IFMBE Cellular Engineering Working Group: "Engineering with cells and tissues"IntroductionThe current interest in the biological cell exists not only among many scientific and engineering professions and clinical sub-specialities but also within the general public. There have clearly been milestones along the way from the origin of cells on earth some 3.5 billion years ago through to the discovery, by Watson and Crick in 1953, of the genetic code carried by DNA within cells. Since that vital discovery there have been other developments arising from the investigation and use of cellular phenomena and materials. Importantly, those professionals attracted into this pursuit have come from many disciplines within the life sciences, the physical sciences and many branches of engineering. It was with this background that the IFMBE, whilst reviewing its strategy at an Administrative Council meeting held in Patras, Greece, in 1989, took a positive step to create a Working Group to investigate the possible opportunities for Biomedical Engineers to contribute to this emerging field. The term Cellular Engineering was used to describe this. Early developmentsThere was a temptation to try to devise a definition for cellular engineering in the first few years in the life of the group. This became an impossible task, similar to trying to define physics chemistry and biology in the same breath. More importantly it was concluded that a definition could impose too much of a restriction and this might prevent the emerging field finding its own true identity and role. Grasping the essence of the subject of cellular engineering was easier than devising definitions. This was also greatly aided by organising events that provided the opportunity for people from many disciplines to gather and talk about work that they thought was within the field of cellular engineering. In this way the Working Group moved forward over the first three-year period of its existence: Early activities of the group1989 Working Group formed, Patras, Greece. 1991 February: First Symposium on Cellular Engineering, Nice July: Workshop and Theme track in World Congress on BME and MP, Kyoto, Japan 1992 July: Symposium, Track and Keynote within IFMBE MEDICON 92 conference, Capri, Italy October: Symposium, Track and Keynote in IEEE EMBS conference, Paris, France November: Workshop on Cellular Engineering, SERC, Keele, UK Stimulating new international venturesThe true international nature of the IFMBE provided excellent opportunities to stimulate new cellular engineering efforts around the world. This had been seen at the Kyoto World Congress on Biomedical Engineering and Medical Physics in 1991 and again at the Medicon 1992 Regional Conference of the IFMBE in Capri. The success of our activities within these international events led the Working Group to establish the series of international conferences on cellular engineering. These are now established firmly in the conference calendar, with the next event taking place in Nara, the old capital city of Japan, from the 30 November to the 3 December, 1999. International research groupsIt is clear that many groups working on what they and we believe to be cellular engineering now exists in many countries around the world. Some of these groups are new and quite small, in some cases having only two or three people. Others are more established single or perhaps dual discipline departments or units, based in universities or in hospitals. To meet the needs for close inter-disciplinary collaboration there are now emerging specialist centres which often combine the staff and resources from two or more single discipline departments. The exciting thing is that such centres appear to be successful in raising support funding from government or charitable foundation sources. In Europe there has been a four-year programme of funding to cover topics in biomedical engineering and cellular engineering was identified as one priority topic. In the USA the National Science Foundation and the Whitaker Foundation have provided substantial funding for this area. National venturesThere are several groups well established in the United Kingdom, for example in London, Nottingham, Bangor and Glasgow. In London there are two main groups based on University College and Imperial College. The broad based centre at UCL is administered by Dr Robert Brown who also runs a cellular engineering-oriented Tissue Repair Unit within the Department of Plastic and Reconstructive Surgery. Within this unit there is an aim to understand the basic processes of tissue repair in order to achieve rational control. Supply of exogenous control cues, such as substrate contact guidance and directional mechanical loading, to regulate architecture of tissues from which scars form is one example of this. The Imperial College group is chaired by Professor Julia Polak based at the Hammersmith Hospital. In Italy there are strong activities at the University of Genova where at least three groups exist. Work includes: modelling of cell and molecular processes, especially protein adsorption and cytoskeletal function ( Professor Carmelina Ruggiero); interfacing neurones with electronic substrates (Professor Massimo Grattarola); tissue engineering of bone and cartilage (Professor Ranieri Cancedda). Professor Carmelina Ruggiero has also taken the initiative to form a specialist group on cellular engineering within