Healthy Tendon Research Articles

Involvement of Bacteria in the Pathological Changes Before Achilles Tendon Rupture: A Case Series Investigating 16S rDNA in 20 Consecutive Ruptures.

Background:The source of the pathological changes that occur before an acute Achilles tendon rupture (ATR) is not fully understood. Bacterial DNA has previously been detected in samples from ruptured Achilles tendons, suggesting a pathogenic role of bacteria in ATR.Purpose/Hypothesis:The purpose of this study was to investigate if DNA from bacteria was present in acutely ruptured Achilles tendons. We hypothesized that 20% to 30% of the samples from the rupture site and no samples from healthy tissue would be positive for bacterial DNA.Study Design:Case series; Level of evidence, 4.Methods:This study included 20 consecutive patients scheduled for surgical repair of an acute ATR. Tendon biopsy specimens were taken from the rupture site and from the healthy tendon tissue proximal to the rupture to act as a control. Samples were blinded to the technician and analyzed using polymerase chain reaction targeted to the bacterial 16S rDNA gene and Sanger sequencing to identify the bacterial species present. McNemar test for paired proportions was performed to test for statistically significant differences in the number of samples positive for bacterial DNA between the ruptured and control regions of the Achilles tendon.Results:Of the 20 patients, 1 (5%) had a positive sample with bacterial DNA from the ruptured part of the Achilles tendon. The same patient also had a positive control sample, although with different bacterial DNA. An additional patient had a positive control sample. There was no statistically significant difference in the number of bacterial DNA–positive samples between the ruptured and control regions of the Achilles tendon. The bacteria found (Staphylococcus sp, Micrococcus sp, and Staphylococcus epidermidis) were normal commensal organisms on the human skin.Conclusion:Bacterial DNA was infrequent in tissue from ruptured Achilles tendons and, if identified, likely was a result of contamination. This suggests that bacteria are not involved in the pathological changes occurring before rupture of the Achilles tendon.

Complement factor D as a predictor of Achilles tendon healing and long‐term patient outcomes

Dense connective tissue healing, such as tendon, is protracted leading to highly variable and unsatisfactory patient outcomes. Biomarkers prognostic of long-term clinical outcomes is, however, unknown. The present study was designed to investigate the proteomic profile of healing, identify potential biomarkers, and assess their association with the patient's long-term outcomes after ATR. Quantitative mass spectrometry analysis demonstrated 1423 proteins in healing and contralateral healthy Achilles tendons of 28 ATR patients. Comparing healing at 2weeks and healthy protein profiles, we identified 821 overlapping, 390 upregulated, and 17 downregulated proteins. Upregulated proteins are related mainly to extracellular matrix organization and metabolism, while downregulated pathways were associated with exocytosis in immune modulation and thrombosis formation. Further proteomic profiling in relation to validated patient outcomes revealed the downregulated pro-inflammatory complement factor D (CFD) as the most reliable predictive biomarker of successful tendon healing. Our finding showed a comprehensive proteomic landscape and bioinformatics on human connective tissue, indicating subtype-specific and shared biological processes and proteins in healing and healthy Achilles tendons, as well as in tendons related to good and poor patient outcomes. Inflammatory protein CFD and serpin family B member 1 were finally identified as potential predictive biomarkers of effective healing outcomes when combined the proteomic profiles with a validated clinical database. Following the future elucidation of the mechanisms associated with the identified biomarkers as predictors of good outcomes, our findings could lead to improved prognostic accuracy and development of targeted treatments, thus improving the long-term healing outcomes for all patients.

Metabolic regulation of intrasynovial flexor tendon repair: The effects of dichloroacetate administration on early tendon healing in a canine model.

