A growing body of evidence supports the following hypotheses: (1) chondrocyte apoptosis is associated with cartilage injury and degeneration; (2) chondrocyte apoptosis is a consequence of osteochondral graft storage, preparation and implantation; and (3) chondrocyte apoptosis is at least partially preventable through the inhibition of key apoptotic pathways. Therefore, apoptosis inhibition would seem to be a rational strategy to pursue in order to enhance the clinical results of osteochondral allograft transplantation. Theoretically, apoptosis inhibition could increase the percentage of viable chondrocytes in cold-stored grafts, and extend the “shelf-life” of these grafts making them more available to surgeons. By limiting apoptosis induced by matrix damage localized to the peripheral margins of the donor and recipient sites, cartilage edge integration could be enhanced. Furthermore, by blocking apoptosis caused during graft impaction, chondrocyte viability, particularly viability of critical superficial zone cells, could enhance the function and durability of transplanted osteochondral grafts.
While the benefits of apoptosis inhibition have been demonstrated in animal models of degenerative arthritis, cartilage injury, and cartilage repair using marrow-stimulation techniques [13
], the in vivo effects of apoptosis inhibition in the setting of osteochondral allograft transplantation have not been reported. Based upon existing research, beneficial effects would be anticipated. Whether or not beneficial effects seen in animal models will translate into clinical efficacy remains an unanswered question. Furthermore, the difficulty in proving clinical efficacy should not be underestimated as demonstrated by the inability of recent randomized clinical trials to demonstrate differences between competing cartilage repair techniques such as microfracture, autologous chondrocyte implantation, and mosaicplasty [47
]. Nevertheless, well-designed animal studies are the obvious next step. Although small animal models can provide important information, studies in large animal models will be necessary since factors such as the thickness of articular cartilage and the size of transplanted grafts are likely to have a major effect on the extent and pattern of apoptosis that occurs and the response to apoptosis inhibition.
While it is generally thought that increased chondrocyte viability in transplanted osteochondral grafts will lead to superior long-term clinical results, this hypothesis has not been proven definitively. Frozen osteochondral grafts have been used successfully for decades, particularly in orthopaedic oncology. These grafts have no viable chondrocytes yet appear to function well clinically for many years. Mankin and colleagues [34
] report on a large series of allograft reconstruction including frozen osteoarticular grafts, and the development of arthritis was stated to become a problem after approximately 6 years. However, only 16% of the patients in their series went on to joint replacement. Why the articular cartilage in these grafts does not degenerate more rapidly and consistently in the absence of viable cells is not well understood. We are not aware of any human studies directly comparing the results of osteochondral transplantation using fresh and frozen grafts. However, in a dog model, results using fresh grafts were shown to be markedly superior to frozen grafts [45
], suggesting that cell viability is an important contributor to osteochondral graft performance.
From a practical standpoint, osteochondral allograft transplantation is a particularly attractive target for apoptosis inhibition therapy for several reasons. First, much of the treatment could be performed outside the body, greatly limiting systemic side effects. For example, very high doses of potentially toxic agents could be applied to the grafts ex vivo to maximize efficacy. Second, treatment could be initiated before mechanical injury when it is most effective rather than afterwards as would be the case for degenerative conditions and traumatic injuries. Third, treatment could be focused specifically during the intraoperative, or perhaps perioperative, period when apoptosis is maximal. In contrast, longer-term treatment would be necessary for degenerative conditions such as osteoarthritis. Fourth, since these procedures are almost always performed as an open procedure, treatment directed at the donor site could be focused specifically in that location, perhaps by direct application of a bioactive gel, rather than throughout the entire joint.
In summary, substantial scientific evidence demonstrates an important association of chondrocyte apoptosis with osteochondral allograft transplantation. In the not too distant future, this knowledge may be applied to design novel therapeutic approaches that may improve the clinical results of this surgical procedure.