engineering processes. It follows that some of the original basic concepts of classical materials science no longer apply. The first one is that a material had to be a solid. This no longer applies and therefore liquid contrast agents, some soluble pharmaceutical preparations and liquid injectable tissue engineering matrices all qualify as biomaterials. The second is that if something is made from this substance we should be able to see it or hold it. We cannot see nanoparticles, but they may be biomaterials. The third is that there was an implicit assumption that these objects would be inanimate and indeed all initial definitions of biomaterials determined that they were nonviable. That is no longer the case; many of today’s biomaterials contain living cells.

Viability and biological activity

These changing concepts may not be easy to assimilate and we need some justification for such a major adjustment in emphasis. For example, take the concept of viable bio-materials. Normal healthy human tissues or organs are not biomaterials. Similarly, an organ or tissue that is transplanted from a donor to a recipient or from a donor site to a recipient site in the same person without any significant manipulation should be considered to be human tissue rather than a biomaterial. If, however, that tissue or organ is manipulated to change its character or to modify the anticipated response from the recipient, we should consider it to be a biomaterial. This is already the case when bioprosthetic heart valves are derived from xenogeneic collagenous tissue in which the tissue is rendered acellular and nonviable. It should also be the case when any tissue derived substance is substantially modified, even if it retains cells and its viability; it would be appropriate to consider this as an engineered tissue, which I believe qualifies it as a biomaterial.

We may follow a similar type of argument when we consider pharmaceutical agents. There are clear definitions of classical drugs, which have legal and regulatory consequences. But this situation is also changing. Already the coupling of some anticancer drugs to antibodies, serum proteins and synthetic polymers has been achieved, which remarkably increases the therapeutic index of those cytotoxic drugs. Much of this technology is within the realm of the nanoscale and I believe that these engineered drugs are also biomaterials. Perhaps even more significantly, we have seen the use of material–drug combinations such as drug-eluting stents and bone morphogenetic protein releasing spinal implants, where the pharmacokinetics of the drugs in question appear to be different from those of the original drug. It seems naïve to consider the materials and drugs of those combinations as separate entities and it is sensible to consider the engineered composites as biomaterials in their own right.

A new definition

In these and other examples,2 it has to be concluded that once a structure or a substance is engineered in some way to meet the requirements of a medical technology, then that structure qualifies as a biomaterial (for a detailed discussion of what engineering means here see reference 3). There are, of course, serious consequences of such a change, ranging from regulatory to economic, thus this is not merely a matter of semantics. I do believe that we are now in a position to alter our definition of a biomaterial to bring it into line with applications in the twenty-first century and I suggest the following:

A biomaterial is a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure.

David Williams, Morgan & Masterson, Avenue de la Forêt 103, Brussels 1000, Belgium, tel. +32 4 7597 0556, e-mail: peggy@morgan-masterson.com, www.morgan-masterson.com