Enriched in glycolytic enzymes, paucicellular and hypovascular intrasynovial flexor tendons fail to mount an effective healing response after injury and repair. In contrast, well-vascularized extrasynovial flexor tendons possess high levels of oxidative phosphorylation (OXPHOS) enzymes and have a markedly improved healing capacity. This study was designed to compare the metabolic profiles of the two types of tendons and to evaluate the impact of metabolic reprogramming on early intrasynovial tendon healing in a clinically relevant canine model. Results showed that healthy intrasynovial tendons expressed higher levels of PDK1 and GAPDH and lower levels of SCX and IGF1 than did extrasynovial tendons. PDK1 encodes a subtype of pyruvate dehydrogenase kinase (PDK) that inhibits OXPHOS. Consistently, ATP production via glycolysis was favored in intrasynovial tendon cells whereas OXPHOS was the preferred pathway in extrasynovial tendon cells. Inhibition of glycolysis in vitro increased SCX expression in intrasynovial tendon cells. Therefore, dichloroacetate (DCA), a PDK1 inhibitor, was used in vivo to shift intrasynovial tendon ATP production from glycolysis to OXPHOS. Oral DCA administration reduced serum lactate concentration and increased acetyl-CoA content in repaired intrasynovial tendons and led to reduced TLR4 and IL1B and increased IGF1, SCX, and TGFB3 expressions in treated intrasynovial tendons compared to controls. Immunohistochemistry staining with anti-Ki67 and anti-CD31 antibodies revealed marked increases in cellularity and neovascularization in treated intrasynovial tendons. Clinical significance: The findings of this experiment indicate that improved gene expression and histological outcomes can be achieved by regulating glucose metabolism in the early stages following intrasynovial tendon repair.

The acute effects of higher versus lower load duration and intensity on morphological and mechanical properties of the healthy Achilles tendon: a randomized crossover trial.

ABSTRACTThe Achilles tendon (AT) exhibits volume changes related to fluid flow under acute load which may be linked to changes in stiffness. Fluid flow provides a mechanical signal for cellular activity and may be one mechanism that facilitates tendon adaptation. This study aimed to investigate whether isometric intervention involving a high level of load duration and intensity could maximize the immediate reduction in AT volume and stiffness compared with interventions involving a lower level of load duration and intensity. Sixteen healthy participants (12 males, 4 females; age 24.4±9.4 years, body mass 70.9±16.1 kg, height 1.7±0.1 m) performed three isometric interventions of varying levels of load duration (2 s and 8 s) and intensity (35% and 75% maximal voluntary isometric contraction) over a 3 week period. Freehand 3D ultrasound was used to measure free AT volume (at rest) and length (at 35%, 55% and 75% of maximum plantarflexion force) pre- and post-interventions. The slope of the force–elongation curve over these force levels represented individual stiffness (N mm−1). Large reductions in free AT volume and stiffness resulted in response to long-duration high-intensity loading whilst less reduction was produced with a lower load intensity. In contrast, no change in free AT volume and a small increase in AT stiffness occurred with lower load duration. These findings suggest that the applied load on the AT must be heavy and sustained for a long duration to maximize immediate volume reduction, which might be an acute response that enables optimal long-term tendon adaptation via mechanotransduction pathways.

Blood Flow Restriction Resistance Training in Tendon Rehabilitation: A Scoping Review on Intervention Parameters, Physiological Effects, and Outcomes

ObjectiveTo identify current evidence on blood flow restriction training (BFRT) in tendon injuries and healthy tendons, evaluating physiological tendon effects, intervention parameters, and outcomes.MethodsThis scoping review was reported in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR). Databases searched included MEDLINE, CINAHL, AMED, EMBase, SPORTDiscus, Cochrane library (Controlled trials, Systematic reviews), and five trial registries. Two independent reviewers screened studies at title/abstract and full text. Following screening, data was extracted and charted, and presented as figures and tables alongside a narrative synthesis. Any study design conducted on adults, investigating the effects of BFRT on healthy tendons or tendon pathology were included. Data were extracted on physiological tendon effects, intervention parameters and outcomes with BFRT.ResultsThirteen studies were included, three on tendinopathy, two on tendon ruptures, and eight on healthy Achilles, patellar, and supraspinatus tendons. A variety of outcomes were assessed, including pain, function, strength, and tendon morphological and mechanical properties, particularly changes in tendon thickness. BFRT intervention parameters were heterogeneously prescribed.ConclusionDespite a dearth of studies to date on the effects of BFRT on healthy tendons and in tendon pathologies, preliminary evidence for beneficial effects of BFRT on tendons and clinical outcomes is encouraging. As BFRT is a relatively novel method, definitive conclusions, and recommendations on BFRT in tendon rehabilitation cannot be made at present, which should be addressed in future research, due to the potential therapeutic benefits highlighted in this review.

