Adult articular cartilage exhibits little capacity for intrinsic repair, and thus even minor injuries or lesions may lead to progressive damage and osteoarthritic joint degeneration, resulting in significant pain and disability. While there have been numerous attempts to develop tissue-engineered grafts or patches to repair focal chondral and osteochondral defects, there remain significant challenges in the clinical application of cell-based therapies for cartilage repair. This paper reviews the current state of cartilage tissue engineering with respect to different cell sources and their potential genetic modification, biomaterial scaffolds and growth factors, as well as preclinical testing in various animal models. This is not intended as a systematic review, rather an opinion of where the field is moving in light of current literature. While significant advances have been made in recent years, the complexity of this problem suggests that a multidisciplinary approach -combining a clinical perspective with expertise in cell biology, biomechanics, biomaterials science and high-throughput analysis will likely be necessary to address the challenge of developing functional cartilage replacements. With this approach we are more likely to realise the clinical goal of treating both focal defects and even large-scale osteoarthritic degenerative changes in the joint.
Articular cartilage destruction and loss of function in arthritic diseases involves proteolytic degradation of the connective tissue matrix. We have investigated the degradation of cartilage collagen by developing immunochemical methods that permit the identification and analysis of type II collagen degradation in situ. Previously, a technique to specifically identify type II collagen degradation in situ in articular cartilage did not exist. These methods utilize a polyclonal antiserum (R181) that specifically reacts with unwound a-chains and CNBr-derived peptides, al(II)CB11 and al(II)CB8, of human and bovine type II collagens. The experimental approach is based on the fact that when fibrillar collagens are cleaved the helical collagen molecule unwinds, exposing hidden epitopes. Here we demonstrate the use of R181 in studying type II collagen degradation in bovine articular cartilage that has been cultured with or without IL-1 and in human normal, rheumatoid, and osteoarthritic articular cartilages. Compared to cartilages either freshly isolated or cultured without IL-1, bovine cartilage cultured with IL-1 for 3-5 d showed an increase in both pericellular and intercellular immunohistochemical staining. Extracts of these cartilages contained type II collagen a chains that were increased in amount after culture with IL-1 for 11 d. In addition, culture with IL-1 resulted in the appearance of a chain fragments of lower molecular weight. All human arthritic tissues examined showed areas of pronounced pericellular and territorial staining for collagen degradation as compared with nondiseased tissues, indicating that chondrocytes are responsible in part for this degradation as compared with nondiseased tissues. In most cases rheumatoid cartilage was stained most intensely at the articular surface and in the deep and midzones, whereas osteoarthritic cartilage usually stained more in the superficial and mid-zones, but less intensely. Distinct patterns of sites of collagen degradation reflect differences in collagen destruction in these diseases, suggesting possible different sources of chondrocyte activation. These experiments demonstrate the application of immunological methods to detect collagen degradation and demonstrate an increase of collagen degradation in human arthritides and in IL-1-treated viable bovine cartilage.
Purpose:To establish the specificity of T 1 with respect to fixed charge density (FCD) as a measure of proteoglycan (PG) content in cartilage during the onset of osteoarthritis (OA). Materials and Methods:T 1 -weighted and sodium MRI were performed on cartilage samples of enzymatically degraded bovine explants and natural osteoarthritic human samples representing controlled and physiological models of OA, respectively. Spatial maps of T 1 and FCD (measured using the previously validated method of sodium MRI) were calculated from image data. Data were extracted from the maps and subjected to linear regression to compare changes in T 1 with changes in FCD in each model. Tissue samples were subjected to histological staining for a reduction in PG content.Results: Plots of normalized T 1 rate vs. FCD were found to be strongly correlated (R 2 Ͼ 0.75 and 0.85) in both models with nearly the same slope of Ϸ1/2 (P Ͼ 0.51). Loss of PG in bovine and human tissue was confirmed by histology. Conclusion:The strong correlation of the FCD and T 1 data in both the controlled and physiological models demonstrates that changes in T 1 are due predominantly to changes in PG content. This work is a first step in establishing T 1 as a method of quantifying PG changes in early-stage OA. THE PATHOLOGY OF THE disease osteoarthritis (OA) results in significant changes to the biochemical composition of cartilage. Loss of proteoglycan content (PG) from the extracellular matrix (ECM) is characteristic of the early development of OA (1-3). Although changes in collagen content and structure have been discerned, during the beginning stages of the disease the collagenous component of the ECM is often preserved (3-5). A noninvasive technique to detect biochemical changes that precede morphological degeneration in tissue will have a substantial impact on early diagnosis and the evaluation of therapeutic efficacy of treatment.The sodium MRI method has previously been established as an accurate measure of fixed charge density (FCD), as validated by spectrophotometric assay (6). The direct relationship between FCD and PG allows FCD data obtained via sodium MRI to be used as a spatially resolved measure of PG. Since the FCD measurement is affected only by charged species, sodium MRI provides a highly specific measure of PG and can be used as a gold standard for validating other methods of PG quantification.A promising alternative to sodium MRI to detect PG changes in vivo is T 1 -weighted MRI (7). T 1 , the spinlattice relaxation in the rotating frame, is sensitive to low frequency interactions between water molecules and their local macromolecular environment, such as the PG constituent of the ECM in cartilage. T 1 -weighting can be incorporated into an MR imaging sequence by "T 1 -preparing" the magnetization using a long duration spin-lock pulse. The amplitude of the spin-lock pulse is commonly referenced in terms of its nutation frequency (␥B 1 ), which is on the order of a few kilohertz. T 1 is sensitive to molecular interaction processes having...
The bony remodeling observed in this model system appears to be a biological phenomena and not a result of altered mechanical loading, with the depth of the focal chondral defect (partial vs. full thickness) dictating the bony remodeling response. The type of cartilage injury should be carefully controlled in studies utilizing this model to evaluate TE approaches for cartilage repair.
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