Plastic fantastic

The provision of a safe, plentiful alternative to donated blood has come a step closer recently thanks to pioneering work at the University of Sheffield, as transfusion scientist Barry Hill reports

For transfusion scientists, the search to create a readily available universal artificial blood substitute has been likened to trying to find their own personal holy grail. But despite many promising alternatives being put forward, particularly by the biotechnical and pharmaceutical communities, there still seems to be no substitute for the real thing, namely donated human allogeneic blood. Phase III clinical trials of artificial blood products such as haemoglobin solutions and perfluorocarbons are now in progress and are some are proving a useful temporary oxygen carrier during surgery and an alternative to donated blood. However these haemoglobin-based products tend to have a reduced effectiveness. Additionally the possibility of hypertensive side-effects and the relatively short half-lives of these recombinant or synthetically created substitutes have so far limited their overall beneficial use. However if such a product could be produced safely and cost effectively then its value in routine, emergency and even battlefield situations would be enormous.

Blood as a resource has never been more in demand than it is today. Escalating elective surgery, an aging population and spiraling costs due to ongoing safety introductions have all conspired to ensure that blood remains very much a liquid asset to the NHS. Ensuring donated blood is safe for transfusion to patients is an expensive and time-consuming process, involving collection, fractionation, testing and issuing at blood centres. A series of new safety tests have been introduced over recent years to minimise the risks of viral transmissions such as HIV and hepatitis C, as well as removing the possibility of bacterial contamination in components such as platelets. In addition, the possibility of vCJD transmission via blood products is another factor, resulting in the introduction of the leucodepletion of all blood components by the National Blood Service (NBS) in 1999 to remove the mostly likely transmission route. The threat posed by vCJD to the blood supply has also resulted in stringent NBS donor restrictions being introduced in April 2004 which has reduced availability by an estimated 52,000 donors, with more forecasted shortfalls in the future expected in the coming years in the wake of the possible introduction of a donor screening test for the presence of vCJD itself. And once in the hospital blood bank environment itself, there is still an element of risk attached to donor blood, primarily as a result of clerical or procedural errors which can result in an inappropriate transfusion occurring or worse still, a component intended for a different patient being transfused.

In addition to its strict storage temperature requirements and a limited life cycle of 35 days, the availability of certain blood groups is another problem. In particular stocks of group O RhD Negative, the so-called universal donor are always in demand due to its requirement for emergency situations. Clearly if a universal blood substitute could be made readily available then the problems of maintaining the safety of the existing blood supply would be relieved considerably, and now thanks to a breakthrough by scientists at the University of Sheffield, this could soon become a reality

Like many important potential scientific breakthroughs, Dr Lance Twyman’s came almost by accident. Twyman, who is based in the Biochemistry Department at the University of Sheffield realised that his work on porphyrin and polymer chemistry had created a branch-like structure that had significant similarities to the haemoglobin molecule itself in size and shape, whilst providing exactly the right environment around the porphyrin core for iron to bind and release oxygen. From this Twyman effectively created an artificial blood composed of plastic molecules that hold an iron atom at their core just like haemoglobin. The small plastic molecules join together in a tree-like branching structure, with a size and shape very similar to that of natural haemoglobin molecules. This creates the right environment for the iron to bind oxygen in the lungs and release it in the body.

Best described therefore as ‘plastic blood’, Twyman outlines its possible uses. “Because the artificial blood is made from a plastic, it is affordable, light, easy to store and stable at room temperature. Doctors could store the substitute as a thick paste in a blood bag and then dissolve it in water just before transfusing it to patients. At the moment, we have no idea regarding the polymer's lifetime in the body, however, for its intended application, a short lifetime is an advantage. One obvious application is the battlefield or site of a major incident where replacing blood loss quickly can save lives. A second-generation molecule is now being developed for more rigorous investigation and, if all goes well, human use may eventually follow”.

Dr Twyman and his team’s preliminary results were published in the journals Chemical Communications and Supramolecular Chemistry in 2006. The scientists working on the research for the past five years have been funded by the University of Sheffield and the Engineering and Physical Sciences Research Council. Twyman has also received funding through one of Yorkshire Forward’s Bioscience Yorkshire Enterprise Fellowships. A sample of the current artificial blood prototype has been on display at the London Science Museum from May 2007 as part of a new exhibition entitled `Plasticity – 100 years of making plastics´. The exhibition, which will run until January 2009, will cover the history, development and future of plastics and present some of the most practical, ingenious and strange uses of polythene, PVC, nylon, polyester and many others in fashion, the home, design, transport and more. Twyman and his team are now seeking further funding to develop a final prototype that would be suitable for biological testing. "We are very excited about the potential for this product and about the fact that this could save lives. I hope people therefore take the opportunity to go and see the display at the Science Museum and hopefully in the future it will be more than just a prototype, but will be a real product used in life or death situations."

But despite the promising results coming from Sheffield, some transfusion scientists remain unconvinced regarding the long term future of artificial blood substitutes. Grant Webb, Blood Transfusion Training Officer at the Leeds Teaching Hospitals and a member of the British Blood Transfusion Society seriously doubts that we will ever see the routine clinical use in the hospital environment in our lifetimes. “There are currently no artificial oxygen carriers licensed for use in the UK and there are none likely to be licensed in the near to medium future. So far, despite enormous investment, particularly by the US Navy, all haemoglobin-based products have bound nitric oxide (NO), causing undesirable venoconstriction as NO is an important vasodilator. Accordingly, several leading commercial companies have effectively abandoned their efforts in this field. Perfluorocarbons only fare a little better, they have been used in clinical trials for cardiac surgery in Canada and clinically in South Africa. The problem with them is that the patient has to breathe hyperbaric oxygen for them to carry much more oxygen than albumin. They are not readily excreted from the body and pool in the liver, sometimes causing fatty liver changes similar to that of alcohol related liver damage.”

Webb considers therefore that the transfusion community in general has lost interest in blood substitutes to a significant extent. “Papers on blood substitutes are now a rarity in mainstream transfusion journals and commercial companies do not see a profit in the foreseeable future. One of the key drivers for development of these products has been the perceived biological risk of transfusion of infection by donated blood products. This problem is now very small, indeed it represents an unsung triumph of the transfusion community over the last thirty years or so to reduce the biological risk of blood products so dramatically that they now represent trivial risk in comparison to other lifestyle risks widely accepted by the community. Ongoing developments such psoralin treatment will reduce this risk still further if we decide to introduce it, although in my opinion the cost benefit does not support its use. The money could be better spent elsewhere in the healthcare system with a far greater patient benefit.”

By Barry Hill. Barry has worked within pathology for over 30 years and specialises in the discipline of blood transfusion & haematology. A former member of the IBMS Blood Transfusion Special Advisory Panel, he is also a prolific freelance writer of short medical articles for a wide range of medical & scientific based publications. Outside of work he enjoys walking the beaches of Anglesey with his family and dog where they have a weekend retreat, as well as playing his guitar and harmonica.