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Morgan & Masterson Consulting

Selection of Clinical Biomaterials

David F Williams, PhD, DSc, FREng, FLSW
Author, Scientist & Consultant
David F Williams
Author, Scientist & Consultant

Selection of Clinical Biomaterials

When I entered this profession, the materials used in medical devices were not subject to the rigors of standard specifications or regulatory-prescribed safety testing, nor were there records of ‘acceptable materials’; it was, literally, a cottage industry, with many devices incorporating well- known fabrics, alloys, gels, fibers and plastics that had traditional household or industrial uses. There were no academic centers providing knowledge or experience about suitable materials – in 1968, my laboratory in Liverpool was one of the first in Europe to focus on this subject.

But slowly things changed – they had to. Steels were corroding in the body, metallic plates and rods became deformed because anatomy and elasticity could not be matched, plastics quickly wore out, elastomers started to crumble and gels would migrate, and many materials placed within circulating blood rapidly thrombosed. So, biomaterials laboratories were established, academic journals on biomaterials science found their way to library bookshelves and biomaterials societies were formed, in the USA and then in Europe.

Over the years, the number of clinically-applied biomaterials increased, although few were specifically designed for use within the body. Although some of the most unsuitable of these materials were eliminated from consideration because of demonstrably poor performance, catalogues of biomaterials kept getting larger, especially within the realm of polymers, where variations on a simple structure, through copolymers, blends, composites, surface treatments and so on, expanded the repertoire enormously. This scenario has been tempered somewhat in recent years as standard specifications introduced by bodies such as the International Standards Organization (ISO) and the American Society for Testing and Materials (ASTM) defined precise compositions and performance specifications, and as regulatory bodies such as the Food and Drugs Administration (FDA) demanded compliance with these characteristics.

The selection of materials for a specific application, however, involves a great deal more than plugging the required performance requirements into a searchable database and coming up with the ideal match; there are no algorithms here since clinical performance is influenced by a multitude of factors, and since a very wide spectrum of material characteristics join together, sometimes antagonistically, sometimes synergistically, sometimes totally independently, to determine outcomes.

This is where the knowledge and experience of a consultant comes in. Such a consultant may be retained by a materials company that is developing and supplying new products to the industry and needs to know how the properties of candidate materials can be refined and targeted to device applications. Alternatively, the consultant may be retained by a medical device manufacturer that has defined the ‘user needs’ for a new product and has to select the most appropriate material(s) to satisfy those needs.

Consulting for Biomaterials Companies

The biomaterials supply chain incorporates several different types of companies, ranging from major multinationals with either chemicals, materials or pharmaceuticals expertise and capacity, to small specialist groups, either university-based spin-offs or discrete start-ups derived from the major conglomerates. Whilst the attractiveness of high added value within the healthcare sector, often with very limited development costs, led to the rapid involvement of these major players within the medical device sector, including Dow Chemicals, 3M, Pfizer, Bristol Myers Squibb, and DuPont, the realization that this could attract profound litigation if things went wrong, forced many of them to rethink and find other ways to be involved. The field is now dominated by the smaller companies that are structured to be legally and financially distant from these major companies. In this form, such companies often do not have requisite skills in-house and rely extensively on outside consultants. Some examples are given here briefly:

Polyetheretherketone (PEEK) and other thermoplastic polymers

There are many opportunities for thermoplastic polymers in implanted devices, but since the majority of them are far more rigid than the soft tissues of the body, great care has to be taken with respect to biomechanical compatibility. High density polyethylene, used as a bearing surface in many joint replacements, is probably the best example of such a use, but its mechanical properties, especially creep and wear resistance are unsuitable for some highly stressed situations. In the late 1970s a laboratory in one of the UKs largest chemical / materials companies developed an exceptional high-performance thermoplastic, polyetheretherketone (PEEK). The multinational created a separate company to develop and market PEEK and some derivatives, and out of this was formed a separate company to explore healthcare applications. Working with the parent company I had already carried out investigations on the biocompatibility of PEEK and carbon-fiber reinforced PEEK, and I then acted as consultant to the healthcare derivative on matching some of the excellent properties to applications, especially in spinal fusion devices and craniofacial reconstruction.