Sonoelastography findings of the patellar tendon in Osgood-Schlatter disease

Objectives: There are ultrasonographic findings defined in Osgood-Schlatter disease. However, sonoelastographic findings of the disease have not been previously defined. The aim of this study was to evaluate the B-mode ultrasonography (US), Color Doppler ultrasonography (CDUS), and sonoelastography (SEL) findings of the patellar tendon in patients with Osgood-Schlatter disease (OSD) and compare it with healthy individuals. Methods: A total of 36 patellar tendons were evaluated in 12 patients with OSD and 10 healthy individuals by US, CDUS, and SEL. Thickness, echogenicity, CDUS, and SEL findings of the distal patellar tendon in each group were evaluated. Results: A total of 22 individuals (19 males, 3 females) and 36 tendons (9 with acute OSD, 7 with chronic OSD and 20 control healthy tendons) were included in this study. The patellar tendons were statistically significantly thicker in OSD patients in comparison with healthy volunteers (5.68±2.32 mm versus 3.42±0.55 mm) (p=0.001). According to the SEL evaluation, all of the patellar tendons in patients with OSD were of type 2 in contrast with all of the patellar tendons in healthy volunteers were of type 1 (p<0.001). Conclusion: Distal patellar tendon in patients with OSD was thicker and softer in comparison with healthy volunteers. The intratendinous and/or peritendinous vascularity on CDUS was increased in patients with acute OSD. We suggest that these findings could be associated with tendon degeneration in OSD patients and can be useful in the evaluation of the disease.

Using the KI-67 proliferation marker to evaluate tendon regeneration in rabbits in an experiment

The goal is to assess the influence of platelet autoplasm on healing damaged tendons in rabbits.Materials and methods. The study on the effect of platelet autoplasma on the regeneration of damaged tendon fabric was carried out on rabbits.In the experiment, rabbits were applied in the field of Achille tendons, since this tendon in animals is injured quite often [1]. Then in the area of ​​damage to the tendon, the experimental group of rabbits was administered tap, while the injured tendons of rabbits of the control group were left without treatment. An intradermal seam was imposed on wounds in the field of leather. A month later, animals of experimental and control groups took samples of tendon fabric in places of damage to immunohistochemical research using the Ki-67 marker, which made it possible to visually demonstrate the action of platelet autoplasm for the regeneration of damaged tendons.Results. The Ki-67 proliferation marker made it possible to clearly reveal the effect of tap on regeneration during damage to the tendon fabric in rabbits. In damaged tendon tissues in rabbits, proliferative processes go more active than in a healthy tendon. Thanks to the studies carried out, it was established that TAP stimulates proliferative processes in tendon tissues. The proliferation index is higher in the tendon tissues of the experimental group of rabbits, which was administered by TAP than in the control group and in a healthy tendon fabric.

Characterization of scar tissue biomechanics during adult murine flexor tendon healing

Tendon injuries are very common and result in significant impairments in mobility and quality of life. During healing, tendons produce a scar at the injury site, characterized by abundant and disorganized extracellular matrix and by permanent deficits in mechanical integrity compared to healthy tendon. Although a significant amount of work has been done to understand the healing process of tendons and to develop potential therapeutics for tendon regeneration, there is still a significant gap in terms of assessing the direct effects of therapeutics on the functional and material quality specifically of the scar tissue, and thus, on the overall tendon healing process. In this study, we focused on characterizing the mechanical properties of only the scar tissue in flexor digitorum longus (FDL) tendons during the proliferative and early remodeling healing phases and comparing these properties with the mechanical properties of the composite healing tissue. Our method was sensitive enough to identify significant differences in structural and material properties between the scar and tendon-scar composite tissues. To account for possible inaccuracies due to the small aspect ratio of scar tissue, we also applied inverse finite element analysis (iFEA) to compute mechanical properties based on simulated tests with accurate specimen geometries and boundary conditions. We found that the scar tissue linear tangent moduli calculated from iFEA were not significantly different from those calculated experimentally at all healing timepoints, validating our experimental findings, and suggesting the assumptions in our experimental calculations were accurate. Taken together, this study first demonstrates that due to the presence of uninjured stubs, testing composite healing tendons without isolating the scar tissue overestimates the material properties of the scar itself. Second, our scar isolation method promises to enable more direct assessment of how different treatment regimens (e.g., cellular ablation, biomechanical and/or biochemical stimuli, tissue engineered scaffolds) affect scar tissue function and material quality in multiple different types of tendons.

