Reprinted with permission from EPSRC Spotlight: Border-Crossing Science, Summer 2003.
Human skin is a vital borderland between the world and our bodies: When its protective layers are removed, due to severe burns from fire or corrosive chemicals, we soon die. As many EPSRC -supported researchers are discovering it could also be one of the most exciting areas for collaboration between scientists from different disciplines.
Dangling on a rope, 50 metres up a sheer rock wall, may not sound like the best place to forge a research collaboration but for Martin Berzins and Annette Bunge rock climbing and research are a good mix. They first met each other when mutual climbing friends suggested they collaborate and although they work in very different fields of research, they soon realised that by putting their heads together they could tackle an interesting problem.
Professor Annette Bunge, from the Colorado School of Mines, USA, is a chemical engineer who is used to work on modelling the flow of oil through rocks. More recently she has moved towards multidisciplinary biological problems and currently she is studying the structure of human skin. In particular she is interested in how chemicals are absorbed and penetrate through skin and according to her, "the techniques used to model how substances diffuse through skin are not so different from those used to model the flow of oil through rocks!"
Meanwhile Professor Martin Berzins, based in the School of Computing at the University of Leeds, is an expert in computer modelling. Previously he has written numerical simulations to represent a wide variety of systems ranging from the microscopic deformation in the cogs and gears of machinery to the evolution of jellyfish. When Berzins and Bunge met they recognised the potential of combining their research skills and now the EPSRC has funded Dr Chris Goodyer at Leeds to work with them to try and model how quickly different chemicals penetrate through a layer of skin.
Every day our skin comes into contact with a multitude of substances. From soap to cosmetics and even droplets of liquid in the air, our skin has to cope with it all. So what proportion of those substances stay on the outside and how much manages to pass through our skin and into our bodies? This question becomes particularly pertinent when considering toxic substances such as pesticides and some of the ingredients that go into cosmetics.
Skin has a very complex structure and the current models of skin tend to ignore the microscopic details. Berzins, Bunge and Goodyer are aiming to develop a higher resolution model of skin so that they can predict how skin structure affects the rate of chemical penetration through skin and give a level of confidence for their result. This will enable organisations like the environment agency to assess safe levels for chemicals such as those found in pesticides. Professor Bunge's experimental work has provided a detailed knowledge of the microstructure of skin. "Human skin cells are known as corneocytes and look like little hexagonal lozenges," she explains. The layered structure of corneocytes is crucial in controlling how much evaporation and chemical adsorption occurs through the skin. Berzins and Goodyer are building up a model of skin structure by using Bunge's experimental results. "Skin is a bit like a dry stone wall," says Professor Berzins. "The path of a fluid around the corneocytes is very complex and similar to water flowing around stones."
Despite the fact that Bunge is based in Colorado, Berzins is visiting the University of Utah and Goodyer remains in the UK, they manage to work together on the same research problem. This is partly thanks to Grid-based computing, being developed as part of the UK e-Science program, which is managed by the EPSRC. Grid-based computing is like a glorified version of the internet that enables scientists to share access to large data collections and computing resources. "Even though there are thousands of miles between us, the Grid enables us to both work on our model simultaneously," explains Professor Berzins. "We can still talk about results and change parameters as if we were sitting in the same room, with the video conferencing of the Access Grid providing a means of communication," he adds.
Models and Drug Delivery
Professor Berzins has frequently worked on multidisciplinary projects and feels there are many advantages. "Aside from the fact that it is fun and interesting, I also find that multidisciplinary research makes me re-think my own core area and approaches and helps me to look at problems from a different angle," he says. However, it isn't all plain sailing and getting funding for multidisciplinary research is sometimes the biggest hurdle. "It can be difficult to convince a panel of specialists from a single discipline of the benefits of multidisciplinary research," he adds. Multidisciplinary Life Sciences funding panels are one way of addressing this issue. Berzins, Bunge and Goodyer managed to convince such a panel of the importance of their research and now they have been given three years to build up computer models of skin. It is early days yet, but all three researchers are confident that by working together and pooling their skills they will be able to make an impact on understanding how chemicals penetrate through skin.
One scientist who is particularly interested in the work of Berzins, Bunge and Goodyer is Professor Jonathan Hadgraft from the University of Greenwich. Professor Hadgraft is a physical chemist who works on skin permeation and is currently looking at drug delivery via the skin.
Compared to popping a pill, delivering a drug via a skin patch can provide a much more constant and smooth supply. However, the rate of flow through the skin depends upon the nature of the skin and the chemical properties of the drug being delivered. For this reason it is vital that drug flow is fully understood before a particular drug is delivered via a skin patch. The research being carried out by Berzins, Bunge and Goodyer is extremely relevant to drug delivery via skin patches and Professor Hadgraft has an ongoing collaboration with them. They hope to be able to model drug delivery through skin using the computer simulations developed by the team.
