Medical Device Link.

MATERIAL MATTERS COLUMN

I suppose that we should not be too surprised at the medical interest in the element magnesium. The therapeutic effects of the mineral waters in Epsom, UK, which are rich in magnesium sulphate and called Epsom’s salt or “sal anglicum,” have been known since the end of the 17th century, and magnesium supplements are popular today in preventive therapies. Nor should we be surprised at the serious engineering interest in magnesium alloys: their light weight means they are employed in the aerospace and automotive industries and their favourable nuclear properties led to their use as fuel element cladding in the Magnox reactors. Nevertheless, I suspect most people would be startled to see magnesium alloys now being used for implantable devices; these are currently at the experimental stage and just moving into the clinical arena. This is happening not just in one minor area, but also in at least two substantial and quite different settings and deserves some attention. These applications represent the first situations in which alloys that are known to corrode fairly rapidly are being intentionally used for implantable devices; of course, this goes against the trend to use ever more corrosion-resistant materials for long-term implantable devices.

Bioabsorbable stents

The first application area is that of intravascular stents. For a couple of years now, Biotronik GmbH & Co.¹ has been manufacturing and undertaking clinical trials with a magnesium alloy stent.² The preferred alloys appear to either contain 2% aluminium and 1% rare earth metals, or small amounts of zirconium and yttrium. Depending on the alloy composition and stent design, the corrosion period could range from a matter of a few days to a few months. Some animal studies have shed a little light on what could be expected from these stents, bearing in mind the performance of existing stents and their deficiencies. Most bare metallic stents are made from stainless steel, Nitinol or cobalt-chromium alloys and, although they have many good attributes, they still often lead to restenosis because of the prolonged irritation of the endothelium and the ensuing hyperplasia. Several versions of the stents incorporate antiproliferative drugs within a polymer coating and the release of these drugs reduces the tendency to restenosis. The driving force for degradable stents is that if the stent disappears through a degradation process, the stimulus for intimal hyperplasia disappears. Some attempts have been made to make biodegradable polymeric stents: now it is the turn of corrodible metals. The magnesium alloy stents corrode completely, which means the inflammatory stimulus could be removed. At this stage, there are a few unanswered questions, especially because experience with almost all corrosion processes shows that the release of metal ions, soluble salts or corrosion particles are likely, de facto, to stimulate inflammation. The animal studies suggest increased inflammation and early stage intimal proliferation, but the apparent remodelling of the blood vessel wall once the corrosion is complete results in a stable, clinically patent artery.³ It is notable that the so-called biodegradable metal stent has now been used in paediatric patients with congenital heart disease because blood-vessel growth would be compromised with a nondegradable stent.⁴

Orthopaedic applications

The second application area of interest is orthopaedics. Some of the first orthopaedic alloys involved magnesium, but they were not successful and fell into disuse. Changes to the alloying additions have allowed, as with the stents, the possibility of modifying the corrosion rate, again with rare earth elements such as neodymium, cerium and dysprosium together with minor percentages of aluminium and zinc, which are valuable in this respect. This has led to the experimental use of magnesium alloys in some orthopaedic applications, especially for those devices that have a specific short function such as the assistance of bone repair (plates, screws and wires) and which, ideally, should be removed once this function has been achieved.⁵ Some studies have shown that corrosion of plates fabricated from magnesium alloys could take place over four to five months without significant detrimental effects to bone or soft tissue. The fact that magnesium may stimulate bone repair in some circumstances⁶ has intensified the interest in this possible application. Yet, the observation that when magnesium-alloy devices corrode they may liberate hydrogen gas, which can accumulate in the surrounding tissue (one of the main phenomena which led to the abandonment of magnesium alloys about a century ago), suggests that caution still has to be exercised.

The physiology of magnesium

Clearly, it is not a trivial issue placing an intentionally degradable metal into tissues for critical therapeutic purposes when it is known that a corrosion process itself may be damaging to those tissues. One powerful argument in support of this use, however, could be that although the corrosion products of most conventional surgical alloys (such as cobalt, chromium and nickel-based products) may be considered potentially harmful, the products of the magnesium corrosion process are more likely to be physiologically beneficial than harmful.

David Williams Clinical Engineering Department, Royal Liverpool University Hospital, Liverpool L69 3BX, UK, tel. +44 151 706 5606 fax +44 151 706 5803, e-mail: dfw.ce@liverpool.ac.uk

The adult human body contains about 30 g of magnesium, most of it being present in muscle and bone.⁷ It is a cofactor in many enzymatic reactions and is especially involved in electrostatic binding to proteins and nucleic acids. It is essential for normal neurological and muscular function. Dietary magnesium deficiency perturbs bone and mineral homeostasis (at least in the mouse8), and magnesium depletion inhibits the function of bone-producing cells (the osteoblasts) while increasing the function of the bone-resorbing cells (the osteoclasts). Also, because magnesium binds strongly to phosphates, its presence influences the mineralisation of bony tissue through its control of hydroxyapatite (calcium phosphate) formation. In the cardiovascular system, magnesium depletion is associated with cardiac arrhythmias, the development of atherosclerosis, vasoconstriction of coronary arteries and increased blood pressure. It is no wonder that magnesium features so strongly in a wide variety of drugs and food supplements. The therapeutic window for magnesium supplements is wide and side effects are rare. Together with calcium, sodium and potassium, magnesium is efficiently controlled in the body by homeostatic mechanisms and toxicity is not generally a problem.

There is every good reason, therefore, to believe that the release of elemental magnesium from corroding magnesium alloys should not cause toxicity (either locally or systemically) and may even have positive beneficial effects on some of the structures, including cells, in the relevant local tissue. However, as is so often the case, a corrosion process cannot always be relied upon to be homogeneous and uniform, and we have yet to learn how soft tissues will respond to the release of particulate corrosion products that are going to be released from some of these devices.