Cell and Tissue Banking 1: 105–109, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.

Bone allografts: Past, present and future

William W. Tomford Massachusetts General Hospital, Department of Orthopaedic Surgery, Boston, MA 02114, USA

Abstract

Bone allograft transplantation has been performed in humans for more than one hundred and twenty years. During the first one hundred years (1880–1980), the major problem in bone allograft transplantation was availability. Most of the bone grafts used during this time were autografts. Allografts were not available due to a lack of legislation protecting procurers and processers. In addition, surgical procedures requiring allografts were not being performed. During the next twenty years (1980–2000), as allografis began to be used, the major issue was safety. Diseases transmitted during this period included AIDS and hepatitis. Avoidance of disease transmission became paramount. Sensitive blood tests and extensive efforts by bone banks to develop ways to clean. bone and clear it of infectious agents helped provide safe transplants. With concerns of availability and safety receding, the major issue in the future (2000–?) will be the efficacy of the transplant. How allograft bone remodels in the host, how it incorporates and heals to host bone and how it integrates with the host skeleton will be the most important concerns of bone bankers and tissue transplant surgeons. Future research efforts will be applied to bone allograft transplantation to ensure that bone transplants heal quickly and sufficiently to be able to function as part of the weight-bearing skeletal system.

Bone transplantation has been performed between humeral shaft [1]. Osteomyelitis is one of the few con- humans for over one hundred and twenty years. During ditions that may involve the entire shaft of a bone, and this time, several significant changes have occurred this was the case in this patient’s condition. Because in the types of bone allografts transplanted and in there were no antibiotics available, the treatment of their application. These changes have not occurred in bone infection was surgical resection of the infected a progressive periodic fashion. For example, in the bone, and therefore the patient had the entire diaphysis first one hundred (l889–1980) of these one hundred of his humerus removed. Once the infection cleared, a and twenty years, few differences can be discerned process that took several years, the surgeon re-operated between the types of grafts used in the earlier years to replace the missing humeral shaft with several fresh of this period compared to the later years. In the next bone allografts consisting of diaphyseal segments from twenty years (1980–2000), however, advances which the tibial shafts of patients who had rickets and were were as significant as those that occurred in the first undergoing corrective osteotomies for anterior bowing one hundred years were incorporated into the science of the lower leg [2,3]. Over the subsequent seven years, of transplantation of bone. In future years, even more the transplanted segments became incorporated into the important changes in the field of bone transplanta- proximal and distal sections of the host humerus, and tion can be expected. A review of changes that have the allografts transplanted into the original diaphyseal taken place in bone allograft transplantation over the section remodeled to form a new shaft. past and in the present, with a discussion of possible Transplantation of large fresh segments of long future transplants, provides interesting and important bone allografts continued and was expanded over the knowledge to surgeons seeking safe and efficacious next ninety years. The most famous of the trans- bone allografts. planting surgeons was Lexer, a German surgeon who treated osteomyelitis and septic arthritis with the use of long bone transplants [4]. Using bones from Allografts of the past (l880–1980) freshly amputated limbs, Lexer reported an approxi- mate 50% success rate when evaluating return to nor- The first reported human bone allograft was trans- mal limb function following half-joint and whole joint planted in a young male who had osteomyelitis of his osteoarticular allograft transplantation [5]. 106 W.W. Tomford

