skip to main content

This content will become publicly available on January 1, 2024

Title: 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 more » therapies in this group at high risk of foot and ankle morbidity. « less
; ;
Award ID(s):
Publication Date:
Journal Name:
Journal of Diabetes Science and Technology
Page Range or eLocation-ID:
89 to 98
Sponsoring Org:
National Science Foundation
More Like this
  1. 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).
  2. 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.

  3. 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 elongatedmore »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.

    « less
  4. 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.

  5. Abstract

    Clinical and animal studies have reported the influence of sex on the incidence and progression of tendinopathy, which results in disparate structural and biomechanical outcomes. However, there remains a paucity in our understanding of the sex‐specific biological mechanisms underlying effective tendon healing. To overcome this hurdle, our group has investigated the impact of sex on tendon regeneration using the super‐healer Murphy Roths Large (MRL/MpJ) mouse strain. We have previously shown that the scarless healing capacity of MRL/MpJ patellar tendons is associated with sexually dimorphic regulation of gene expression for pathways involved in fibrosis, cell migration, adhesion, and extracellular matrix (ECM) remodeling following an acute mid‐substance injury. Thus, we hypothesized that MRL/MpJ scarless tendon healing is mediated by sex‐specific and temporally distinct orchestration of cell–ECM interactions. Accordingly, the present study comparatively evaluated MRL/MpJ tendon cells on two‐dimensional (2D; glass) and scaffold platforms to examine cell behavior under biochemical and topographical cues associated with tendon homeostasis and healing. Female MRL/MpJ cells showed reduced 2D migration and spreading area accompanied by enhanced mechanosensing, ECM alignment, and fibronectin‐mediated cell proliferation compared to male MRL/MpJ cells. Interestingly, female MRL/MpJ cells cultured on isotropic scaffolds showed diminished cell–ECM organization compared to male MRL/MpJ cells. Lastly,more »MRL/MpJ cells elicited enhanced cytoskeletal elongation and alignment, ECM deposition and organization, and connexin 43‐mediated intercellular communication compared to male B6 cells, regardless of culture condition or sex. These results provide insight into the cellular features conserved within the MRL/MpJ phenotype and potential sex‐specific targets for the development of more equitable therapeutics.

    « less