the Italian Society of Biomedical Engineering to focus national interests and develop the subject. In fact, a similar development is being taken forward in Germany, by Professor Gerhard Artmann in Aachen, who is establishing a specialist group within the German Biomedical Engineering Society. The focus of work in Ljubljana, Slovenia is the investigation of the response of cells and tissues to electrical currents and fields. Electric field induces spatially dependent trans-membrane potential and when this exceeds a certain level electroporation occurs. Electroporation causes transiently increased plasma membrane permeability, cells in contact with each other or tissue fuse and proteins can be inserted into the plasma membrane. Manipulation of cells by means of high voltage electric pulses already found its use in laboratory and clinical practise. An important development in this field is electro-permeabilisation of cells and tissues which allows the introduction of otherwise non-permeant molecules into the cells. Based on this phenomenon potentiation of cytotoxicity of some anticancer drugs for which plasma membrane represents barrier was demonstrated. Increased cellular drug uptake was named electrochemotherapy and has already entered into clinical trials. Electroporation is also widely and successfully used for gene transfection in vitro as well as in vivo. Japan has a wide range of work underway in topics related to Cellular Engineering. One example of this work is in the group led by Prof. Masuo Aizawa in the Department of Bioengineering at Tokyo Institute of Technology. Here the research focuses on four main areas. First, cellular responses to physical stresses; secondly regulation of cellular network and tissue formation by physical stimuli; thirdly, cellular engineering for environment responsive cells; and fourthly, design of cell-based biosensors. The Graduate School of Biomedical Engineering at the University of New South Wales, Australia has a number of research foci which cover biomaterials, vascular mechanics and medical devices. Specific areas of interest include: the development of an artificial cornea which is based on corneal epithelial cell coverage of a permeable polymeric substrate; the investigation of endothelial cell proliferation on polymers; the development of systems for cell separation and expansion for cell therapy applications; and the development of techniques for macro-encapsulation of cells with membranes. These research areas are being conducted with a number of collaborative centres which include the CSIRO Division of Molecular Science and the Cooperative Research Centre for Eye Research and Technology based at the University of NSW. In the USA the growth of what is termed 'tissue engineering' has been extensive. There are strong groups both in academia and in industry. Those based in universities or hospitals are sited in bioengineering, chemical engineering, biology, cell biology, molecular biology, pathology, biophysics, surgery, orthopaedic surgery and vascular surgery. Dr Krystyna Tatarakiwicz works in the Islet Transplantation and Cell Biology section at the Joslin Diabetes Center, which is affiliated at Harvard Medical School in Boston, USA. The group is led by Prof. Gordon C. Weir and is focused on the pathophysiology of diabetes and xenotransplantation of encapsulated pancreatic islets to cure diabetes. Recent studies have been concerned with islet transplantation in planar diffusion chambers in rodents. There is also extensive work on porcine neonatal pancreatic cell clusters as a potential source of insulin-producing tissue, which might be transplanted into human diabetic patients in the future. As the first step before transplantation of tissue from non-human species, the group plans to isolate and transplant allogeneic islets in the humans. The National Science Foundation (NSF) has provided Georgia Tech with a five-year, $12.5 million grant to support the establishment of a new Engineering Research Centre (ERC) in the area of tissue engineering. The goal of the Research Centre for the Engineering of Living Tissues is to harness the advances being made in molecular and cell biology for the development of the next generation of medical implants, products that have been tissue engineered. This new NSF/ERC will have three major thrusts. These are (1) cell technology, (2) construct technology, and (3) the technologies required for the integration of constructs into living systems. The major areas of application will be cardiovascular substitutes, encapsulated cell therapies, and orthopaedic tissue engineering. There are a dozen companies with which this new centre is partnered. The centre will be housed in the 150,000 foot facility now being built for Georgia Tech's Institute for Bioengineering and Bioscience. Occupancy is expected in August 1999. In the Division of Bioengineering and Environmental Health, at MIT, USA, Douglas Lauffenburger leads a group with interests in molecular cell bioengineering. This is concerned with the application of engineering approaches to develop quantitative understanding of cell function in terms of fundamental molecular properties, and to apply this understanding for improved design of cell-based technologies. The group focuses on elucidating important aspects of receptor-mediated regulation of mammalian blood and tissue cell behavioural functions such as