Cross-species tissue transplantation presents distinct challenges
Attempts at xenograft transplantation (the transmission of living organs, tissues, or cells from one species to another) were first performed in the early twentieth century. Today, the relative shortage of human organs and tissue available for transplantation has amplified interest in xenografts as alternatives to human-tissue transplants.
Although the obvious advantage of xenotransplantation is the almost infinite amount of nonhuman animal tissue that might be considered for transplantation, its major disadvantage is the risk of cross-species disease transmission. Because xenograft tissue is being increasingly used for both routine and complex orthopaedic procedures (Fig. 1), a basic understanding of xenografts may be important to today’s orthopaedist. Orthopaedic surgeons should be able to answer the following three questions:
- What is an orthopaedic xenograft?
- What role do xenografts play in current orthopaedic practice?
- What are the unique safety risks of xenografts?
What is an orthopaedic xenograft?
The U.S. Public Health Service has defined xenotransplantation as “…any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a non-human animal source or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live non-human animal cells, tissues, or organs.” This definition, which restricts xenotransplantation to “live” products, is probably misleading. Many orthopaedic xenografts are not living tissue, but they share features of xenotransplants of live tissue, particularly some unique safety risks.
The U.S. Public Health Service defines live cells, tissues, and organs as xenotransplantation products; nonliving tissue transplants are called xenografts. From a practical standpoint, today’s orthopaedist is most concerned with xenografts.
What role do xenografts play?
Allografts, now a mainstay of surgical intervention in many subspecialty orthopaedic practices, are increasingly used in general orthopaedic applications. In contrast to a relative shortage of allograft tissue, virtually an infinite amount of xenograft tissue is available. This availability has been the basis for the rapidly developing xenograft market.
Xenografts are often used as scaffolds and are thought to allow for ingrowth, and sometimes replacement, by host tissue while also providing structural support for deficient tissue. Table 1 summarizes some of the current products and their proposed indications.
The role of these products has yet to be defined. Although xenograft availability and use in orthopaedic procedures have increased dramatically, outcomes data are scarce. Some early reports on orthopaedic xenograft efficacy have yielded mixed reviews. Which xenograft products, if any, are best suited for orthopaedic applications remains to be seen.
Perhaps the most important thing the orthopaedist should know about these products is that many types are now available commercially and may be on supply room shelves. The orthopaedist should take care to distinguish xenografts and allografts because although the difference may not always be obvious, the distinction is important due to the unique risks for infection posed by xenograft products.
What are the unique safety risks of xenografts?
Cross-species tissue transplantation presents challenges distinct from those of allograft tissue transplantation. The risks of infection that plague all transplants are compounded by the unique risks posed by zoonoses, infectious diseases that may be passed across species lines from animals to humans.
Zoonotic disease can cause public health problems, such as Lyme disease, in the general population, but the breaches of normal host defenses inherent with xenotransplantation may enable agents formerly incapable of causing infections in humans to do so. Such infections have been termed “xenozoonoses.”
Xenozoonoses are of special concern because the pathogens that cause clinical disease in other animals might cause similar disease in humans. In addition, pathogens that do not cause clinical disease in other animals might do so in humans because species lines have been crossed. Diseases crossing species lines may become transmissible in other ways from human to human, which would increase the public health risk exponentially. For example, the human immunodeficiency virus (HIV) is thought by some to have crossed species lines from nonhuman primates to become a global pandemic.
Potential xenozoonotic infections in orthopaedic surgery can be divided into the following three basic categories: viral infection, prion-mediated infection, and bacterial infection.
Nonhuman sources of viral disease transmission are well documented in the literature, and the risk of cross-species disease transmission with the use of orthopaedic xenografts is of concern. Although no published evidence of disease transmissions from orthopaedic xenografts could be found, the expanding use of these products increases the risk. A basic understanding of viral disease transmission, the limited ability to screen for these viruses, and the potential sequelae of disease transmission should provide a framework for understanding this risk.
Viruses endemic to two species are of special concern for xenotransplantation. Both nonhuman primates and pigs harbor retroviruses that have been proven to infect human cells. Nonhuman primate xenotransplantations remain controversial; some scientists want a moratorium on the use of these products. Porcine xenografts are particularly relevant to this discussion because of their prevalence in the orthopaedic marketplace. Porcine endogenous retrovirus (PERV) is the most scrutinized of the porcine viruses because it can infect human cells in vitro.