Professor Hadgraft met Professor Berzins through a group that he co-ordinates called the Skin Forum. This is intended to encourage national and international collaborations and bring together academics and companies carrying out skin research. "The aim of the skin forum is to identify people who have an interest in skin permeation and bring them together to exchange ideas," explains Professor Hadgraft. "In addition we try to attract people on the periphery of the area who may be able to contribute new techniques," he adds. For the last three years the EPSRC has funded the forum, along with companies such as GlaxoSmithKline. The main event is an annual meeting, bringing together companies and academics with an interest in skin research but the Skin Forum also makes sure that it keeps abreast of current thinking and that research is aimed at something applicable and useful: "We commissioned a survey that was sent out to both pharmaceutical and cosmetic industries to see what areas of skin research were thought to be most relevant and should be covered in grant applications," says Professor Hadgraft. The Skin Forum provides an ideal place to exchange ideas as well as initiating a link between academic research and industrial and clinical applications. "By discussing research outside one's normal network of colleagues you generate new ideas and meet people who you would have never met otherwise," says Professor Hadgraft. "These interactions encourage synergistic research projects that will ultimately provide a better understanding of skin permeation and hence provide improved skin medicines for the future," he adds.
The Skin Engineers
Meanwhile over at the University of Sheffield another group of scientists are being funded by the EPSRC to look at skin from a different angle. Professor Tony Ryan from the Department of Chemistry is leading an inter-disciplinary research team to develop tissue-engineered skin for accident victims.
At the moment if someone is unfortunate enough to suffer a serious burns injury then they will require extensive skin grafting. When there is insufficient of the patient's own skin to graft all the burned areas rapidly, the surgeons have to wait for these areas to heal and then take another skin graft from them. Additionally, it is possible to take small pieces of the patient's skin, expand these in the laboratory and then graft them back onto the patient as very thin sheets of cells. The disadvantages are that it takes at least two to three weeks to produce a useful area of skin and the skin cells cultured in this way don't have the ideal two tiered structure (epidermal and dermal layers) of normal skin.
Professor Ryan and his team want to find a way of making a replacement skin that has both epidermal and dermal layers. To do this they intend to build a scaffold out of polymers that will replace the patient's skin and help to promote rapid wound healing. The aim is to make a synthetic skin substitute that is based on biodegradable polymers and peptides which can be reconstituted with the patients own cells.
Making a synthetic replacement skin requires a wide background of specialist knowledge and this is reflected in the members of the research team. Professor Sheila MacNeil and Dr John Haycock both come from biological backgrounds and contribute a detailed knowledge of the structure and functioning of real skin. Professor MacNeil has spent many years working with plastic surgeons, culturing cells for burns patients. Professor Chris Hunter is a chemist who works on proteins chemistry, while Professor Ryan's expertise lies in making polymers with different structures.
MacNeil and Haycock have been working on producing peptides that can be added to the replacement skin to help the healing process. "New skin has to cope with hard times," says Professor MacNeil. "The skin cells suffer from hypoxia and have no waste removal system so we are trying to find peptides that will help the cells to survive their surroundings." In particular they have been looking at a peptide that helps to modulate inflammation of the skin. "Inflammation is important in an injury because it helps to kill off bugs and prevent infection, but during a skin graft inflammation is a problem and can cause rejection of the new skin," explains Dr Haycock. They hope to incorporate an anti-inflammatory peptide into the synthetic skin scaffold to control the inflammation.
Professor Hunter has the task of trying to introduce peptides to the synthetic skin. He takes the protective peptides that MacNeil and Haycock have identified and looks at ways of combining them with the synthetic skin structure that Ryan has created. If he can successfully get the synthetic skin to combine with the peptide then the new skin will contain its own 'medical kit' to repair itself.
Professor Ryan's job is to experiment with different polymer architectures that could be used as the basic structure for the replacement skin. "It needs to be porous at the bottom of the skin to allow diffusion of body fluids, but relatively impervious at the top to prevent bacterial and fungal infections," he tells us. When Professor Ryan presented the Royal Institution's Christmas Lectures 2002 the team managed to make him a personalised 'plaster'. With the help of another colleague, Professor Rob Short, and using techniques they had already developed, they managed to grow the word 'Tony' using his own skin cells. "A sample of my skin cells was taken and sprayed onto a special cell friendly surface," explains Professor Ryan. The surface consisted of a pattern of water attracting and water repelling areas. Tony was spelt out in water attracting polymers and this attracted the skin cells to grow there. "My skin cells grew just like a layer of grass," he adds.
Working in a team with such diverse backgrounds is not always easy and one of the biggest problems is communication. "Misinterpretations are all too easy and we all have to be careful to explain everything clearly and talk each other's language," says Dr Haycock. However, the team have discovered that the benefits of working together far outweigh the difficulties. "Between us we have many different tools and resources to share and everyone approaches the problem from a different aspect," says Professor MacNeil. They are now one year into the project. Already they have managed to develop a 3D scaffold that cells like to attach to and are developing an understanding of what sort of 3D space skin cells like to call home. Within the next two years they are hopeful of producing something that will be ready for clinical use.
All these projects researching into the wonder material that is, literally, all around us are only possible because of support for border-crossing science. Funding through EPSRC's Life Sciences Interface Programme, as well as funding in partnership with the other UK Research Councils, has given scientists from a host of different backgrounds the chance to work together. In the future not just chemical engineers, materials scientists and biologists but everyone wearing a human skin stands to bene