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Diabetes mellitus (DM) is associated with musculoskeletal complications—including tendon dysfunction and injury. Patients with DM show altered foot and ankle mechanics that have been attributed to tendon dysfunction as well as impaired recovery post-tendon injury. Despite the problem of DM-related tendon complications, treatment guidelines specific to this population of individuals are lacking. DM impairs tendon structure, function, and healing capacity in tendons throughout the body, but the Achilles tendon is of particular concern and most studied in the diabetic foot. At macroscopic levels, asymptomatic, diabetic Achilles tendons may show morphological abnormalities such as thickening, collagen disorganization, and/or calcific changes at the tendon enthesis. At smaller length scales, DM affects collagen sliding and discrete plasticity due to glycation of collagen. However, how these alterations translate to mechanical deficits observed at larger length scales is an area of continued investigation. In addition to dysfunction of the extracellular matrix, tendon cells such as tenocytes and tendon stem/progenitor cells show significant abnormalities in proliferation, apoptosis, and remodeling capacity in the presence of hyperglycemia and advanced glycation end-products, thus contributing to the disruption of tendon homeostasis and healing. Improving our understanding of the effects of DM on tendons—from molecular pathways to patients—will progress toward targetedmore »therapies in this group at high risk of foot and ankle morbidity.« less

Abstract Diabetes is associated with impaired tendon homeostasis and subsequent tendon dysfunction, but the mechanisms underlying these associations is unclear. Advanced glycation end-products (AGEs) accumulate with diabetes and have been suggested to alter tendon function. In vivo imaging in humans has suggested collagen disorganization is more frequent in individuals with diabetes, which could also impair tendon mechanical function. The purpose of this study was to examine relationships between tendon tensile mechanics in human Achilles tendon with accumulation of advanced glycation end-products and collagen disorganization. Achilles tendon specimens (n = 16) were collected from individuals undergoing lower extremity amputation or from autopsy. Tendons were tensile tested with simultaneous quantitative polarized light imaging to assess collagen organization, after which AGEs content was assessed using a fluorescence assay. Moderate to strong relationships were observed between measures of collagen organization and tendon tensile mechanics (range of correlation coefficients: 0.570–0.727), whereas no statistically significant relationships were observed between AGEs content and mechanical parameters (range of correlation coefficients: 0.020–0.210). Results suggest that the relationship between AGEs content and tendon tensile mechanics may be masked by multifactorial collagen disorganization at larger length scales (i.e., the fascicle level).

Fibre topography of the extracellular matrix governs local mechanical properties and cellular behaviour including migration and gene expression. While quantifying properties of the fibrous network provides valuable data that could be used across a breadth of biomedical disciplines, most available techniques are limited to two dimensions and, therefore, do not fully capture the architecture of three-dimensional (3D) tissue. The currently available 3D techniques have limited accuracy and applicability and many are restricted to a specific imaging modality. To address this need, we developed a novel fibre analysis algorithm capable of determining fibre orientation, fibre diameter and fibre branching on a voxel-wise basis in image stacks with distinct fibre populations. The accuracy of the technique is demonstrated on computer-generated phantom image stacks spanning a range of features and complexities, as well as on two-photon microscopy image stacks of elastic fibres in bovine tendon and dermis. Additionally, we propose a measure of axial spherical variance which can be used to define the degree of fibre alignment in a distribution of 3D orientations. This method provides a useful tool to quantify orientation distributions and variance on image stacks with distinguishable fibres or fibre-like structures.