Perspectives On Medical Research

Volume 2, 1990

Evaluation of Bone Graft Research

Neal D. Barnard, M.D

The Physicians Committee for Responsible has received the expert opinions of several orthopedic surgeons and pathologists regarding the protocols for proposed bone-replacement research on greyhound dogs at the Letterman Army Institute of Research. A thorough evaluation of the project, however, will require more complete information about the experiments. The following is a preliminary analysis, based on the materials we have received to date.

Background

Bone grafting has been an active field in orthopedic research for at least 65 years. Three basic types of bone grafts exists: autografts, in which bone is taken from one part of the patient's body and utilized at another site; allografts which generally involve bone obtained from bone banks; and synthetic grafts.

A variety of synthetic materials have been tested for use in grafting. The most successful to date appears to be coralline hydroxyapatite, a substance manufactured by Interpore International of Irvine, California. This substance, which is produced from the calcium carbonate skeletal structure of reef-building sea corals, has been used as a bone replacement in animal and human studies since 1978 and has received pre-market approval from the Food and Drug Administration (FDA).

Synthetic grafts have limitations. Chief among these is the patient's immunologic response to a foreign substance and the possibility of infection. (Since synthetic materials are not vascularized, it is difficult to deliver antibiotics to the site of the infection.) Oral surgeons once used synthetic bone grafts, but later they all but abandoned the practice due to high infection rates.¹ Potential toxicity and carcinogemcity of synthetic compounds are also concerns.

Justification for the Study

In order to evaluate the need for the proposed study properly, it is necessary to have more information about the 3M synthetic that the Letterman researchers intend to investigate. The protocols indicate that the synthetic has exhibited osteoinductive properties, implying that some testing has been done. Have toxicity and efficacy studies been conducted by the manufacturer? It would be foolish to proceed with large-scale, expensive studies on dogs if the material in question is likely to be toxic to humans. Is there reason to believe that the substance will have advantages over coraffine hydroxyapatite, for which substantial data exist?

The Experimental Model

While the canine model has been used extensively in orthopedic research, its clinical relevance is less than clear. For example, Pierre M. Galleti, professor of medical science and head of the graduate program in artificial organs and biomaterials at Brown University, described the inadequacies of animal models in this type of research. In 1988, he wrote:

Research using animals simply will not suffice ... The replacement of wrists, knees, hips and finger joints generally poses complex engineering problems because of the hea~y mechanical loads involved and the range of motion required. Since there is no generally accepted large-animal model for most of the bones and joints that ortliopalic devices arc designed to replace, clinical evaluation in humans is the most significant test. Finally, humans live much longer than most animals. For prostheses that are intended to last a lifetime, animal studies are inadequate!

The criticism is relevant to bone graft research as well, because many of the same parameters -- compatibility, durability, toxicity -- are involved.

While the research protocol states that other animal models are inappropriate because of anatomical and biomechanical differences, it does not explain why the dog is an appropriate model for this kind of study. It may be that the dog is better than other animal models, but it does not necessarily mean that the dog model is adequate for clinically applicable investigations in bone replacement.

In addition, the use of former race dogs may introduce complicating variables to the experiment It is known that these dogs commonly sustain stress fractures, ligament damage and other injuries, and the effect of these factors on the ultimate success of the bone grafts is unknown and unaccounted for in these protocols.

Finally, the protocols state that the fibula has been the typical model for bone repair in the dog. Why is it necessary to establish a new model, using the femur as the site for bone grafting? The protocol states that the femur is more highly vascularized, but it does not explain why this is a better model than the fibula, for which there is extensive research experience. One wonders whether the 3M synthetic has already been tested unsuccessfully in the fibula.

Model for Battlefield Injury

The goal of the experiments is to explore alternative methods of fracture treatment to expedite the healing of long bone injuries suffered in combat. Surgical defects will be created in the dogs without significant injury to surrounding nerves and blood vessels, and without loss of surrounding tissue. Yet, a critical element of bone healing is the viability of the soft tissues, particularly the blood vessels, around the injury site. Bone fractures always damage these tissues, and the damage is particularly severe in military wounds. This experimental protocol, which carefully avoids soft tissue damage, is fundamentally different from any kind of human traumatic bone fracture. It is ironic that the military is funding this research, because the model least applies to military-type orthopedic injuries.

The protocol states that "the vast majority of these soldiers have fractures which are open, comminuted and contaminated." Indeed, battlefield wounds are particularly susceptible to infection. Yet the surgical defect is created under sterile conditions, thus eliminating the possibility of infections. Furthermore, as stated before, the problem of infection is a serious one for synthetic bone replacement. The use of synthetic grafts for the type of wounds sustained by soldiers in combat, is likely to be very problematic, at best.

Costs

The proposed study, if completed, would involve as many as 112 retired greyhound race dogs. According to the protocols, the cost of purchasing these dogs would be $41,000 and housing them for the duration of the experiment would cost as much at $48,000. The costs of other supplies and salaries for personnel, combined with the $89,000 for purchase and housing of the dogs, make this experiment an expensive endeavor. There are also legitimate humane concerns. After creating painful skeletal defects, the protocols state that analgesics and sedatives will be provided "as needed." However, no criteria for such decisions are mentioned. The way in which the researchers intend to prevent the dogs from harming the surgical site is unclear.

Summary

The fracture-repair experiments proposed by researchers at the Letterman Army Institute of Research are costly, both in terms of tax dollars and animal suffering. The Army's reluctance to release the name of the compound to be investigated is puzzling in light of the fact that the material is already patented. Clearly, information about the compound's toxicity and potential for success is necessary before the experiments proceed. We presume that relevant information addressing these concerns exists, but it is not provided in the research protocols. Furthermore, information about the researchers' backgrounds and experience in the field of bone replacement research and a bibliography of papers which describe the strengths and weaknesses of existing animal models are necessary for a thorough evaluation of this proposal. Such documentation would be provided routinely in a grant application to the National Institute of Health.

Based on the information available to us, the proposed model for bone replacement study appears scientifically flawed and not worthy of funding. Should more information become available, we will most certainly consult our orthopedic surgeons and pathologists for a more complete evaluation.

References

1. Orthopedic and Rehabilitation Devices Panel of the FDA Transcript of a meeting. June 4 1989.

2 Galletti PM: Artificial organs: Learning to live with risk. Technology Review Nov/Dec 1988, pp 35-40.

Contents