Full-thickness cartilage defects present a substantial clinical challenge. People are remaining active longer, and orthopaedic surgeons need techniques that effectively produce repair tissue that can withstand the test of time. The challenge is to find a way to achieve filling of cartilage defects with sufficiently cartilage-like tissue that is able to withstand repetitive loads without degeneration and loss of function. To date, efforts have failed to achieve good long-term results, at least in part because of the inability to recapitulate the type-II-collagen and aggrecan content of normal hyaline cartilage. Recent efforts have focused on cellular therapies—using chondrocytes or mesenchymal stem cells—as the basis for regeneration of repair tissue and for gene therapy approaches to enhance healing. Chondrocytes are ideally suited for the production of hyaline cartilage but challenging to obtain without donor site morbidity or the potential for inciting an immune response to allogenic cells. Bone-marrow-derived mesenchymal stem cells (BMDMSCs) provide an appealing alternative cell source with the potential to differentiate into chondrocytes following implantation and ease of collection with acceptable morbidity. Platelet-rich plasma has also gained recent attention as a readily available source of anabolic growth factors and cytokines with the potential to drive chondrogenesis.
The paper by Goodrich et al. describes the use of culture-expanded BMDMSCs combined with platelet-rich plasma in the form of an autologous platelet-enhanced fibrin (APEF) scaffold to enhance cartilage repair in a full-thickness cartilage defect model in the horse. APEF alone served as the control in the paired, contralateral limb of each horse. The horse provides an excellent model for cartilage healing because the large articular surface enables creation of a critical-size defect (15 mm in diameter) that does not heal simply by flow of normal cartilage from the healthy margin and because of the relatively high loads comparable with those in people. The technique investigated has the advantages of being deliverable by minimally invasive techniques using an arthroscope and of being autologous in nature. Lesions were evaluated in the short term (at three months with arthroscopy) and long term (at twelve months with arthroscopy, histological analysis, magnetic resonance imaging, micro-computed tomography, and biomechanical testing).
Although the short-term results for both the treated and the control defects showed promising filling with repair tissue and firm attachment to underlying bone, the addition of BMDMSCs to APEF did not improve repair compared with that observed with APEF alone in the long term. The only difference between the treated and control defects for the various parameters investigated was a significant increase in trabecular bone edema in the APEF+BMDMSC group, which the authors suggested may have been related to the tendency for bone formation in the combined treatment group. These findings are consistent with those of other studies of similar design and corroborate the challenges associated with achieving repair with a tissue that matches the mechanical, biochemical, and biological properties of normal cartilage. Previous studies using chondrocytes in place of BMDMSCs appear to have had better success in achieving improved repair tissue1, although earlier studies did not involve good long-term follow-up2-4. These differences highlight the debate over the ideal cell source for cartilage regeneration—one from the cartilage niche in which it will be implanted, or a progenitor theoretically capable of differentiation in response to environmental stimuli. Although BMDMSCs show good chondrogenic potential in vitro, the load-bearing articular milieu may simply be too challenging an environment in which to achieve chondrogenic differentiation or local biological factors may not be appropriate. Predifferentiation of BMDMSCs in vitro may provide an alternative approach to enhance their ability to withstand the demands of the articular environment.
An interesting and important finding in this study is the unusually high number of APEF+BMDMSC-treated defects (four of twelve) in which ectopic bone developed in the repair tissue during the healing process. This finding is in contrast to previous studies involving a similar horse model treated with BMDMSCs or chondrocytes embedded in a fibrin scaffold (without autologous platelets) and followed for eight2 or twelve months1. Although it is possible that eight months was simply too short a time for bone to form in response to BMDMSCs, it is more likely that the presence of APEF in the current study provided osteogenic signaling from the growth factor milieu released by the platelets, as the authors clearly stated in the Discussion. Frisbie et al. did not observe bone formation at twelve months1. These findings point to two variables in the current study that may have resulted in environmental conditions conducive to bone formation—use of BMDMSCs and the presence of growth-factor-rich platelets. BMDMSCs are reported to preferentially differentiate into osteoblasts, which is logical considering their origin in bone marrow. The ability to induce chondrogenic differentiation in vivo is based on controlling the environmental cues to which BMDMSCs are exposed, which may be difficult in the synovial environment. Also, the biological and mechanical stimuli adjacent to subchondral bone may not be conducive to chondrogenesis.
The authors are to be commended for a well-designed, thorough study targeting an area of high clinical importance. The major strengths of the study include the use of a long-term equine model with the ability to control for variation between animals through the use of the contralateral limb as a control and the completeness of the study design with respect to outcome measures. Study limitations are inherent in the relatively small number of animals included and in the lack of quantitative data presented regarding the platelet and white blood-cell (WBC) content of the APEF. The authors stated that the APEF did not contain WBCs; however, there is nothing in the methods that suggests WBC depletion and no data are presented documenting the lack of WBCs. This is important in light of a study reporting that higher WBC counts in platelet-rich plasma increased the osteogenic potential of BMDMSCs5. Additional studies—in vitro and in vivo—are required to further elucidate the mechanisms at play and advance the quality of cartilage repair tissue.
↵* Disclosure: The author received no payments or services, either directly or indirectly (i.e., via her institution), from a third party in support of any aspect of this work. Neither the author nor her institution has had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, the author has not had any other relationships, or engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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