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).
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Effect of Diabetes on Tendon Structure and Function: Not Limited to Collagen Crosslinking
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 targeted therapies in this group at high risk of foot and ankle morbidity.
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- Award ID(s):
- 2037125
- PAR ID:
- 10399451
- Date Published:
- Journal Name:
- Journal of Diabetes Science and Technology
- Volume:
- 17
- Issue:
- 1
- ISSN:
- 1932-2968
- Page Range / eLocation ID:
- 89 to 98
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract The extracellular matrix (ECM) is the primary biomechanical environment that interacts with tendon cells (tenocytes). Stresses applied via muscle contraction during skeletal movement transfer across structural hierarchies to the tenocyte nucleus in native uninjured tendons. Alterations to ECM structural and mechanical properties due to mechanical loading and tissue healing may affect this multiscale strain transfer and stress transmission through the ECM. This study explores the interface between dynamic loading and tendon healing across multiple length scales using living tendon explants. Results show that macroscale mechanical and structural properties are inferior following high magnitude dynamic loading (fatigue) in uninjured living tendon and that these effects propagate to the microscale. Although similar macroscale mechanical effects of dynamic loading are present in healing tendon compared to uninjured tendon, the microscale properties differed greatly during early healing. Regression analysis identified several variables (collagen and nuclear disorganization, cellularity, and F-actin) that directly predict nuclear deformation under loading. Finite element modeling predicted deficits in ECM stress transmission following fatigue loading and during healing. Together, this work identifies the multiscale response of tendon to dynamic loading and healing, and provides new insight into microenvironmental features that tenocytes may experience following injury and after cell delivery therapies.
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Abstract Subfailure ligament and tendon injury remain a significant burden to global healthcare. Here, we present the use of biocompatible single‐walled carbon nanohorns (CNH) as a potential treatment for the repair of sub‐failure injury in tendons. First, in vitro exposure of CNH to human tenocytes revealed no change in collagen deposition but a significant decrease in cell metabolic activity after 14 days. Additionally, gene expression studies revealed significant downregulation of collagen Types I and III mRNA at 7 days with some recovery after 14 days of exposure. Biomechanical tests with explanted porcine digitorum tendons showed the ability of CNH suspensions to modulate tendon biomechanics, most notably elastic moduli immediately after treatment. in vivo experiments demonstrated the ability of CNH to persist in the damaged matrix of stretch‐injured Sprague Dawley rat Achilles tendon but not significantly modify tendon biomechanics after 7 days of treatment. Although these results demonstrate the early feasibility of utility of CNH as a potential modality for tendon subfailure injury, additional work is needed to further validate and ensure clinical efficacy.
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Abstract Achilles tendon injury is one of the challenges of sports medicine, the aetiology of which remains unknown. For a long time, estrogen receptor β (ERβ) has been known as a regulating factor of the metabolism in many connective tissues, such as bone, muscle and cartilage, but little is known about its role in tendon. Recent studies have implicated ERβ as involved in the process of tendon healing. Tendon‐derived stem cells (TDSCs) are getting more and more attention in tendon physiological and pathological process. In this study, we investigated how ERβ played a role in Achilles tendon healing. Achilles tendon injury model was established to analyse how ERβ affected on healing process in vivo. Cell proliferation assay, Western blots, qRT‐PCR and immunocytochemistry were performed to investigate the effect of ERβ on TDSCs. Here, we showed that ERβ deletion in mice resulted in inferior gross appearance, histological scores and, most importantly, increased accumulation of adipocytes during the early tendon healing which involved activation of peroxisome proliferator‐activated receptor γ (PPARγ) signalling. Furthermore, in vitro results of ours confirmed that the abnormity might be the result of abnormal TDSC adipogenic differentiation which could be partially reversed by the treatment of ERβ agonist LY3201. These data revealed a role of ERβ in Achilles tendon healing for the first time, thereby providing a new target for clinical treatment of Achilles tendon injury.
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Abstract Rodent tendons are widely used to study human pathologies such as tendinopathy and repair, and to address fundamental physiological questions about development, growth, and remodeling. However, how the gross morphology and multi‐scale hierarchical structure of rat tendons, such as the tail, plantaris, and Achilles tendons, compare with that of human tendons are unknown. In addition, there remains disagreement about terminology and definitions. Specifically, the definitions of fascicle and fiber are often dependent on diameter sizes, not their characteristic features, and these definitions impair the ability to compare hierarchical structure across species, where the sizes of the fiber and fascicle may change with animal size and tendon function. Thus, the objective of the study was to select a single species that is commonly used for tendon research (rat) and tendons with varying mechanical functions (tail, plantaris, Achilles) to evaluate the hierarchical structure at multiple length scales using histology,
SEM , and confocal imaging. With the exception of the specialized rat tail tendon, we confirmed that in rat tendons there are no fascicles and the fiber is the largest subunit. In addition, we provided a structurally based definition of a fiber as a bundle of collagen fibrils that is surrounded by elongated cells, and this definition was supported by both histologically processed and unprocessed samples. In all rat tendons studied, the fiber diameters were consistently between 10 and 50 μm, and this diameter range appears to be conserved across larger species. Specific recommendations were made highlighting the strengths and limitations of each rat tendon as a research model. Understanding the hierarchical structure of tendon can advance the design and interpretation of experiments and development of tissue‐engineered constructs.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1177/19322968221100842