Electrospun Scaffold Micro-Architecture Induces an Activated Transcriptional Phenotype within Tendon Fibroblasts.

Biomaterial augmentation of surgically repaired rotator cuff tendon tears aims to improve the high failure rates (∼40%) of traditional repairs. Biomaterials that can alter cellular phenotypes through the provision of microscale topographical cues are now under development. We aimed to systematically evaluate the effect of topographic architecture on the cellular phenotype of fibroblasts from healthy and diseased tendons. Electrospun polydioxanone scaffolds with fiber diameters ranging from 300 to 4000 nm, in either a highly aligned or random configuration, were produced. Healthy tendon fibroblasts cultured for 7 days on scaffolds with highly aligned fibers demonstrated a distinctive elongated morphology, whilst those cultured on randomly configured fibers demonstrated a flattened and spread morphology. The effect of scaffold micro-architecture on the transcriptome of both healthy and diseased tendon fibroblasts was assessed with bulk RNA-seq. Both healthy (n = 3) and diseased tendon cells (n = 3) demonstrated a similar transcriptional response to architectural variants. Gene set enrichment analysis revealed that large diameter (≥2000 nm) aligned scaffolds induced an upregulation of genes involved in cellular replication and a downregulation of genes defining inflammatory responses and cell adhesion. Similarly, PDPN and CD248, markers of inflammatory or “activated” fibroblasts, were downregulated during culture of both healthy and diseased fibroblasts on aligned scaffolds with large (≥2000 nm) fiber diameters. In conclusion scaffold architectures resembling that of disordered type III collagen, typically present during the earlier phases of wound healing, resulted in tendon fibroblast activation. Conversely, scaffolds mimicking aligned diameter collagen I fibrils, present during tissue remodelling, did not activate tendon derived fibroblasts. This has implications for the design of scaffolds used during rotator cuff repair augmentation.

Novel insights into the pathogenesis of tendon injury: mechanotransduction and neuroplasticity.

Novel insights into the pathogenesis of tendon injury: mechanotransduction and neuroplasticity.

