Allograft science: What is new, what are the challenges?

In this interview, William F. Enneking talks about recent developments discussed at an international symposium on allograft research.

Issue: March 2004

It is my pleasure to present this interview with William F. Enneking, MD. He is the Eugene L. Jewett Professor of Orthopaedic Surgery and Distinguished Service Professor in the department of orthopedics at the University of Florida in Gainesville.

Dr. Enneking has published extensively in the field of clinical musculoskeletal pathology and has received numerous distinguished awards and international recognitions. One of his current positions is chairman of the board of directors of the Musculoskeletal Transplant Foundation. He recently participated in the MTF’s international symposium on allograft research held in Edinburgh, Scotland.

I chose Dr. Enneking for this interview to update our readership about some of the new information presented at this symposium.

Douglas W. Jackson, MD
Chief Medical Editor

Douglas W. Jackson, MD: Dr. Enneking, what is the Musculoskeletal Transplant Foundation and why did the organization sponsor an international symposium on allograft science in Edinburgh, Scotland?

William F. Enneking, MD [photo]

William F. Enneking, MD
is the Eugene L. Jewett Professor of
Orthopaedic Surgery and Distinguished Service Professor in the department of orthopedics at the
University of Florida

William F. Enneking, MD: MTF is a nonprofit foundation composed of 36 academic institutions and 21 organ procurement organizations whose missions are to provide the orthopedic community with the highest quality biologic tissues for musculoskeletal reconstruction, to support basic and clinical research in musculoskeletal reconstruction, and to provide instruction in biologic reconstruction.

Located in Edison, New Jersey, MTF operates the largest musculoskeletal tissue bank in the world. It has procured, processed, stored and distributed tissues from more than 3000 donors in the past year, provided more than $6 million in research grants and fellowships through its academic members, promoted tissue donation through its organ procurement members, and sponsored educational programs in biologic reconstruction.

This symposium was the fourth in a series to provide a forum for scientific interchange in allograft science. Edinburgh was selected as the site to promote interchange between North American investigators and their European counterparts.

Jackson: What topics were discussed during the symposium?

Enneking: The symposium was divided into sessions with topics that included allograft safety; ethical considerations; tissue processing; immunological aspects of allografting; cartilage repair and replacement; and the role of growth factors, mesenchymal stem cells and gene therapy in skeletal reconstruction.

Jackson: Allograft safety is of interest to every surgeon and patient. What information was shared at the symposium?

radiograph
Two cases demonstrating reconstruction of extensive skeletal defects with intercalary allografts stabilized with plates and screws. Union has been achieved at the osteosynthesis sites.

COURTESY OF WILLIAM F. ENNEKING

Enneking: Allografts, in terms of viral transmission, particularly HIV and hepatitis C, are remarkably safe with the risk of transmission less than 1:2,000,000. Bacterial contamination is also very rare due to vastly improved techniques of sterile procurement, rigid donor criteria, and strict culture surveillance.

Secondary sterilization with either ethylene oxide or irradiation produces both biologic and biomechanical damage to the tissue so that so-called “clean” procurement requiring secondary sterilization as opposed to sterile procurement in an operating room environment is seldom done anymore.

However, there are pressures to develop chemical techniques that make tissues even safer without degrading either the biologic or biomechanical quality of the tissue. Therefore, the safety issue must constantly be balanced against efficacy.

Much of our information and regulation has come from the device field. The Food and Drug Administration requires a device to be both safe and efficacious. But in the tissue field, efficacy has not been required; it has been assumed. It is likely that that will change in the future and that accurate methods of assaying the osteoinductive qualities of tissue will have to be developed.

Jackson: What is the length of time that fresh allogeneic osteochondral transplants will remain viable for transplantation?

Enneking: The sooner they are used the better. When stored in an appropriate environment, seven to 10 days appears to be the outer limit for a high percentage of the chondrocytes to survive. This is a very narrow window to perform the necessary laboratory and administrative measures to ensure patient safety.

Although claims are made for up to 45 days of storage with “adequate” chondrocyte survival, there are little data to support those claims. There are several ongoing investigations to establish the optimal and acceptable time intervals. There needs to be significant acceleration in both administrative and laboratory procedures to provide for safe tissue in an acceptable time frame.

Jackson: What is the current role of growth factors?

Enneking: Following Dr. Marshall Urist’s seminal identification of bone morphogenetic protein, there has been a plethora of growth factors that are known to promote bone growth and healing. There is also ample evidence that various combinations are better than an individual factor. Clearly there are also the critical factors of the timing, presence or absence, and amount of growth factor(s) that remain to be established. We have just begun to scratch the surface of understanding in areas where great progress appears possible.

Secondly is the determination of which carriers are the most effective for the situations in which they are needed. Currently, dematerialized bone matrix is the most widely used but there are little data yet available to compare the various other carriers.

Jackson: There has been a lot of excitement generated by the prospect of stem cell therapy. Was this a hot topic at the symposium?

“This is a field of incredible potential, perhaps the greatest in our lifetime. The ability to introduce cells and genes back into the patient has tremendous promise.”
— William F. Enneking

Enneking: It certainly was. There seems to be little doubt that from animal experiments, mesenchymal stem cells placed in a matrix and planted in a defect have produced very impressive data in both biological and biomechanical terms. Dr. Joseph Buckwalter, the leader of this discussion, noted that more than 200 articles were published in the previous 12 months showing the formation of new cartilage, bone, tendon and ligament.

However, there are several unresolved issues: What is the effect of the cells on the recipient, can neoplasms be inadvertently created, are generations of permanently altered cells created in the patient, can the production of growth factors produced by the stem cells be turned off once they have done their job, to name only a few.

This is a field of incredible potential, perhaps the greatest in our lifetime. The ability to introduce cells and genes back into the patient has tremendous promise but there are many problems to be solved before this science can be used in clinical practice: efficacy, delivery, liability, and, last but not least, efficacy vs. cost.

None of these very promising techniques will suffice for biologic skeletal reconstruction alone. Methods of implantation with appropriate carriers customized to cell type and differentiation all pose great challenges but are not insurmountable.

Jackson: Are there immunologic barriers to allograft efficacy?

Enneking: That is a puzzling question. It has long been recognized that mesenchymal cells contain the same antigenic determinants as other organs, but because of the slow revascularization and repair of transplanted bone, the role of the patient’s immunologic response to an allograft is unpredictable.

New immunologic techniques have identified tissue-specific antibodies in some allograft recipients but whether or not they are responsible for interfering with a patient’s ability to incorporate the allograft has not been established. In addition, the logistical problems in tissue typing — as well as matching size, site and quality — pose formidable problems for as yet undetermined benefits.