After antibiotics were introduced into general Maryland [12]. Dr. George Hyatt, the first director medical use in the early 1950’s, and the incidence of the Navy Bone Bank, foresaw a potential military and treatment of infection changed from surgical to need for bone allografts. By obtaining donors from pharmacological, the transplantation of large bone allo- the National Naval Medical Center, to which the Navy grafts began to be applied to the treatment of bone Bone Bank was attached, Hyatt pioneered a system of tumors. Frank Parrish at the M.D. Anderson Hospital in cadaver donation in an operating room dedicated solely Houston began a revival of Lexer’s work by transplant- to tissue procurement. By concentrating efforts in bone ing large osteoarticular grafts of the proximal tibia and transplantation, this idea significantly increased the distal femur as a limb salvage treatment for primary donation and procurement of allografts. Hyatt’s sec- high grade malignances in bone [6]. He reported sat- ond significant contribution to increasing availability isfactory functional results but could not predict the was the application of freeze–drying to the preserva- ultimate fate of the grafts. tion of bone. Prior to Dr. Hyatt’s research, bone was Others who continued Parrish’s work in bone tumor stored by refrigeration or by freezing. In an attempt surgery included Enneking and Mankin. Enneking, to find a method of preservation by which bone could with the assistance of Burchardt and others at the be shipped overseas at room temperature, Dr. Hyatt University of Florida, produced a series of elegant adapted the principles of lyophilization to the storage experiments on the fate of large bone allografts [7,8]. of bone [13]. This process allowed bone to be stored in Their research showed that these grafts are not well a relatively simple, low cost manner for several years incorporated into host bone and are subject to infection without freezing or refrigeration. and fatigue fractures. Starting in the 1970’s, Mankin In the first one hundred years of transplantation has produced the largest clinical series of skeletal allo- of bone allografts, disease transmission was a minor graft replacements for bone tumors [9]. He showed concern. Tissue banks used cultures to detect bac- that satisfactory results of long bone replacement can teria, but there were few serological tests available be expected in about 75% of patients. Good results for diseases other than syphilis. Fortunately, the total are diminished by the concomitant use of radiation and number of bone grafts used in the U.S. annually num- chemotherapy [10]. bered less than 2,000. The most publicized grafts During the first one hundred years of bone trans- were large osteoarticular grafts but only approxi- plantation, the major impediment to the use of large mately two hundred of these were transplanted annu- numbers of grafts was a lack of available bone to ally. As more complex surgical procedures began to be transplanted. Almost all allografts were obtained be performed, the demand for bone grafts, particu- from amputated limbs which resulted in a very limited larly in spine surgery, hip surgery and fracture surgery supply. In addition, there was no means of long-term increased. preservation of tissues. Furthermore, no national or state laws protected those involved in the procurement of tissues. For these reasons, most surgeons preferred to obtain autograft bone from the patient who needed Allografts of the present (1980–2000) a bone graft, store it by chemical means or on ice for a short time, and reimplant it into the donor. Under The most important issue of the present period of these circumstances, autografts were used much more bone allograft transplantation has been a concern for frequently than allografts. safety in the use of bone allografts. AIDS as a disease As a potential solution to the problem of a shortage was first reported in 1981 [14]. Although it became of bone allografts, Alexis Carrell published an article clear that the virus was 100% effectively transmitted in in 1912 in which he predicted that organs and tissues blood, whether or not the virus could be transmitted in would eventually be stored to be retrieved whenever a bone, and in what type of bone – frozen, freeze–dried, particular patient needed a particular body part [11]. processed, irradiated or unprocessed – was unknown. However, it was not until the 1940’s that storage meth- The first reported case of HIV-1transmission in bone ods were developed for tissue storage for longer than a occurred in 1984 [15]. At the time of transmission, no few days. blood test was available to be used as a screening test Two important events that occurred early in the for tissue donors. When a test became available shortly 1950’s helped solve the problem of a lack of available after this incident, many tissue bankers believed that a bone for use as bone transplants. The first event was repeat case of transmission would be all but impossible. the development of the Navy Tissue Bank in Bethesda, However, due most likely to a very recent infection Bone allografts: Past, present and future 107 in the donor, a second case of HIV-1 transmission recently been developed and in retrospect was probably occurred in 1985. not very accurate. In addition to changes within the In addition to transmission of the AIDS virus, tissue banking field, therefore, more reliable blood tests two cases of hepatitis C virus transmission have also were adopted by tissue banks. The ELISA antibody test occurred in this present period [16,17]. One of these for the AIDS virus was significantly improved [18] cases occurred prior to the availability of a specific and new tests such as the polymerase chain reaction blood test for HCV, and the second occurred in spite of (PCR) [19] and p24 antigen tests [20] were instituted a sensitive but first generation viral detection test. as screening devices for all donors. Although PCR is As a result of these two incidents of disease transmis- not licensed by the FDA for donor screening, tissue sion, safety replaced availability as the most important banks routinely employ the test. issue in bone transplantation. From providers to users As safety rose in importance in the present period, to federal authorities, everyone became alarmed about the issue of availability, the main concern of the earlier the possibility of new cases of disease transmission. period, diminished in importance. Perhaps the most As a result of an increased awareness of the possibility significant events that increased tissue availability in of transmission, investigations were conducted, meth- the present period was national or federal efforts to ods of screening donors changed, and new methods of increase the number of organ donors. Although legis- preparing and processing bone were developed. lation such as the National Transplant Act [21] and the Following the first case of AIDS transmission, the Budget Reconciliation Act were designed to increase Centers for Disease Control (CDC) convened a con- the number of organ donors, growth in this num- ference in 1987 in which donor testing was the sub- ber has remained relatively flat. While the number of ject. Relying on expert testimony, the CDC published organ donors did not increase significantly with these guidelines for testing donors which pertained chiefly efforts, the by-product effect has been an increase in to femoral head donors. These guidelines required that the number of tissue donors. living donors be re-tested at six months following dona- The safety of bone allografts can never be taken for tion. Cadaver donors could not be re-tested, so the CDC granted, and the recent safety record for bone allografts developed detailed guidelines for historical review of has been outstanding. Over 1,000,000 bone allografts cadaver donors. have been implanted in the past ten years without evi- The most important conclusion from the cases in dence of AIDS or hepatitis transmission. Since the last which transmission of diseases occurred was that bone case of HIV-1 transmission, which occurred in 1985 allografts that contain blood can transmit blood-borne and was reported in 1992 [22], there have been no diseases. All of the grafts that transmitted the AIDS reported cases of transmission of the AIDS virus in the virus contained blood and bone marrow because they U.S. through bone allografts. This fact suggests that were unprocessed. In contrast, the grafts that did not tissue banks are screening donors and processing allo- transmit the virus had been processed to remove blood grafts to successfully remove all pathogens. Nonethe- and bone marrow. This finding emphasized the need for less, as new pathogens emerge or are discovered, the removal of blood and bone marrow from bone grafts challenge for tissue banks will be to continually revise whenever possible in order to reduce the risk of disease and improve their practices. transmission. Tissue banks responded to the challenge of providing safer grafts by developing new methods of processing Future allografts (2000–?) and preparation of bone grafts. For example, several banks developed proprietary bone washes which have Because availability and safety are able to be man- been shown to be virucidal to any exposed bone aged by tissue banks, more complex issues affecting surfaces. New developments in clean roomtechnology tissue allografts will become important in the future. were adopted, and stricter environmental controls of One of these new issues will be improvement of allo- tissue preparation areas were initiated. graft revascularization, incorporation, remodeling and Serological blood testing for donor screening is skeletal integration. We know that a large, long bone dependent upon the reliability and accuracy of the sero- allograft is poorly remodeled into host bone, and logical blood tests used. If the test being used is not remains essentially unchanged for several years [23]. very sensitive, the test result may be inaccurate. In This situation results in a large piece of dead organic the second case of HIV-l transmission, the viral test tissue present in the host skeleton which may serve as that was available to the screen the donor had only a nidus for infection or fracture from fatigue. 108 W.W. Tomford