Transglutaminase Modification of Tendon Collagen

Category:AnkleIntroduction/Purpose:Achilles tendinopathy is one of the most common overuse conditions encountered in foot and ankle surgery. Various etiological risk factors for this disease have been explored: age, body-mass index, and patient specific biomechanics. However, the pathogenesis remains poorly understood. Healthy tendon is composed primarily of type III and I collagen, which undergo post-translationally modification by lysyl oxidase and transglutaminase (TG) enzymes. The expression and activity in the latter of these two is poorly characterized in Achilles tendon. This study aims to describe the function of a specific transglutaminase, TG2, within solubilized collagen and Achilles tenocyte cultures, and to demonstrate evidence of TG2 activity within pathologic human Achilles tendon tissue.Methods:Acellular Collagen: Type I collagen gels were aliquoted into a silicone well plate. Gels were then seeded with either 2.4 ng of TG2 or a control. Two sets of gels were prepared; one undergoing a 10% stretch at 2Hz for 24 hours and the other a static control. TG2 substrates were labelled, and the relative quantity of higher molecular weight collagens produced by TG2 activity was compared. Tenocytes: Human tenocytes were grown in 3D cultures as well as traditional cultures in a conditioned fibroblast growth media. Proteins expressed by tenocytes in both cultures were extracted and examined for TG modification. Pathologic Tendon: After receiving Institutional Review Board approval, tissue was collected from patients undergoing debridement of Achilles tendinopathy. Collagen was extracted in 0.1M acetic acid and Western blot analysis was used to identify TG2 crosslink epitopes.Results:In each of three experimental paradigms: acellular, cellular, and human tendon extracts, evidence for transglutaminase modification of collagen I was noted. Dynamic conditions increased TG2 modification of collagen in acellular cultures, as evidenced by higher molecular weight collagen forms. Western blot analysis of protein expression demonstrated that tenocytes cultured in 3-D produced higher levels of TG-modified proteins than those in 2-D. Similarly, western blot analysis demonstrated presence of TG2 modification epitopes in the harvested human Achilles tendon tissue. However, the enzyme itself did not appear to be strongly expressed and could not be detected from the samples.Conclusion:Transglutaminase 2 expression by tenocytes in 3D culture and evidence for transglutaminase-dependent modification of collagen I by TG2 under dynamic loading supports a key role for transglutaminase in tendon biology and in repair. Though evidence of TG2 modification was found in diseased human samples, the absence of detectable TG2 expression suggests that it may play a significant role in the healthy physiologic turnover of Achilles tendon collagen.

Ultrasound strain mapping of the mouse Achilles tendon during passive dorsiflexion

Immediately prior to inserting into bone, many healthy tendons experience impingement from nearby bony structures. However, super-physiological levels of impingement are implicated in insertional tendinopathies. Unfortunately, the mechanisms underlying the connection between impingement and tendon pathology remain poorly understood, in part due to the shortage of well-characterized animal models of impingement at clinically relevant sites. As a first step towards developing a model of excessive tendon impingement, the objective of this study was to characterize the mechanical strain environment in the mouse Achilles tendon insertion under passive dorsiflexion and confirm that – like humans – mice experience impingement of the tendon insertion from the calcaneus (heel bone) in dorsiflexed ankle positions. Based on previous work in humans, we hypothesized that during dorsiflexion, the mouse Achilles tendon insertion would experience high levels of transverse compressive strain due to calcaneal impingement. A custom-built loading platform was used to apply passive dorsiflexion, while an ultrasound transducer positioned over the Achilles tendon captured radiofrequency images. A non-rigid image registration algorithm was then used to map the transverse compressive strain based on the acquired ultrasound image sequences. Our results demonstrate that during passive dorsiflexion, transverse compressive strains were produced throughout the Achilles tendon, with significantly larger strain magnitudes at the tendon insertion than at the midsubstance. Furthermore, there was increasing transverse compressive strain observed within the Achilles tendon as a function of increasing dorsiflexion angle. This study enhances our understanding of the unique mechanical loading environment of the Achilles tendon under physiologically relevant conditions.

Mesenchymal Stromal Cells Adapt to Chronic Tendon Disease Environment with an Initial Reduction in Matrix Remodeling

Tendon lesions are common sporting injuries in humans and horses alike. The healing process of acute tendon lesions frequently results in fibrosis and chronic disease. In horses, local mesenchymal stromal cell (MSC) injection is an accepted therapeutic strategy with positive influence on acute lesions. Concerning the use of MSCs in chronic tendon disease, data are scarce but suggest less therapeutic benefit. However, it has been shown that MSCs can have a positive effect on fibrotic tissue. Therefore, we aimed to elucidate the interplay of MSCs and healthy or chronically diseased tendon matrix. Equine MSCs were cultured either as cell aggregates or on scaffolds from healthy or diseased equine tendons. Higher expression of tendon-related matrix genes and tissue inhibitors of metalloproteinases (TIMPs) was found in aggregate cultures. However, the tenogenic transcription factor scleraxis was upregulated on healthy and diseased tendon scaffolds. Matrix metalloproteinase (MMPs) expression and activity were highest in healthy scaffold cultures but showed a strong transient decrease in diseased scaffold cultures. The release of glycosaminoglycan and collagen was also higher in scaffold cultures, even more so in those with tendon disease. This study points to an early suppression of MSC matrix remodeling activity by diseased tendon matrix, while tenogenic differentiation remained unaffected.

