Tendinopathy and tendon material response to load: What we can learn from small animal studies

Williamson, Patrick M.; Freedman, Benjamin R.; Kwok, Nicholas; Beeram, Indeevar; Pennings, Jan; Johnson, Jeremy; Hamparian, Daron; Cohen, Emily B.; Galloway, Jenna L.; Ramappa, Arun J.; DeAngelis, Joseph P.; Nazarian, Ara

doi:10.1016/j.actbio.2021.07.046

Cited by 17 publications

(13 citation statements)

References 198 publications

(335 reference statements)

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“…The cause of elevated inflammation in repaired tendons may be due to multiple reasons including damage associated with suturing and loading of the tissue interface that may affect both tendon and muscle. 14 The effect of surgical repair on neighboring muscle is often understudied. In this study, we found that surgical repair promoted elevated MMP activity in muscle.…”

Section: Discussionmentioning

confidence: 99%

“…This may limit the effect of physical therapy and exercise on Achilles tendons, which are known to adapt to mechanical loading. 13,14 Additionally, suturing may also stimulate inflammation in tendon similar to dry needling, 15 which may reduce its capacity to heal. Uncovering the biological and structural processes that differ between repaired (surgical repair) and non-repaired (nonsurgical repair) treatments may provide key insights into novel therapeutics to enhance Achilles tendon healing.…”

Section: Differences In Operative and Conservative Management Ofmentioning

confidence: 99%

“…Suturing may result in stress concentrations at the injury site which may contribute to inferior healing. This may limit the effect of physical therapy and exercise on Achilles tendons, which are known to adapt to mechanical loading 13,14 . Additionally, suturing may also stimulate inflammation in tendon similar to dry needling, 15 which may reduce its capacity to heal.…”

Section: Introductionmentioning

confidence: 99%

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Nonsurgical treatment reduces tendon inflammation and elevates tendon markers in early healing

Freedman

Adu-Berchie

Barnum

et al. 2022

Journal Orthopaedic Research

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Operative treatment is assumed to provide superior outcomes to nonoperative (conservative) treatment following Achilles tendon rupture, however, this remains controversial. This study explores the effect of surgical repair on Achilles tendon healing. Rat Achilles tendons (n = 101) were bluntly transected and were randomized into groups receiving repair or non‐repair treatments. By 1 week after injury, repaired tendons had inferior mechanical properties, which continued to 3‐ and 6‐week post‐injury, evidenced by decreased dynamic modulus and failure stress. Transcriptomics analysis revealed >7000 differentially expressed genes between repaired and non‐repaired tendons after 1‐week post‐injury. While repaired tendons showed enriched inflammatory gene signatures, non‐repaired tendons showed increased tenogenic, myogenic, and mechanosensitive gene signatures, with >200‐fold enrichment in Tnmd expression. Analysis of gastrocnemius muscle revealed elevated MMP activity in tendons receiving repair treatment, despite no differences in muscle fiber morphology. Transcriptional regulation analysis highlighted that the highest expressed transcription factors in repaired tendons were associated with inflammation (Nfκb, SpI1, RelA, and Stat1), whereas non‐repaired tendons expressed markers associated with tissue development and mechano‐activation (Smarca1, Bnc2, Znf521, Fbn1, and Gli3). Taken together, these data highlight distinct differences in healing mechanism occurring immediately following injury and provide insights for new therapies to further augment tendons receiving repaired and non‐repaired treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Differences In Operative and Conservative Management Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nonsurgical treatment reduces tendon inflammation and elevates tendon markers in early healing

Freedman

Adu-Berchie

Barnum

et al. 2022

Journal Orthopaedic Research

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“…T he pathogenesis of tendinopathy is multifactorial and complex, and current treatment strategies are associated with variable efficacy and a high rate of recurrent symptoms, possibly owing to the poor regenerative potential of tendon and incomplete characterization of the underlying pathophysiology 1,33 . Our recent studies have revealed the role of mitochondrial dysfunction in the onset and progression of tendinopathy 3,6 .…”

