Osteochondral allograft (OCA) transplantation has become one of the foremost methods for treating articular cartilage injury and disease, largely due to the work of William D. Bugbee, MD, of Scripps Clinic, La Jolla, and his colleagues at the University of California, San Diego (UCSD).
“Our intense research efforts over the last 2 decades have helped transform this procedure from experimental ‘niche’ status to a mainstay of orthopaedic practice,” said Dr. Bugbee, professor of orthopaedic surgery at UCSD and attending physician in the division of orthopedic surgery at Scripps Clinic.
Dr. Bugbee and his colleagues have helped define the current standards for allograft processing and storage prior to implantation and have made novel observations on the biologic and clinical behavior of allograft transplants in vivo. As a result, OCA transplantation (Fig. 1) is now a viable option for patients with disabling articular cartilage pathology.
These basic science and translational studies have been summarized in “Osteochondral Allograft Transplantation in Cartilage Repair: Graft Storage Paradigm, Translational Models, and Clinical Applications.” The paper, which drew on 15 years of basic science research as well as extensive clinical experience from more than 800 OCA procedures, received the 2015 Kappa Delta Elizabeth Winston Lanier Award.
Developing storage protocols
For OCA transplantation to become widely available, effective OCA storage protocols first had to be developed. Nine different studies investigated methods for preserving long-term chondrocyte viability prior to allograft implantation.
The researchers found that OCA stored via the traditional method—ie, using Ringer’s solution—should be implanted in the patient within 7 days. With the addition of tissue culture media (TCM), however, storage duration could be extended up to 4 weeks, thus “opening the possibilities of extended graft testing and distribution to physicians and their patients outside of specialized centers,” noted Dr. Bugbee.
In another study, the investigators collected and analyzed allograft tissue that was unused during surgery. In the tissue, which had a mean storage time of approximately 20 days, the researchers found that “chondrocyte viability, viable cell density, and sodium sulfate (SO4) uptake were significantly lower in cartilage of OCA at implantation when compared to fresh, unstored control cartilage, especially in the important superficial zone.” They concluded there was substantial room for improvement in OCA storage procedures, noting that screening and processing protocols sometimes delayed surgical implantation of grafts by 3 weeks to 6 weeks after recovery.
Other studies suggested that adding fetal bovine serum to TCM during storage at 4 degrees Celsius (4ºC) enhances the quality of cartilage in OCA after 28 days. Another study found that “the bone-to-cartilage ratio plays a minimal role in the preservation of chondrocyte viability during prolonged storage and, thus, confirmed empirical tissue banking practice,” wrote Dr. Bugbee. The researchers went on to study tissue storage at 37ºC, as well as the addition of growth factors and inhibitors of cell death, all of which appear to improve cell viability, especially at the important superficial zone of articular cartilage.
“Our basic science studies have enabled us to define not only the biologic behavior of OCA,” noted Dr. Bugbee, “but also storage conditions in which chondrocyte viability can be preserved for as long as 4 weeks prior to surgical implantation. As a result, our findings have defined tissue bank practices for graft storage nationwide.”
In vivo studies
Another important aspect of the investigators’ research was their use of an animal model to conduct a systematic and temporal assessment of cartilage repair and remodeling.
“We set out to design intradisciplinary and multiscale analyses of cartilage repair in an animal model to elucidate tissue changes within the allograft as well as the recipient, to provide insight into the time-course of cartilage and bone remodeling and/or deterioration,” explained Dr. Bugbee. “In spite of the fact that fresh allografts had been used clinically for years, no systematic understanding of their biologic behavior had ever been undertaken.”
Using a goat model, the researchers examined the effects of various OCA storage methods on cartilage properties at 6 and 12 months after implantation.
“Frozen OCA already exhibited clear progression toward failure, with loss of chondrocytes, reduced proteoglycan content and cartilage stiffness, and associated surface and/or bone collapse at the medial femoral condyle,” noted
Dr. Bugbee. “In contrast, fresh OCA preserved depth-dependent tissue properties similar to non-operated cartilage, and thus maintained its capacity for biological homeostasis.”
