Medical Device Link.

I am writing this column while travelling to Beijing, China, where the host to some lectures I shall give will be Professor George Chen of Tsinghua University (www.tsinghua.edu.cn/eng/index.jsp). Professor Chen, who is a microbiologist, has conducted a great deal of work in recent years on polymers based on polyhydroxybutyrate (PHB). His studies remind me of some work I did more than twenty years ago on these materials.

PHB belongs to a family of polymers, the polyhydroxyalkanoates (PHA). These are linear polyesters that are produced naturally during bacterial fermentation. Certain microbes are able to convert sugars and lipids into PHAs in order to store carbon and energy; this process is reversible so that the bacterial cells in which the PHA crystals reside are able to utilise the energy as and when required. The precise type of PHA that is produced, and there are more than one hundred forms, depends on the bacterial culture conditions. Many years ago it was found that the PHAs synthesised by bacteria in large scale fermentation processes could be extracted from the culture and processed into solid thermoplastic polymers. Because the conversion of the polymer into small molecules, with the associated release of energy, is mediated by intracellular enzymes, it was assumed by some that this process could be replicated outside the bacterial culture system and that the polymers would be naturally biodegradable. A wide variety of potential commercial uses were discussed ranging from degradable plastic bags to biodegradable medical devices. The leading chemical company operating in this area set up a subsidiary to market these products. That company no longer exists, partly because of the erroneous assumptions that had been made, that is, that bacterially derived polymers such as the PHAs would be naturally degradable in any environment, including land fill and the human body. There had been strong commercial pressure to develop these nonpetrochemical based polymers as a result of the oil crisis and rapidly increasing oil prices in the 1980s.

Because I was conducting research on biodegradation phenomena in relation to medical technology at the time, that company asked me to confirm the biodegradability of its preferred PHA option, PHB, under in vitro and in vivo conditions. To everyone’s surprise, not least the company itself, which had already produced its glossy marketing brochure describing its resorbable PHB surgical sutures, the PHB steadfastly refused to degrade under any experimental conditions.1 We were able to see some degradation when the PHB was copolymerised with hydroxyvalerate to give PHB–PHV blends, but even then it was difficult. These results were supported by a telephone call I received many years later from a scientist in a different division of the parent company, who had investigated the potential of PHB for use in drug delivery systems. He made samples and exposed them to various fluids for varying periods of time; he forgot about those he was storing for a year in saline, until he came across them five years later in a cupboard. They had not changed at all in that time.

The lessons of biodegradation mechanisms

The lesson here was that just because bacteria can convert sugars into PHAs and then depolymerise them through the activity of their own intracellular enzymes under aqueous condition, it does not mean that other biological environments can cause the same degradation process, even if, as within the human body, a wide variety of enzymes are present. The lack of degradation, together with the fall in oil prices that made the requisite fermentation processes for PHB far less economically attractive, put a halt to these developments.

However, the renewed interest in biodegradable polymers for some of the rapidly growing areas of medical technology, including tissue engineering, has led to a reappraisal of these materials, and some formulations of PHAs that do possess the characteristics of biodegradation have been produced. These developments have had to be based on copolymer and composite systems (including soma nanocomposites) to achieve a good balance of biodegradability and mechanical properties. Although some PHA materials are thermoplastic with good formability and good strength, many are rather brittle and much effort has been exerted to improve these properties. There has been progress with the structural characteristics of the PHB and polyhydroxyvalerate, but the major contribution of Professor Chen has been to incorporate hydroxyhexanoate groups into the PHB chains.2 The poly(R-3-hydroxybutyrate-co-R-3-hydroxyhexanoate) (PHBHHx) polymers, for example, show excellent combinations of these characteristics.3

Other developments have occurred on the commercial side. The United States (US) company Tepha4 has recently received clearance from the US Food and Drug Administration to market its TephaFlex absorbable suture. This is made from a poly(4 hydroxybutyrate) variety using recombinant DNA technology5 and has biodegradable characteristics engineered into the structure, as well as good all-round mechanical properties and the handling features required of sutures. It is interesting to note that the bacterial fermentation route may well become redundant in PHA technology, because some plants such as switchgrass, which is cheap to grow, is able to produce PHAs in its root system; an acre yields more than 1 ton of PHA.6

As a final note on the work of Professor Chen, he and his colleagues have found that mice injected with the degradation products of PHB, 3-hydroxybutyrate, show improved learning capacity compared with controls.7 This results from increased neuroglial cell metabolic activity that enhances communication across the gaps between neurons. This is the first time, as far as I am aware, that the degradation products of polymers produces a beneficial effect, and this is in sharp contrast to the detrimental, proinflammatory characteristics of most polymer degradation products.

It has taken more than 20 years to move from a rather hopeless case of a failed “new biomaterial” to the situation where these biopolymers now have a new lease of life. Let us hope that this leads to really successful clinical applications.

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