Section: Discussionmentioning

confidence: 99%

SS-31 as a Mitochondrial Protectant in the Treatment of Tendinopathy

Zhang

Bowen

Zhang

et al. 2022

Journal of Bone and Joint Surgery

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Background: Prior studies have demonstrated mitochondrial dysfunction in tendinopathy. The objective of this investigation was to explore the potential of SS-31 (elamipretide), a mitochondrial protectant, to improve mitochondrial function and promote tendon healing in a murine supraspinatus tendinopathy model.Methods: One hundred and twenty-six mice (252 limbs) were divided into 6 groups (42 limbs/group) that received (I) 4 weeks of impingement; (II) 8 weeks of impingement; (III) 8 weeks of impingement including 4 weeks of SS-31 treatment (5 mg/kg/d) starting after 4 weeks of impingement; (IV) 4 weeks of impingement ending with clip removal, followed by harvesting 4 weeks later; and (V) 4 weeks of impingement ending with clip removal, followed by 4 weeks of SS-31 treatment and harvesting; and a control group. Specimens were prepared for biomechanical testing, histological analysis, transmission electron microscopy, measurement of superoxidative dismutase (SOD) activity, and measurement of gene expression.Results: Failure force decreased after impingement, compared with the intact tendon, and the decrease was partially reversed after clip removal, SS-31 treatment, and the 2 treatments combined. A similar pattern was observed for stiffness. Histological analysis demonstrated higher modified Bonar scores in the impingement groups; however, the changes in tendon morphology were partially reversed following all treatments, especially the combined treatment. Decreased mitochondrial number and altered organization and density of cristae were observed in the impingement groups. Mitochondrial structure and number became more normal, with improvement in morphology of the cristae, after clip removal and/or SS-31 treatment. SOD activity decreased after impingement, compared with the control group, then increased significantly again after treatment, especially in the combined treatment group. Mitochondria-related gene expression decreased in the impingement groups and increased again after treatment. Conclusions:The mitochondrial protectant SS-31 improved mitochondrial function, promoting tendon healing, especially when combined with removal of subacromial impingement.Clinical Relevance: Improving mitochondrial function with agents such as SS-31 may represent an effective treatment to promote healing in the setting of supraspinatus tendinopathy.T he term tendinopathy describes a spectrum of pathological processes characterized by abnormalities in tendon structure, composition, and material properties, resulting in pain and reduced function 1 . Recent studies have elucidated risk factors, pathophysiology, and management of tendinopathy; however, treatment failure and unpredictable outcomes remain a challenge 2 . Therefore, further therapeutic strategies for tendinopathy are required.Mitochondria are the powerhouses of cells and play fundamental roles in basic development and repair processes 3,4 . Mitochondrial dysfunction has been found to influence tendon healing following rotator cuff injury 5 . Previous work in our laborat...

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“…Thus, multiscale investigations of tendon damage are critical to understanding how damage propagates spatially and temporally. In vivo animal models of tendon overuse and overload (such as treadmill running, repetitive reaching, climbing, direct tendon loading, and synergist ablation) have been used in such work ( Williamson et al, 2021 ; Bloom et al, 2023 ). Recently developed ex vivo model systems-designed to mimic in vivo tendon biomechanics and load the tendon in isolation-demonstrated that cyclically loading tendons to physiological stresses and strains results in temporal inflammatory as well as matrix degradation responses ( Benage et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Successive tendon injury in an in vivo rat overload model induces early damage and acute healing responses

Chainani,

Buzo Mena,

Yeritsyan

et al. 2024

Front. Bioeng. Biotechnol.

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Introduction: Tendinopathy is a degenerative condition resulting from tendons experiencing abnormal levels of multi-scale damage over time, impairing their ability to repair. However, the damage markers associated with the initiation of tendinopathy are poorly understood, as the disease is largely characterized by end-stage clinical phenotypes. Thus, this study aimed to evaluate the acute tendon responses to successive fatigue bouts of tendon overload using an in vivo passive ankle dorsiflexion system.Methods: Sprague Dawley female rats underwent fatigue overloading to their Achilles tendons for 1, 2, or 3 loading bouts, with two days of rest in between each bout. Mechanical, structural, and biological assays were performed on tendon samples to evaluate the innate acute healing response to overload injuries.Results: Here, we show that fatigue overloading significantly reduces in vivo functional and mechanical properties, with reductions in hysteresis, peak stress, and loading and unloading moduli. Multi-scale structural damage on cellular, fibril, and fiber levels demonstrated accumulated micro-damage that may have induced a reparative response to successive loading bouts. The acute healing response resulted in alterations in matrix turnover and early inflammatory upregulations associated with matrix remodeling and acute responses to injuries.Discussion: This work demonstrates accumulated damage and acute changes to the tendon healing response caused by successive bouts of in vivo fatigue overloads. These results provide the avenue for future investigations of long-term evaluations of tendon overload in the context of tendinopathy.

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Tendinopathy and tendon material response to load: What we can learn from small animal studies

Cited by 17 publications

References 198 publications

Nonsurgical treatment reduces tendon inflammation and elevates tendon markers in early healing

Nonsurgical treatment reduces tendon inflammation and elevates tendon markers in early healing

SS-31 as a Mitochondrial Protectant in the Treatment of Tendinopathy

Successive tendon injury in an in vivo rat overload model induces early damage and acute healing responses

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