Retroviruses are present in all vertebrates and are currently impossible to eradicate. PERV, first described in 1971, has been found in all types of porcine tissue. In vitro PERV infections of human cell lines have been documented, and inoculation with cell-free PERVs has yielded no infection in animal models. Although animal infection has been confirmed with the transplant of primary porcine cells, no infection has been documented in humans exposed to live porcine cells or tissues.
Retrospective studies of patients treated with porcine cells, tissues, and organs have not provided evidence of PERV infection, although one study found that 23 of 160 human patients showed microchimerism, the presence of donor cells in their serum, for up to 8.5 years after temporary exposure to splenic perfusions from porcine sources. Four patients showed seroreactivity to PERV, but no patient had a PERV infection.
Although PERV infections may be the most concerning, they are not the only potential viral human pathogen from porcine xenografts: swine influenza virus, parvovirus, and African swine fever virus are also potential risks. Some recent viral infection epidemics in humans have been traced to animal-derived strains (e.g., hantavirus and mice, HIV and primates), which gives pause to skeptics about viral risk in porcine xenografts.
The lack of apparent disease transmission to humans is reassuring, but the orthopaedist should consider that most studies ruling out porcine-human viral transmission have involved patients with limited short-term exposure to porcine tissue or cells. Orthopaedic xenografts have the potential to remain in place for years, and the comparative long-term risks of transplantation tissue potentially infected with PERV or other viruses have not been identified.
Prions are naturally occurring glycoproteins normally found in the neuronal cell membrane and lymphoreticular tissue. Their function is not known. Exposure to abnormal prions (PrPsc) can result in conversion of normal prions (PrPc) to PrPsc. This exposure can occur through mutation, iatrogenic exposure, or oral ingestion of PrPsc prion proteins. PrPsc has been a known source of disease transmission since 1921.
Transmissible forms of prion disease were identified when a kuru epidemic was documented in 1957. Prion-related disease transmission was recognized as a modern public health threat in Britain when human ingestion of PrPsc-infected beef led to an outbreak of bovine spongiform encephalopathy, or “mad cow disease.” This outbreak raised concerns around the world.
Although iatrogenic prion-mediated disease transmissions to orthopaedic patients have not been documented, transmissions have been documented from otolaryngeal and corneal xenografts, and from other procedures. Because prions transmit disease with a pathogenic protein (PrPsc) indistinguishable from a normal protein (PrPc), tissue cannot be screened for prion infection.
Another challenge with this tissue is the long latency period (1 to 40 years), so patients who have been exposed may not become symptomatic for years. Therefore, although prion-related disease is possible with virtually any bovine-tissue transplant, the risk of transmission from a bovine xenograft is difficult to quantify.
The risk of prion disease in orthopaedic xenografts is presumed low for two main reasons: (1) the occurrence of PrPsc in the bovine population is thought to be limited; and (2) it is presumed that surgical implantation near the recipient’s central nervous system—an area not involved in most orthopaedic transplants—carries the greatest risk. Nevertheless, the risk of prion disease transmission with bovine xenografts remains unclear.
According to a 1997 memorandum from the World Health Organization (WHO), “the ideal situation would be to avoid the use of bovine materials in the manufacture of medicinal products.” WHO also acknowledged that some use of bovine tissue implants might be unavoidable. In contrast, a review of the literature on bovine spongiform encephalopathy transmission with bovine bone xenografts in dental applications indicated that the risk of transmission was “negligible.”
Patient counseling should include an honest summary of the risks and should highlight that the risk of prion-mediated disease transplantation from bovine xenografts cannot be accurately assessed. Emphasis should be placed on the apparent lower relative risk with orthopaedic xenograft transplantation compared with other xenotransplants. Finally, a special effort should be made to provide patients with a clear understanding of alternatives to xenografts.
As with all transplants, xenografts have some inherent risks of bacterial infection. Xenografts have the unique theoretical risk of cross-species transmission of bacterial infections endemic to the donor species (e.g., trichinosis in pigs) to the patient. This problem, however, has not yet been seen clinically.
In summary, xenografts are a growing part of orthopaedic practice in this country. Today’s orthopaedist should be alert to their increasing availability and prevalence in products used in the operating room. Knowledge of the unique risks incurred when using these products is essential for both the orthopaedist and the patient.
Dr. Trice disclosed the following conflicts: Genzyme (speakers bureau/paid presentations) and Zimmer (research or institutional support).
Michael E. Trice, MD, is a member of the AAOS Biological Implants Committee. He can be reached at email@example.com
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