The investigators also concluded that proteoglycan 4 secretion may be helpful in identifying chondrocyte viability and allograft performance. They were able to pinpoint biologic and biophysical mechanisms that may play important roles in osseous repair and to develop clinically translatable imaging analyses targeted at evaluating OCA repair, including a magnetic resonance imaging scoring system.
“The results of these studies enable us to better predict OCA outcomes and devise strategies to provide more suitable tissue for transplantation, which in turn will help improve long-term repair efficacy in the clinic,” said Dr. Bugbee.
Surgical techniques and outcomes
The researchers have published many studies detailing the “technical, logistical, and surgical details needed to further the widespread application of OCA in cartilage repair scenarios,” wrote Dr. Bugbee.
These studies have shown that “excessive impact loading of cartilage during insertion of osteochondral grafts should be avoided so as to not jeopardize optimum graft health.” It is critically important, contend the researchers, to preserve chondrocyte viability during insertion to maintain the long-term repair efficacy of OCA.
Dr. Bugbee noted that “the results of these studies forced us to reconsider some surgical protocols, which called for a tight interference fit and often necessitated strong impaction and larger portions of bone to anchor the graft to the host. We also considered alternative strategies for increasing the supply of suitable graft tissue.”
Using data from a comprehensive clinical database, Dr. Bugbee and colleagues prospectively evaluated the outcomes of all patients (n=467; 527 knees) who had undergone OCA transplantation since 1997. The group included 279 males and 188 females with a mean age of 34 years (range, 14 years to 68 years). Diagnoses ranged from traumatic cartilage injury to osteochondritis dissecans and degenerative cartilage lesions.
“The majority of patients—93 percent—reported less pain, and 96 percent of patients were satisfied with their outcomes,” noted Dr. Bugbee, adding that “65 grafts failed and additional surgery was required, with a mean time to reoperation of 38 months.”
Clinical studies have added to the knowledge base regarding outcomes for select applications of OCA transplantation. One such study by Dr. Bugbee and his colleagues provided evidence suggesting that fresh OCA transplantation is an effective treatment option for patients with osteochondritis dissecans of the femoral condyle, with more than 70 percent of patients having results rated “good” or “excellent.” Another study found that OCA was “safe, reliable, and effective in treating young patients with difficult osteochondral lesions of the knee.”
The authors have also studied many clinical variables, such as patient age and diagnosis, as well as the effect of previous surgery or the size or location of the allograft in an effort to better define indications and outcomes for specific patients. Female sex, age older than 40 years, and larger graft size were associated with inferior results.
“One unique finding was that revising a failed allograft was effective in the majority of cases,” said Dr. Bugbee, noting that clinical studies are ongoing.
Because allografts are living tissue transplants, Dr Bugbee also investigated the role of blood type and the generation of immune response in allograft recipients.
“Although no tissue or blood type matching is currently performed, our studies suggest that matching ABO antigens was associated with better outcomes,” he explained. “The development of anti-human leukocyte antigen (anti-HLA) antibodies in the recipient was more common in larger grafts, but the clinical consequences of antibody formation is not yet clear.”
These accumulated findings suggest “OCA is useful for a wide spectrum of knee joint pathology and results in significant improvement in pain and function, with high satisfaction in the majority of patients,” wrote Dr. Bugbee.
As OCA transplantation becomes an increasingly common method for restoring diseased or damaged joints, Dr. Bugbee looks forward to additional research that will help contribute to the knowledge base for this important surgical treatment.
“OCA transplantation is now a very successful and widely available treatment for patients with disabling articular cartilage pathology,” stated Dr. Bugbee. “The future promise and utility of OCA relies on continued scientific endeavor to realize its potential in cartilage restoration and bioarthroplasty.”
Dr. Bugbee’s coauthors included Andrea L. Pallante-Kichura, PhD; Simon Görtz, MD; Robert Sah, MD, ScD; and David Amiel, PhD.
The authors’ disclosure information, including potential conflicts of interest, can be viewed at www.aaos.org/disclosure
Jennie McKee is a senior science writer for AAOS Now. She can be reached at firstname.lastname@example.org