Patellar Tendon Structural Adaptations Occur during Pre-Season and First Competitive Cycle in Male Professional Handball Players

Background: While there is evidence that tendon adapts to training load, structural alterations in the patellar tendon in response to training loads are still unclear. The aim of this study is to identify changes in patellar tendon structure throughout pre-season and after finalizing the first competitive cycle. Methods: Nineteen professional handball players participated in the aforesaid cross-sectional study, in which patellar tendon scan and counter movement jump (CMJ) performance were conducted. Measurements were taken on the first and last day of pre-season training, and at the end of the first competitive cycle. Results: The results revealed that variation on the tendon structure occurred, mainly at the end of pre-season training; for injured tendons this occurred at the proximal (Right p = 0.02), distal (Right p = 0.01), and (Left p = 0.02) tendon, while changes in healthy tendons occurred at the mid (Left p = 0.01) and distal tendon (Right p = 0.01). At the end of the first competitive cycle, changes were observed in the distal injured tendon (p = 0.02). Conclusion: Patellar tendon shows greater structural change after completing pre-season training than at the end of the first competitive cycle, from which it may be inferred that gradual loading during pre-season training allows the tendon to adapt and potentially decrease the onset of patellar tendinopathy.

Targeting the CCR6/CCL20 Axis in Entheseal and Cutaneous Inflammation.

To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target. First, we quantified CCL20 levels in peripheral blood and synovial fluid from PsA patients and examined the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an interleukin-23 minicircle DNA (IL-23 MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression as well as the preventive and therapeutic effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1β to assess the production of CCL20 by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated using a Transwell system. We observed an up-regulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsy specimens. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and, accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD. Our study highlights the pathogenic role of the CCR6/CCL20 axis in enthesitis and introduces the prospect of a novel therapeutic approach for treating patients with PsO and PsA.

Gene electrotransfer of FGF2 enhances collagen scaffold biocompatibility

Tendon injuries are a common athletic injury that have been increasing in prevalence. While there are current clinical treatments for tendon injuries, they have relatively long recovery times and often do not restore native function of the tendon. In the current study, gene electrotransfer (GET) parameters for delivery to the skin were optimized with monophasic and biphasic pulses with reporter and effector genes towards optimizing underlying tendon healing. Tissue twitching and damage, as well as gene expression and distribution were evaluated. Bioprinted collagen scaffolds, mimicking healthy tendon structure were then implanted subcutaneously for biocompatibility and angiogenesis analyses when combined with GET to accelerate healing. GET of human fibroblast FGF2 significantly increased angiogenesis and biocompatibility of the bioprinted implants when compared to implant only sites. The combination of bioprinted collagen fibers and angiogenic GET therapy may lead to better graft biocompatibility in tendon repair.

A Tendon-Specific Double Reporter Transgenic Mouse Enables Tracking Cell Lineage and Functions Alteration In Vitro and In Vivo.

We generated and characterized a transgenic mouse line with the tendon-specific expression of a double fluorescent reporter system, which will fulfill an unmet need for animal models to support real-time monitoring cell behaviors during tendon development, growth, and repair in vitro and in vivo. The mScarlet red fluorescent protein is driven by the Scleraxis (Scx) promoter to report the cell lineage alteration. The blue fluorescent protein reporter is expressed under the control of the 3.6kb Collagen Type I Alpha 1 Chain (Col1a1) proximal promoter. In this promoter, the existence of two promoter regions named tendon-specific cis-acting elements (TSE1, TSE2) ensure the specific expression of blue fluorescent protein (BFP) in tendon tissue. Collagen I is a crucial marker for tendon regeneration that is a major component of healthy tendons. Thus, the alteration of function during tendon repair can be estimated by BFP expression. After mechanical stimulation, the expression of mScarlet and BFP increased in adipose-derived mesenchymal stem cells (ADMSCs) from our transgenic mouse line, and there was a rising trend on tendon key markers. These results suggest that our tendon-specific double reporter system is a novel model used to study cell re-differentiation and extracellular matrix alteration in vitro and in vivo.