Degradable polymers

At the other end of the polymer spectrum are those materials designed to be biodegradable rather than biostable. These have potential uses in implantable drug delivery systems, where the presence of the delivery vehicle is not required (or disadvantageous) after the drug has been administered, and in those devices that have a transient function (e.g., assisting in fracture repair) where continued residence in tissues for the lifetime of the patient could have adverse consequences. Of course, the degradation process itself should not harm the patient, so that the majority of approved degradable systems are based on naturally occurring substances that can be converted to high molecular weight polymers which are then degraded, for example by hydrolysis, within the body and eventually metabolized and excreted. Several companies devoted themselves to the search for optimal materials, where the choice was determined by combination of functional properties, such as strength or drug diffusion, and degradation profile, including rates of degradation and biocompatibility of the degradation properties. The most widely used family of polymers here have been the aliphatic polyesters; these primarily include the polymeric forms of lactic acid and glycolic acid. The matching of composition to function has not been a trivial matter, since polylactic acid exists in two isomeric forms and since a series of copolymers, polylactide-glycolides, of varying composition can be synthesized, with degradation rates ranging from weeks to years. I have consulted with manufacturers of these and other biodegradable systems to establish optimal (and precise) compositions and to present information on these forms to clinical audiences.

Surface coatings

While the performance of most implantable devices is dependent on the bulk properties of a biomaterial, such as mechanical and physical properties, the intricacies of that performance are determined by the interface between the biomaterial and the tissues. Thus, the success or otherwise of a device is as much, if not more, dependent on the surface characteristics than on those bulk properties. There are many ways in which the surface properties can be modulated in order to improve performance; sometimes these involve surface treatments such as anodizing of alloys, ion implantation, plasma treatment of polymers and, more recently, modifying surface topography at the nano-scale. Such modifications are normally achieved by the device manufacturer. An alternative approach involves applying a coating of an entirely different substance to the surface. Surface coating technology features very strongly within the biomaterials community, and several companies have been engaged in the development and application of anti-bacterial or non-thrombogenic coatings, or lubricious surfaces to improve clinical techniques. This is not a trivial task since medical device surfaces tend to be quickly covered by a layer of proteins once placed within the body, so that the desired characteristics are masked, or even destroyed. Over the years, I have consulted with several companies with the objectives of optimizing the performance of surface coatings.

Bioactive ceramics

The mineral phase of bones and teeth is a version of a calcium phosphate ceramic, specifically a calcium hydroxyapatite. This basic fact has encouraged academics and manufacturers of pharmaceutical grade calcium phosphates to search for uses of these materials in medical technologies, including reinforcement or replacement of mineralized tissues in orthopedics and dentistry. Once again, such a search has not been easy, partly because the outstanding contribution that hydroxyapatite makes to the characteristics of bones and teeth is highly dependent on the synergistic effect of this ceramic when embedded in structural proteins, such behavior not being seen in the native ceramic itself. Furthermore, there is a very wide range of calcium phosphate substances, with varying stoichiometry and crystallinity, the properties of each form being different and not easily matched with the clinical requirements. One of the biggest difficulties here refers to the language that is used to describe the substances, most being referred to as ‘bioactive’, where there is little evidence of specific biological activity. Again, this is an important area of consulting, requiring experience in inorganic chemistry, biocompatibility, and clinical technique.

Bioprinting gels and inks

The advent of 3D printing technology has had a profound impact on many manufacturing processes. The majority of examples here have involved the preparation of products using essentially inert materials, and certainly not those which are living. However, during the last few years, this capability has been extended to situations where the 3D printing process does actually involve living cells. Printed tissues have potential in areas of regenerative medicine and within the pharmaceutical industry where very small volumes of printed cell and their matrices can be used either in drug discovery or toxicological testing. These techniques are usually described under the broad heading of 3D Bioprinting; the processes are made possible by complex instrumentation, at the heart of which, in most cases, are cartridges containing a fluid that encompasses the relevant cells and nutrients and which can gel as it is spun or extruded into the required tissue form. These fluids are referred to as Bioinks, for obvious reasons. Once again, the requirements here are complex and multifactorial, involving strict biocompatibility requirements as well as those features, such as viscosity and time- and temperature-dependent transfer properties, that regulate the printing process.

