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INTRODUCTION:
FROM A COTTAGE INDUSTRY
TO A GLOBAL BUSINESS
Glyn O. Phillips
Although the clinical practice of using bone grafts to repair, replace or supplement the bone stock has a long history, dating back to McEwen in 1881, the production and practices have grown into a truly industrial-scale international business only over the past 10–15 years or so. Human safety considerations led to the articulation of regulatory systems which increasingly became the target of legal challenges as real or apparent shortcomings in the implementation of the practices became more frequent. This book sets out the way in which the current legal approaches to the production and clinical utilisation of human tissue grafts have developed in various parts of the world.
The development of tissue banking throughout the world has been quite uneven and has taken place over a relatively short time scale. The foundation of current tissue banking was set in place, essentially, by a relatively small number of tissue banks. The early pioneers set up organised tissue banks only in the second half of the 20th century. The pace has eventually been set by the United States where production systems and graft quantities have grown exponentially to industrial proportions. Smaller tissue banks in Europe are increasingly being absorbed by their larger counterparts such that the overall production philosophy is spreading internationally. However, the pace at which legal awareness is spreading is not even throughout the world, with the result that certain regions and countries, notably China, have developed their own legal systems. This book describes the situation as currently practised, and will hopefully lead to wider discussions about this subject.
THE DEVELOPMENT OF TISSUE BANKING
When a group of surgeons, in which Geoffrey Burwell from the United Kingdom was a leading figure, showed that frozen preserved allograft could be superior in performance to fresh allogeneic bone, the road was pointed to the more extensive use of bone allografts. However, generally the practice remained a “cottage industry” well into the latter part of the 20th century. This involved orthopaedic surgeons keeping pieces of bone which had been rescued after surgery in individual hospital cold stores. These were usually femoral heads after hip replacement, and these they used as required on an individual basis. There were many exceptions and these surgeons were usually associated with the pioneering tissue banks, which emerged in the 1950s. But progress in the second half of the 20th century was painfully slow. Tissue banking did not easily fit into the medical psyche. While medical education included a consideration of the historical development of transplantation, the message given to the modern era was in many ways counterproductive. Even as the end of the 20th century approached, orthopedic surgeons still had not embraced the new clinical opportunities provided by sterile non-immunogenic allograft bone. There was a legitimate concern about possible disease transfer from contaminated grafts, but there was additionally a deep lack of awareness of the potential of the developing technology. I found this to be so in 1990 even in one of the most famous orthopaedic hospitals in the United Kingdom. A young orthopaedic Registrar who joined our embryonic research tissue bank in North Wales to pursue a higher degree was regarded as an oddity in pursuing such a career path.
Why such ignorance about the potential of these grafts, particularly since many countries such as Poland, for example, from 1975 onwards, had produced thousands of radiation-sterilised allografts which were transplanted successfully every year? Possibly, the medical attitude was unconsciously derived from the experience with skin grafting, which had first suggested that allografts and even xenografts might be grafted p ermanently and be incorporated into the human body. This we now acknowledge was a degree of self-deception. Any skin graft leaves a pad of collagen when it rejects, and this may have been mistaken for a successful graft. Epithelialisation can also occur under a rejected graft by in-growth from the sides, and this new skin can be confused with successful grafting. These spurious successes must have received encouragement from the undoubted success of using allograft bone, first by William MacEwan (1881) and then by the successful grafting of cornea in 1905 by Edward Zirm. The confusing allograft era eventually came to an end. Scientists like Schone in 1912 and Lexer in 1914 clearly stated that rejection of allografts was inevitable. The Danish scientist Jensen even suggested that this was an immunological event. World War II had a profound effect on science and accelerated progress in the understanding of kidney disease and tissue transplantation. Problems like massive burns in the 1939–1945 war, and new forms of renal failure, produced new clinical problems. Existing therapies were ineffective. In Britain, the Medical Research Council Burns Unit at Glasgow was established. There, Peter Medawar became interested in the problems of skin grafting after seeing a seriously burnt patient in an Oxford hospital. In Glasgow, Medawar and Gibson showed that a second set of skin grafts was rejected more quickly than the first set. They reported this work in 1943. For Gibson, a plastic surgeon, it was the final proof that allografts were of no immediate clinical use. For Medawar, it was evidence that allograft rejection was a major, unexplained immunological phenomenon. Back in Oxford, Medawar repeated the experiment using rabbits and termed the rejection mechanism actively acquired immunity. Medawar and colleagues studied this immunological phenomenon intensively and in 1960 Medawar and Burnet shared the Nobel Prize for Medicine and Physiology. We now know that the judgement of Gibson was premature. Human kidney allografts have now been successfully transplanted throughout the world. Indeed, renal transplantation is now the treatment of choice for end-stage renal failure and cornea grafting is so widely practised and successful that it is often forgotten that it is a tissue allograft, albeit a rather special one. Now more than 1,750,000 tissue allografts are transplanted annually in the United States, and the procedure is a fundamental part of modern health care. Yet the developments up to the early 1990s were painfully slow.
The period when the European Association of Tissue Banks (EATB) started (in 1993) and other national associations such as the British Association of Tissue Banks (BATB) started marks the period of acceleration into the modern tissue banking era. The growth, thereafter, has been exponential in the United States, linear in Europe, linear also in Australasia but with a lower slope, and asymptotical in the Asia and Latin America regions. China was slower in embracing this technology but now is moving at an ever increasing pace as noted in this book.