proliferation, adhesion, migration, and macromolecular transport. A central paradigm of the work is development and testing of mechanistic models (based on principles from engineering analysis and synthesis) for receptor regulation of cell function by exploiting techniques of molecular biology to alter parameters characterising receptor or ligand properties in well-characterised cell systems. Quantitative experimental assays are used to measure cell function and receptor/ligand interaction parameters. Problems are motivated by healthcare technologies of interest to pharmaceutical and biotechnology companies. A Swedish group in the Department of Medical Microbiology at Linköping University, led by Professor Tommy Sundqvist, is studying the barrier properties between tissues. All multi-tissues create barriers between different compartments and to create a new tissue we need to know the barrier properties and how these are regulated. Both epithelium and endothelium have a so-called "tight" junction that creates the semi-permeable properties where small molecules but not larger can pass. This structure is connected to the cytoskeleton and is regulated by signal molecules such as nitric oxide, a signal molecule that also reduces adhesion of neutrophils to the cell layer. Apart from regulation, it is also of interest to know how strong the adherence between cells and between cell and substrate is and how this can be changed. A basic knowledge of cellular functions is necessary to succeed in creating new tissues. Industrial interestsIndustrial Interests If the potential of cellular engineering is to be fully realised then industry must be actively involved. There is clear evidence of rapidly growing industrial activities, ranging from small spin-off companies established by academics through to major multi-national companies. Companies include: Advanced Tissue Sciences; Collagen Corporation; Biomatrix; Oxford Bioengineering; Genzyme Tissue Repair; Creative Biomolecules; Smith and Nephew; Atrix Laboratories; Organogenesis; LifeCell Corporation. Basic and applied research being conducted in the universities and hospitals is generating intellectual property which is leading to grant of patents worldwide. Some institutions are clearly more experienced in matters related to the exploitation of such IP and industrial partnerships are being created. Of course industry itself must focus on the development and protection of its own commercial IP and the field of cellular engineering is one in which long-term R&D efforts will be needed before products can enter the marketplace. Oxford Bioengineering therefore has a policy of early identification of patentable ideas and the establishment of a research and funding strategy with academic partners. Its interests range from novel cell processing through to cell-based sensors and tissues. In the European Union the Fifth Framework Programme, in which funding for subjects such as Cellular Engineering will be available, will commence in 1999. The involvement of industrial partners has in the past been considered to be an advantage in the assessment of research proposals. However, in the 5th Framework it is believed that this aspect will be even more important. Future developmentsThe next period in the life of cellular engineering is just as important as the birth of the subject. This is because as the subject expands rapidly there is a need for some degree of co-ordination in planning how best the full potential can be realised. However, funding mechanisms are inevitably competitive within nations and, indeed, within the whole of the EU and, whilst such competition has a positive side, this can work against efforts to bring members of the new field together. Just as competitive can be the organising of conferences and there is certainly a proliferation of these. Our efforts to launch the specialist journal, cellular engineering, have only been partly successful so far but there is still a strong desire for this to be achieved in the medium term. The new journal was launched and grew steadily in terms of papers published but only slowly in terms of subscriptions. It was therefore decided to re-incorporate the subject as a defined section on MBEC until such time that demand has grown. Inevitably, in some countries national societies are recognising cellular engineering as an important emerging field and are responding by setting up specialist groups from within their membership. This of course generally means that the activity has a bias towards the individual specialism of the society concerned, be this essentially engineering, physical science or life science oriented. The Working Group has been considering these matters over the last 12 months in order to effectively plan its future activities. One approach being considered is that of creating a new International Society that could provide a home for all interested disciplines. It would be essential for such a Society to be configured such that it was attractive to biologists, engineers and physicists, and surgeons alike. The true multi-disciplinary nature of Cellular Engineering would therefore be acknowledged and facilitated - this is what the Working Group is hoping to achieve. IFMBE Cellular Engineering Working Group 1998
Peter Rolfe - Chairman of Working Group Oxford Bioengineering Tel: + 44 (0) 1630 653 980; Fax: + 44 (0) 1630 657 240 Email: peter.rolfe@aol.com | ||