Spatiotemporal variations in gene expression, histology and biomechanics in an ovine model of tendinopathy

Abstract

Flexor tendinopathy is a common problem affecting humans and animals. Tendon healing is poorly understood and the outcomes of conservative and surgical management are often suboptimal. While often considered a localized injury, recent evidence indicates that in the short term, tendinopathic changes are distributed widely throughout the tendon, remote from the lesion itself. Whether these changes persist throughout healing is unknown. The aim of this study was to document gene expression, histopathological and biomechanical changes that occur throughout the superficial digital flexor tendon (SDFT) up to 16 weeks post-injury, using an ovine surgical model of tendinopathy. Partial tendon transection was associated with decreased gene expression for aggrecan, decorin, fibromodulin, tissue inhibitors of metalloproteinases (TIMPS 1, 2 and 3), collagen I and collagen II. Gene expression for collagen III, lumican and matrix metalloproteinase 13 (MMP13) increased locally around the lesion site. Expression of collagen III and MMP13 decreased with time, but compared to controls, collagen III, MMP13 and lumican expression remained regionally high throughout the study. An increase in TIMP3 was observed over time. Histologically, operated tendons had higher pathology scores than controls, especially around the injured region. A chondroid phenotype was observed with increased cellular rounding and marked proteoglycan accumulation which only partially improved with time. Biomechanically, partial tendon transection resulted in a localized decrease in elastic modulus (in compression) but only at 8 weeks postoperatively. This study improves our understanding of tendon healing, demonstrating an early ‘peak’ in pathology characterized by altered gene expression and notable histopathological changes. Many of these pathological changes become more localized to the region of injury during healing. Collagen III and MMP13 expression levels remained high close to the lesion throughout the study and may reflect the production of tendon tissue with suboptimal biomechanical properties. Further studies evaluating the long-term response of tendon to injury (6–12 months) are warranted to provide additional information on tendon healing and provide further understanding of the mechanisms underlying the pathology observed in this study.

Changes in Gene Expression Associated with Collagen Regeneration and Remodeling of Extracellular Matrix after Percutaneous Electrolysis on Collagenase-Induced Achilles Tendinopathy in an Experimental Animal Model: A Pilot Study

“…We found an increase in the number of tenocytes, misalignment of collagen fibers, loss of extracellular matrix organization, and increased vascularization in experimentally injured Achilles tendons of rats. The presence of these changes agrees with previous experimental studies in animal models [ 29 , 30 , 31 ].…”

Bimodal Whole-Mount Imaging of Tendon Using Confocal Microscopy and X-ray Micro-Computed Tomography

“…To enhance our methodology, 3D image registration of confocal and μ-CT images could be used for localisation of cellular and structural features of soft tissues such as tendon, whilst also enabling the identification of alterations in tissue sub-structure, such as basement membranes, with ageing and injury models. By combining imaging modalities, our method could visualise and analyse spatiotemporal differences in 3D, and would allow identification of injury-induced changes remote from injury site, especially for large animal tissues [47]. These approaches have already been attempted in renal and cardiac injuries in adult mice, demonstrating that 3D approaches can inform regional differences in tissue repair [48,49].…”

Tendon healing affects the multiscale mechanical, structural and compositional response of tendon to quasi-static tensile loading

“…However, it is well established that tendon's response to loading is inherently nonlinear, and evaluation at additional strains would be necessary to fully describe the multiscale responses. Further, it is likely that the multiscale response evaluated in healing tissues is specific to the injured midsubstance and may vary spatially in the tissue [56]. It is possible that the process of stamping a dog-bone shape in the patellar tendons may alter the material properties of the remaining tendon area, however due to the robust differences observed between groups, this effect is likely very small.…”