252 ACL = anterior cruciate ligament; bFGF = basic fibroblast growth factor; FDP = flexor digitorum profundus; TGF = transforming growth factor; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor. Arthritis Research Vol 4 No 4 Fenwick et al. IntroductionEvidence exists that tendon repair can occur either intrinsically via the resident tenocytes [1,2] or via extrinsic mechanisms, whereby cells from the surrounding sheath or synovium invade the tissue [3]. It seems likely that both mechanisms occur, although the involvement of external cells depends on the site of injury and vascular perfusion. Many in vivo animal studies have been performed on the ability of tendon to repair following laceration, transection and other models of injury [4][5][6][7]. A large number of in vitro studies on animal and human tendon have also been performed [1,2,8,9]. The roles of many factors in tendon repair have been examined, including cell proliferation and DNA synthesis [10,11], collagen [11], noncollagenous protein [12] and proteoglycan synthesis [13]. Intratendinous degenerative change is strongly associated with both chronic tendinopathies and spontaneous tendon rupture [14][15][16][17].Degeneration and subsequent rupture of tendons has been associated with hypovascularity of specific regions within certain tendons [18,19]. A permanent disruption of the central blood vessels to normal tendons has been shown to cause cellular death and disintegration of collagen bundles [20]. Contradictory to this, however, would appear to be the finding that in many cases of chronic tendinopathy that have been examined histologically, there is an 'angiofibroblastic' response, and the presence of many large blood vessels [21][22][23]. The presence of blood vessels was not considered to be an indication of tissue repair [22]. What then is the role of a proliferative vasculature in the damaged tendon?The aim of this review is to discuss the importance of the vasculature in tendon damage and repair, and what is known about factors that regulate changes in the vasculature of what is normally a sparsely vascularised tissue. Tendon vasculatureDuring development, tendons are highly cellular and metabolically active, and are thus supplied with a rich capillary network [20]. Mature tendons, however, are poorly vascularised [24][25][26]; tendon nutrition is more reliant on synovial fluid diffusion than vascular perfusion [27], although they do have more blood vessels than is commonly accepted. Like any other connective tissue, tendon does not undergo neovascularisation under normal circum- ReviewThe vasculature and its role in the damaged and healing tendon AbstractTendon pathology has many manifestations, from spontaneous rupture to chronic tendinitis or tendinosis; the etiology and pathology of each are very different, and poorly understood. Tendon is a comparatively poorly vascularised tissue that relies heavily upon synovial fluid diffusion to provide nutrition. During tendon injury, as with damage to any t...

Objective. To determine whether the fluoroquinolone antibiotic ciprofloxacin, which can cause tendon pain and rupture in a proportion of treated patients, affects the expression of matrix metalloproteinases (MMPs) in human tendon-derived cells in culture.Methods. Cell cultures were derived from 6 separate tendon explants, and were incubated in 6-well culture plates for 2 periods of 48 hours each, with ciprofloxacin (or DMSO in controls) and interleukin-1␤ (IL-1␤), alone and in combination. Samples of supernatant medium from the second 48-hour incubation were assayed for MMPs 1, 2, and 3 by Western blotting. RNA was extracted from the cells and assayed for MMP messenger RNA (mRNA) by semiquantitative reverse transcription-polymerase chain reaction, with normalization for GAPDH mRNA.Results. Unstimulated tendon cells expressed low or undetectable levels of MMP-1 and MMP-3, and substantial levels of MMP-2. IL-1␤ induced a substantial output of both MMP-1 and MMP-3 into cell supernatants, reflecting increases (typically 100-fold) in MMP mRNA, but had only minor effects on MMP-2 expression. Ciprofloxacin had no detectable effect on MMP output in unstimulated cells. Preincubation with ciprofloxacin potentiated IL-1␤-stimulated MMP-3 output, reflecting a similar effect on MMP-3 mRNA expression. Ciprofloxacin also potentiated IL-1␤-stimulated MMP-1 mRNA expression, but did not potentiate the output of MMP-1, and had no significant effects on MMP-2 mRNA expression or output.Conclusion. Ciprofloxacin can selectively enhance MMP expression in tendon-derived cells. Such effects might compromise tendon microstructure and integrity.

Chronic tendon lesions are degenerative conditions and may represent a failure to repair or remodel the extracellular matrix after repeated micro-injury. Since TGF-β is strongly associated with tissue repair, we investigated the expression of TGF-β isoforms ( β1, β2 and β3) and their 2 signalling receptors (TGF-βRI and TGF-βRII) in normal and pathological Achilles tendons. In all tissues, all 3 TGF-β isoforms and the 2 receptors were present at sites of blood vessels. Cells in the matrix showed no staining for TGF-β1 or β3, while TGF-β2 was associated with cells throughout the normal cadaver tendon. Tissue from tendons with pathological lesions showed an increase in cell numbers and percentage TGF-β2 expression. TGF-βRII showed a wide distribution in cells throughout the tissue sections. As with TGF-β2, there was an increase in the number of cells expressing TGF-βRII in pathological tissue. TGF-βRI was restricted to blood vessels and was absent from the fibrillar matrix. We conclude that despite the presence and upregulation of TGF-β2, TGF-β signalling is not propagated due to the lack of TGF-βRI. This might explain why chronic tendon lesions fail to resolve and suggests that the addition of exogenous TGF-β will have little effect on chronic tendinopathy.

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Wear debris generation in total joint replacement remains a concern because of its association with aseptic loosening, osteolysis, and ultimately implant failure. In a quest to develop new implant materials with reduced wear and improved biocompatibility a new composition of oxidized Zr2.5Nb alloy; diffusion hardened oxidized zirconium (DHOxZr) has been developed. In this study, we have determined the in vitro biocompatibility of the wear debris of this new composition and compared it to wear debris particles of Ti6Al4V, Cobalt, and CoCr. The cytotoxicity of these particles on fibroblast-like cells (L929) and osteoblast-like cells (SaOS2) was assessed using lactate dehydrogenase and DNA quantification assays. The inflammatory response to these particles was assessed by release of interleukin-1 beta and tumor necrosis factor from macrophage-like cells. The results showed that wear debris generated from DHOxZr was less cytotoxic and elicited a reduced inflammatory response as compared to that of Cobalt or CoCr and might therefore offer a benefit as a joint prosthesis.