In the 1980s, it became clear that there were problems with the use of polyurethane, most famously the foamed polyurethane used as the outer casing for breast implants. This material was particularly chosen because it reduced the problem of ''capsular contracture", a common complication in breast augmentation surgery where tissue forming around the implant contracts and causes the implant to appear hardened (Handel and Gutierrez, 2006). It was found that on removal of the implants substantial amounts of the polyurethane material was missing (Slade 1982) this led to concerns that the degradation of the polyurethane in these materials could release substantial amounts of toluene diisocyanate, a potential carcinogen. Though there was found to be evidence of the presence of this material in women with polyurethane-coated implants, the levels were small and the risks felt to be remote (Sepai et al., 1995), this particular approach is no longer used in the US and Europe at least. There would appear to be no evidence of any long-term health problems as a result of the use of these devices.

From a mechanistic point of view the degradation of catheter leads used for pacemaker leads was a more informative problem (Santerre et al., 2005) and was particularly studied by Stokes (1993). On the basis of this work and others, it is apparent that there are a number of processes that can contribute to the in vivo degradation of polyurethane systems, these include hydrolysis of the polymer; in particular the ester linkages in ester urethane based systems are susceptible, in the case of the degradation of catheter leads the polyether urethane system degrades via an oxidative process, and that this was catalysed by metal ions present in the pacemaker leads. Thus in the most general terms it would appear that polyether urethanes degrade by oxidation and polyester urethanes by hydrolysis.

There are many approaches to this problem but a chemical approach has been to utilise variations on the ester or ether flexible component. For example, the polycarbonate systems [8] [bionateā„¢ 80A, which has a MDI hard segment chain extended with butane diol and a poly(1,6-hexyl 1,2-ethylcarbonate) soft segment] has been shown to be less labile towards oxidation than the polyether urethanes [9] [ElasthaneTM, with the same type of hard segment, but a poly(tetramethylene oxide) soft segment] (Seifaliana et al., 2003).

Unfortunately, while more stable, there is evidence that polycarbonate systems also degrade. It has been suggested that the mechanism is also oxidative and involves the in vivo formation of reactive oxygen radicals (Christenson,

Anderson and Hiltner, 2004). The biological system represents a hostile environment to the polymer thus poly ether systems are oxidised it would seem by reactive oxygen species generated from adherent macrophages and foreign body giant cells (Christenson, Wiggins et al., 2004). The reactive oxygen radicals then react at the carbon adjacent to the oxygen creating a site for cross-linking or subsequent chain scission (Handel and Gutierrez, 2006). In this case the ether oxygen provides additional stability to the unpaired electron by virtue of its lone pairs [Fig. 3.13(a)]. It has been suggested that the (albeit a smaller amount of) degradation by polycarbonate occurs in the same way through reaction at the carbon adjacent to the oxygen [Fig. 3.13(b)]; however, it should be noted that the proximity of the p-bonded carbonyl may reduce this stability,5 and this particular hydrogen is not particularly reactive (Qureshi et al., 1995). It has further been suggested, that the degradation then proceeds via further reaction with hydroxyl radicals followed by fragmentation of the hemiacetal produced. Of course in the presence of oxygen an alternative pathway would be the addition of oxygen followed by hydrogen atom abstraction and subsequent decomposition of the hydroperoxide produced, (as in the autoxidation on storage of low molecular weight ethers, which is a well known explosion hazard); but the end result is largely the same. The important point here is that oxidation is the problem and may be countered with appropriate antiox-idants; however, the problem of degradation by hydrolytic enzymes must also be considered (Labow et al., 2005; Tang et al., 2001) although there is some evidence to suggest that this is less of a problem than oxidation (Christenson et al., 2006), the complexities of biological systems suggests that the relative n

Fig. 3.13 The reaction of hydroxyl radicals with

(a) polyether units to form a stabilised radical and

(b) with the carbonate

x h2o

5 The possibility of electron overlap between the oxygen lone pair and the p-electron system of the carbonyl group effectively reduces the availability of the lone pair electrons for interaction with the radical centre.

importance of the two components are likely to vary from material to material and from application to application.

Such is the versatility of the polyurethane approach that there are a number of applications which rely on an entirely the opposite principle; namely the ability of certain polyurethanes to decompose in situ. Applications include the use of polyurethanes for tissue and bone scaffolds and for drug delivery systems. The principal is a simple one namely that the biological tissue once grown back is the most appropriate system and the scaffold provides a temporary structures which allows regeneration. The scaffold may be impregnated with material, such as fibroblast growth factor (bFGF), which is slowly released from the polymer and will assist in tissue development (Guan et al., 2007). One particular concern however with the use of the aromatic systems is any in vivo degradation will result in the generation of harmful amines (Zhang et al., 2000). Thus in general, but particularly for applications where biodegradation might be needed, considerable interest has been shown in the use of lysine diisocyanate (or strictly lysine diisocyanate ethyl ester) and butyl diisocyanate. The likely degradation products of these are lysine and diaminobutane (also known as putrescine) which are commonly found in biological systems and might be expected to be of relatively low toxicity; indeed studies show this to be the case (Guan et al., 2004). The problem the of course being that these aliphatic systems do not exhibit the same properties as the aromatic systems in particular the hard segment may be less rigid. A way around this is to use other aromatic groups such as tyrosine in the chain extender to provide additional rigidity without the potential toxicity and the system outlined in [10] has been prepared (Guelcher et al., 2005).

It is early days in terms of the application of these biodegradable scaffolds, but it is clear that with there are range of materials possible. In particular by varying the nature of the polyester component the rate of degradation can be controlled, and suitable (non toxic) hard segment chemistry can be used to match the mechanical properties to the application required. Processing methodologies such as electrospinning offer substantial control of fibre dimensions, and short of growing biological replacements in vitro, this approach offers probably one of the best options for tissue regeneration.

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