Consulting for Medical Device Companies

Since, as noted earlier, there are now many internationally-recognized standards for biomaterials compositions and functional performance, it might seem to be a straightforward task to consider the details of a device ‘user needs’ file and select the most suitable materials from those standard lists. This is not necessarily the case. Consider the situation, for example, of a drug-eluting coronary artery stent. This, indeed, does look straightforward as the product consists only of a metallic framework and a thin, drug-containing, polymeric coating on that framework. Naturally, in the product development process, design and materials characteristics are considered together, but the overall characteristics that determine clinical outcomes will include elasticity (and possibility superelasticity), fatigue and creep, metallic biocompatibility, polymer stability or degradability, polymer-drug compatibility, drug diffusion, polymer biocompatibility, drug pharmacokinetics and device thrombogenicity. These considerations require a wide array of expertise and experience attributes.

Alloys for orthopedic devices

A hundred years ago, there were vanadium steels; then came stainless steels, and eventually, and specifically, the low carbon, molybdenum-containing series of stainless steels, which represented the foremost of the ferrous alloy used in implants; but it could still show signs of corrosion and released nickel into the body. Challenging this, from 60 years ago, were a series of cobalt alloys, especially ‘vitallium’ and then ‘stellite’ which found use in both dentistry and orthopedics; they were good for castings but, in the early years, were brittle. These alloys have been improved, with varying contents of cobalt, chromium, nickel, tungsten, molybdenum, and other transition metals, giving good corrosion resistance, hardness and toughness. Titanium, and some titanium alloys followed in subsequent years, having superior corrosion resistance, lower elasticity and, according to some people, bone bonding characteristics. Even within the single discipline of orthopedics, the selection of which specific alloy, and in what heat-treated condition or with what surface treatment, is the optimal biomaterial is not straightforward. Coupled to that scenarios is the possibility that shape-memory may be considered for some applications, and then, more recently there is the option of using biodegradable alloys such as those of magnesium for situations requiring only transient presence. Being trained as a metallurgist has given me many opportunities with these various alloys.

Tissue engineering scaffolds

I have defined tissue engineering as ‘the creation of new tissue by the deliberate and controlled stimulation of selected target cells through a systematic combination of molecular and mechanical signals’. Such a definition does not mandate the involvement of biomaterials in tissue engineering processes, but, in the majority of situations, that stimulation is achieved (or at least attempted) through the use of scaffolds, which are either gels or porous solids, within which can be incorporated stimulating molecules and through which mechanical signals can be physically transmitted. The biomaterials that have been used, successfully or, more often, unsuccessfully, have been biodegradable polymers such as polycaprolactone, biopolymers gels such as collagen or hyaluronic acid, or some calcium phosphate based ceramics or glasses. The real problem here, and why expertise is greatly needed, is that virtually all early clinical applications involved modified traditional biomaterials that had received prior FDA approval for use in medical devices; to receive such approval, manufacturers had to show that their material had no effect on the tissues of the body (i.e., they were biologically inert), which is directly opposed to the stimulatory properties that are required for tissue regeneration.

Anti-bacterial silver devices

One clinical problem with prosthetic heart valves is the rare, but usually fatal, episode of bacterial endocarditis, in which the valve becomes infected, and the bacterial colony affects blood flow and potentially leads to systemic infection. A major heart valve device manufacturer decided to solve the problem by coating the sewing ring with a layer of silver, a metallic material with known antibacterial properties. This did not work too well, or rather the company was not able to demonstrate to the satisfaction of the FDA that it worked; which is hardly surprising since it would have required a controlled clinical trial involving thousands of patients to demonstrate a significant reduction in endocarditis rates, which were only of the order of a few percent in normal patients. This device did lead to major litigation, which I shall discuss in the expert witness section; what is relevant here is the controversy that followed about whether silver does have antibacterial properties when applied to biomaterial surfaces, whether the metal can have adverse effects on patients, and what is the best form of silver for medical applications. These forms include silver nanoparticles (‘nanosilver’) wires (‘nanowires’), compounds or alloys. Not all of these questions have been answered.

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