THE EARLY PIONEERS
The foundation of current tissue banking was set in place, essentially, by a relatively small number of tissue banks. Without entering into the debate about which actually was the first, we should recall the contributions of the Bethesda Naval Tissue Bank in the United States which George Hyatt founded in 1950, with Ken Sell becoming Director in 1965. The impetus was the return of the Korean War casualties who required reconstructive surgery. From this beginning came great contributions in the subject from Michael Strong and Gary Friedlander. The early publication Tissue Banking for Transplantation, edited by Sell and Friedlander (1976) and published by Grune and Stratton, New York, was truly a landmark publication.
At about the same time, Rudolph Klen set up the tissue bank in Hradec Kralove in the old Czechoslovakia in 1952. It was a great occasion on 6 July 2006 when a meeting was held to celebrate the contribution of Professor Klen and congratulate him on his 90th birthday. It was a privilege for me to work with Professor Klen to contribute to and translate his previous publication in the Czech language into English. In 1982, another landmark publication by Klen, Biological Principles of Tissue Banking, was published. It is a miracle that Klen emerged to all this great work after being imprisoned as a Jew in a concentration camp during the war years. Letters now exist which were sent by him and his sister Hana and their friend Jura (Jiri) Fantl in 1944 from the ghetto to their families in the Protektorat. We cannot now imagine their suffering and their resilience. Rudolph Klen continued to show this resilience throughout his life, for he had to withstand the communist regime which denied him all recognition, which only came in the form of a professorship from his old university at the end of his life.
The Leeds Tissue Bank was set up in 1956 by another great enthusiast, Frank Dexter. Its early history has been described by his student John Kearney (2006). It all started in the Department of Microbiology of the University of Leeds in 1953. Essentially a technician in microbiology at the University of Leeds Medical School, Dexter had a dream of harvesting tissues for transplantation, and together with Professor Geoffrey Burwell proceeded to use tissues by the hundreds for transplantation. It is a tragedy that this early experience was not recorded in detail. In 1965 when a new purpose-built Regional Burns Unit was opened at Pinderfields, Dexter was invited to be its first Head. His enthusiasm and campaigning for more than 20 years led to the establishment of the Yorkshire Regional Tissue Bank, again at Pinderfield Hospital in Wakefield — an unlikely place some thought to have the flagship tissue bank in the United Kingdom. Frank Dexter, its first Head, retired in 1985, and Dr John Kearney became Director of the Yorkshire Regional Tissue Bank in its new building. I am particularly grateful to Frank Dexter for completely unselfishly helping us to set up our North Wales and Oswestry Tissue Bank in the years up to 1990. Both tissue banks were taken over by the UK Blood Service in the early 2000s.
The Charite Hospital Tissue Bank in Berlin in the old East Germany was set up in 1956, and although well-known in the Eastern block, it was hardly known in the West at the time. The great opening up came in 1990 when an East meets West symposium was held in Berlin, organised by Dr Ruediger von Verson, who had joined the Charite Bank in 1981. The fruits very quickly spilled over and it was a resolution of the meeting to set up an association of tissue banks. After a planning meeting held in Marseilles (with Professor Poitou as host) the European Association of Tissue Banks (EATB) came into being in 1993, and Professor von Verson was its President for the first ten years. In Europe reference should be made also to the pioneers of tissue banking in Poland, namely Professors K. Ostrowski, Anna Dziedic-Goclawska and J. Komander. The tissue bank in Warsaw celebrated its 40th anniversary in 2004.
The sterling work of Dr Nicholas Triantafyllou who started and sustained tissue banking in Greece should also be recognised. He was the first, along with the Polish group, to study in a scientific manner the effects of ionizing radiations on bone and to use the method routinely for end-sterilization. He produced bone grafts and as an orthopaedic surgeon also used them.
The role of the International Atomic Energy Agency (IAEA) in promoting tissue banking (Phillips 1998, 1999, 2001, 2002, 2004; Phillips and Morales 2003; Nather et al., 2003) should also be acknowledged. The IAEA has gained more experience and success than any other international organization in establishing tissue banks in developing countries and applying ionizing radiation for sterilizing tissue grafts, which were then used in transplant surgery (in orthopaedic reconstruction, treatment for cancer, trauma and high velocity impact damage), the treatment of burns, leprosy and intractable skin wounds and pressure sore ulcers. Now due to the diligence of Jorge Morales (a contributor to this volume), who was a powerful manager of these programmes for IAEA, we have a complete record of the achievements of the programme and how each of the countries has contributed.
The main achievements can be summarised as follows:
a) Establishing a program of 25 tissue banks in the Asia Pacific and Latin American regions. Now there are more than 112 tissue banks operating in these two regions.
b) Radiation sterilisation of tissue grafts is the established end-sterilisation method in the countries in the participating regions and has led to a reverse transfer technology effect to the United States and Europe.
c) All countries operate the approved quality assurance programmes.
d) The preparation and training in the use of the following operational documents:
• The IAEA Code of Practice for the Radiation Sterilisation of Tissues Allografts: Requirements for Validation and Routine Control.
• IAEA International Standards for Tissue Banking.
• IAEA Public Awareness Strategies for Tissue Banks.
e) The dissemination of knowledge regarding best practices for tissue banking professionals through training courses, fellowships scientific visits and expert missions.
f) The support and sponsor of several international scientific meetings in the participant regions.
g) The establishment of the Asia-Pacific Association of Surgical Tissue Banking (APASTB) and Latin American Association of Tissue Banks (ALABAT).
h) The establishment of two regional training centres, one in Singapore and another in Buenos Aires, and one interregional centre in Singapore. In these centres 261 students have been trained and 166 have graduated.
i) With the financial and technical support of the IAEA, preparation and utilisation of a comprehensive distance learning curriculum for tissue bank operators and medical doctors in English, Korean and Spanish.
j) The transformation of comprehensive distance learni...