Victorian Institute of Sport Assessment-Achilles (VISA-A) Questionnaire-Minimal Clinically Important Difference for Active People With Midportion Achilles Tendinopathy: A Prospective Cohort Study.

To determine the minimal clinically important difference (MCID) for the Victorian Institute of Sport Assessment-Achilles (VISA-A) score in patients with midportion Achilles tendinopathy (AT). Prospective cohort study. We included physically active patients with midportion AT who received exercises and an injection. We measured the VISA-A score (ranging from 0 to 100 points, where 100 points represents a healthy tendon) at baseline and at 12 weeks and 24 weeks after treatment, and the 7-point Global Assessment Scale (ranging from "worse than ever" to "completely recovered") at 12 weeks and 24 weeks after treatment. We dichotomized the Global Assessment Scale to not improved ("worse than ever" to "unchanged") or improved ("moderately improved" to "completely recovered"). The area under the curve and the Youden's index value closest to 1 were determined for both MCIDs (12 and 24 weeks), with corresponding sensitivity and specificity. Sixty-four patients were included, and 61 patients (95%) completed the 24-week follow-up. The MCID was 14 points (95% confidence interval [CI]: 3, 19) over a 12-week period, corresponding to 57% sensitivity and 88% specificity. The MCID was 7 points (95% CI: -10, 28) over a 24-week period, with 85% sensitivity and 62% specificity. A change in VISA-A score of at least 14 points after 12 weeks or at least 7 points after 24 weeks of exercise therapy and an injection reflects a meaningful change for physically active patients with midportion AT. J Orthop Sports Phys Ther 2021;51(10):510-516. doi:10.2519/jospt.2021.10040.

Tendon blood flow, angiogenesis, and tendinopathy pathogenesis

Physical exercise results in a duration and intensity-dependent vascular response in healthy human tendon. In overused (tendinopathy) and damaged tendon, angiogenic pathways are activated and neovascularization is observed. Whereas no direct relationship exists between the amount of neovessels and degree of tendinopathy symptoms, almost all tendinopathic patients have elevated neovascularization and tendon blood flow, as assessed by Doppler ultrasound methodology. The enhanced flow in tendinopathy can be successfully abolished by heavy resistance training. Already in the early time-phase of tendinopathy (<3 months), neovascularization in the tendon exists but the causal sequence of vascular, metabolic, nociceptive, and matrix tissue changes in tendon pathology is not fully understood. Nevertheless, existing evidences point at neovascularization being an important component of pathogenesis and may occur already before the development of clinical symptoms in tendinopathy.

CD146 Delineates an Interfascicular Cell Sub-Population in Tendon That Is Recruited during Injury through Its Ligand Laminin-α4

The interfascicular matrix (IFM) binds tendon fascicles and contains a population of morphologically distinct cells. However, the role of IFM-localised cell populations in tendon repair remains to be determined. The basement membrane protein laminin-α4 also localises to the IFM. Laminin-α4 is a ligand for several cell surface receptors, including CD146, a marker of pericyte and progenitor cells. We used a needle injury model in the rat Achilles tendon to test the hypothesis that the IFM is a niche for CD146+ cells that are mobilised in response to tendon damage. We also aimed to establish how expression patterns of circulating non-coding RNAs alter with tendon injury and identify potential RNA-based markers of tendon disease. The results demonstrate the formation of a focal lesion at the injury site, which increased in size and cellularity for up to 21 days post injury. In healthy tendon, CD146+ cells localised to the IFM, compared with injury, where CD146+ cells migrated towards the lesion at days 4 and 7, and populated the lesion 21 days post injury. This was accompanied by increased laminin-α4, suggesting that laminin-α4 facilitates CD146+ cell recruitment at injury sites. We also identified a panel of circulating microRNAs that are dysregulated with tendon injury. We propose that the IFM cell niche mediates the intrinsic response to injury, whereby an injury stimulus induces CD146+ cell migration. Further work is required to fully characterise CD146+ subpopulations within the IFM and establish their precise roles during tendon healing.