In bone allografts of the future, emphasis will be in number and popularity. The first one hundred years placed on allograft bone remodeling with bone forma- were characterized by a lack of tissues for transplanta- tion and bone stimulation around and within the graft. tion which stimulated programs designed to promote Integration of the graft into host bone and function of donation and improve the availability of bone allo- the graft as host bone will be the single most impor- grafts. The next twenty years have been characterized tant issue. How these grafts will achieve the goal of by a concern for disease transmission and have stim- transition to normal skeletal bone will be the result of ulated an emphasis on increasing the safety of bone physical and/or chemical modification of the graft. allografts. In the future, emphasis in research, clini- Physical modification of bone allografts is already a cal and basic, will concentrate on how bone allografts reality. For example, several tissue banks are devel- incorporate, remodel and function in the host skeletal oping proprietary femoral bone segments for spine system. Through physical, chemical or genetic engi- fusions. These segments are cut from femoral shafts neering, bone allografts will undoubtedly be developed and are modified by cutting tools to create threaded which provide a transplant that functions as if it were dowels or serrated discs. Others have developed pro- an autograft – readily available, disease-free, integrates cesses using lasers to create perforated cortical struts rapidly and functions normally. At that time, the goal of which are surface demineralized to improve graft a transplant that truly replaces a body part will become revascularization [24]. a reality. Chemical modification of bone allografts is in the research stage but has the potential to revolutionize bone grafting. 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